Prednisone 10 MG Oral Tablet 48 Count Pack

Generic Name: PREDNISONE
Brand Name: Prednisone
  • Substance Name(s):
  • PREDNISONE

WARNINGS

General Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS: Allergic Reactions ).

Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during and after the stressful situation.

Cardio-Renal Average and large doses of hydrocortisone or cortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium.

These effects are less likely to occur with the synthetic derivatives except when used in large doses.

Dietary salt restriction and potassium supplementation may be necessary.

All corticosteroids increase calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Endocrine Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment.

Adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage.

This type of relative insufficiency may persist for up to 12 months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.

If the patient is receiving steroids already, dosage may have to be increased.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients.

Changes in thyroid status of the patient may necessitate adjustment in dosage.

Infection General Patients who are on corticosteroids are more susceptible to infections than are healthy individuals.

There may be decreased resistance and inability to localize infection when corticosteroids are used.

Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents that affect cellular immunity, humoral immunity, or neutrophil function.

1 These infections may be mild, but may be severe and at times fatal.

With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

2 Corticosteroids may also mask some signs of current infection.

Fungal Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control life-threatening drug reactions.

There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS: Drug Interactions: Amphotericin B Injection and Potassium-Depleting Agents ).

Special Pathogens Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma .

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation.

In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

Tuberculosis The use of prednisone in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur.

During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Vaccination Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

Killed or inactivated vaccines may be administered.

However, the response to such vaccines may be diminished and cannot be predicted.

Indicated immunization procedures may be undertaken in patients receiving nonimmunosuppressive doses of corticosteroids as replacement therapy (e.g., for Addison’s disease).

Viral Infections Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids.

In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.

(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi or viruses.

The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

Corticosteroids should not be used in active ocular herpes simplex because of possible corneal perforation.

DRUG INTERACTIONS

Drug Interactions Amphotericin B Injection and Potassium-Depleting Agents When corticosteroids are administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics ), patients should be observed closely for development of hypokalemia.

In addition, there have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Antibiotics Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see PRECAUTIONS: Drug Interactions: Hepatic Enzyme Inducers, Inhibitors and Substrates ).

Anticholinesterases Concomitant use of anticholinesterase agents (e.g., neostigmine, pyridostigmine ) and corticosteroids may produce severe weakness in patients with myasthenia gravis.

If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

If concomitant therapy must occur, it should take place under close supervision and the need for respiratory support should be anticipated.

Anticoagulants, Oral Co-administration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports.

Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Antidiabetics Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Antitubercular drugs Serum concentrations of isoniazid may be decreased.

Bupropion Since systemic steroids, as well as bupropion, can lower the seizure threshold, concurrent administration should be undertaken only with extreme caution; low initial dosing and small gradual increases should be employed.

Cholestyramine Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently.

Convulsions have been reported with this concurrent use.

Digitalis Glycosides Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens, Including Oral Contraceptives Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Fluoroquinolones Post-marketing surveillance reports indicate that the risk of tendon rupture may be increased in patients receiving concomitant fluoroquinolones (e.g., ciprofloxacin, levofloxacin ) and corticosteroids, especially in the elderly.

Tendon rupture can occur during or after treatment with quinolones.

Hepatic Enzyme Inducers, Inhibitors and Substrates Drugs which induce cytochrome P450 3A4 (CYP 3A4) enzyme activity (e.g., barbiturates, phenytoin, carbamazepine, rifampin ) may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Drugs which inhibit CYP 3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, macrolide antibiotics such as erythromycin ) have the potential to result in increased plasma concentrations of corticosteroids.

Glucocorticoids are moderate inducers of CYP 3A4.

Co-administration with other drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin ) may increase their clearance, resulting in decreased plasma concentration.

Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.

In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal.

Nonsteroidal Anti-Inflammatory Agents (NSAIDS) Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents ) and corticosteroids increases the risk of gastrointestinal side effects.

Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

The clearance of salicylates may be increased with concurrent use of corticosteroids; this could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn.

Phenytoin In post-marketing experience, there have been reports of both increases and decreases in phenytoin levels with dexamethasone co-administration, leading to alterations in seizure control.

Phenytoin has been demonstrated to increase the hepatic metabolism of corticosteroids, resulting in a decreased therapeutic effect of the corticosteroid.

Quetiapine Increased doses of quetiapine may be required to maintain control of symptoms of schizophrenia in patients receiving a glucocorticoid, a hepatic enzyme inducer.

Skin Tests Corticosteroids may suppress reactions to skin tests.

Thalidomide Co-administration with thalidomide should be employed cautiously, as toxic epidermal necrolysis has been reported with concomitant use.

Vaccines Patients on corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response.

Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines.

Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS: Infection: Vaccination ).

DESCRIPTION

PredniSONE Tablets contain prednisone which is a glucocorticoid.

Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract.

Prednisone is a white to practically white, odorless, crystalline powder.

It is very slightly soluble in water; slightly soluble in alcohol, chloroform, dioxane, and methanol.

The chemical name for prednisone is pregna-1,4-diene-3,11,20-trione monohydrate,17,21-dihydroxy-.

The structural formula is represented below: PredniSONE Tablets are available in 5 strengths: 1 mg, 2.5 mg, 5 mg, 10 mg and 20 mg.

This is an image of the formula for PredniSONE.

Inactive ingredients: 1 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 2.5 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 5 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 10 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 20 mg — FD&C Yellow #6 Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate.

HOW SUPPLIED

PredniSONE Tablets are available in the following strengths and package sizes: 1 mg (white, round, flat-faced, beveled edge, scored, debossed “5084” on one side and debossed “V” on the reverse side) Bottles of 100 NDC 0603-5335-21 Bottles of 1000 NDC 0603-5335-32 2.5 mg (white, round, flat-faced, beveled edge, scored, debossed “5085” on one side and debossed “V” on the reverse side) Bottles of 100 NDC 0603-5336-21 5 mg (white, round, scored, debossed “5094” on one side and debossed “V” on the reverse side) Bottles of 100 NDC 0603-5337-21 Bottles of 1000 NDC 0603-5337-32 Unit-of-Use (21 Tablets) NDC 0603-5337-15 Unit-of-Use (48 Tablets) NDC 0603-5337-31 10 mg (white, round, scored, debossed “5093” on one side and debossed “V” on the reverse side) Bottles of 100 NDC 0603-5338-21 Bottles of 500 NDC 0603-5338-28 Bottles of 1000 NDC 0603-5338-32 Unit-of-Use (21 Tablets) NDC 0603-5338-15 Unit-of-Use (48 Tablets) NDC 0603-5338-31 20 mg (peach, round, scored, debossed “5092” on one side and debossed “V” on the reverse side) Bottles of 100 NDC 0603-5339-21 Bottles of 500 NDC 0603-5339-28 Bottles of 1000 NDC 0603-5339-32 Dispense in a tight, light-resistant container as defined in the USP.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

GERIATRIC USE

Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In particular, the increased risk of diabetes mellitus, fluid retention and hypertension in elderly patients treated with corticosteroids should be considered.

INDICATIONS AND USAGE

PredniSONE Tablets are indicated in the following conditions: Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance) Congenital adrenal hyperplasia Nonsuppurative thyroiditis Hypercalcemia associated with cancer Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Ankylosing spondylitis Acute and subacute bursitis Acute nonspecific tenosynovitis Acute gouty arthritis Post-traumatic osteoarthritis Synovitis of osteoarthritis Epicondylitis Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis Dermatologic Diseases Pemphigus Bullous dermatitis herpetiformis Severe erythema multiforme (Stevens-Johnson syndrome) Exfoliative dermatitis Mycosis fungoides Severe psoriasis Severe seborrheic dermatitis Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: Seasonal or perennial allergic rhinitis Bronchial asthma Contact dermatitis Atopic dermatitis Serum sickness Drug hypersensitivity reactions Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: Allergic corneal marginal ulcers Herpes zoster ophthalmicus Anterior segment inflammation Diffuse posterior uveitis and choroiditis Sympathetic ophthalmia Allergic conjunctivitis Keratitis Chorioretinitis Optic neuritis Iritis and iridocyclitis Respiratory Diseases Symptomatic sarcoidosis Loeffler’s syndrome not manageable by other means Berylliosis Aspiration pneumonitis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Hematologic Disorders Idiopathic thrombocytopenic purpura in adults Secondary thrombocytopenia in adults Acquired (autoimmune) hemolytic anemia Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood Edematous States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis Regional enteritis Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy Trichinosis with neurologic or myocardial involvement

PEDIATRIC USE

Pediatric Use The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations.

Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (patients >2 years of age), and aggressive lymphomas and leukemias (patients >1 month of age).

Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS ).

Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis.

Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity.

This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels).

Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function.

The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives.

In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category C Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose.

Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring.

There are no adequate and well-controlled studies in pregnant women.

Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

NUSRING MOTHERS

Nursing Mothers Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

INFORMATION FOR PATIENTS

Information for Patients Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision.

As prolonged use may cause adrenal insufficiency and make patients dependent on corticosteroids, they should advise any medical attendants that they are taking corticosteroids and they should seek medical advice at once should they develop an acute illness including fever or other signs of infection.

Following prolonged therapy, withdrawal of corticosteroids may result in symptoms of the corticosteroid withdrawal syndrome including, myalgia, arthralgia, and malaise.

Persons who are on corticosteroids should be warned to avoid exposure to chickenpox or measles.

Patients should also be advised that if they are exposed, medical advice should be sought without delay.

INACTIVE INGREDIENTS

Inactive ingredients: 1 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 2.5 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 5 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 10 mg — colloidal silicon dioxide, lactose monohydrate, magnesium stearate, pregelatinized starch, sodium starch glycolate; 20 mg — FD&C Yellow #6 Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate.

DOSAGE AND ADMINISTRATION

Gastric irritation may be reduced if taken before, during, or immediately after meals or with food or milk.

The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight.

Exogenous corticosteroids suppress adrenocorticoid activity the least when given at the time of maximal activity (am) for single dose administration.

Therefore, it is recommended that prednisone be administered in the morning prior to 9 am and when large doses are given, administration of antacids between meals to help prevent peptic ulcers.

Multiple dose therapy should be evenly distributed in evenly spaced intervals throughout the day.

Dietary salt restriction may be advisable in patients.

Do not stop taking this medicine without first talking to your doctor.

Avoid abrupt withdraw of therapy.

The initial dosage of PredniSONE Tablets may vary from 5 mg to 60 mg per day, depending on the specific disease entity being treated.

In situations of less severity lower doses will generally suffice, while in selected patients higher initial doses may be required.

The initial dosage should be maintained or adjusted until a satisfactory response is noted.

If after a reasonable period of time there is a lack of satisfactory clinical response, PredniSONE should be discontinued and the patient transferred to other appropriate therapy.

IT SHOULD BE EMPHASIZED THAT DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE UNDER TREATMENT AND THE RESPONSE OF THE PATIENT.

After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small increments at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached.

It should be kept in mind that constant monitoring is needed in regard to drug dosage.

Included in the situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment; in this latter situation, it may be necessary to increase the dosage of PredniSONE for a period of time consistent with the patient’s condition.

If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

Multiple Sclerosis In the treatment of acute exacerbations of multiple sclerosis daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective.

(Dosage range is the same for prednisone and prednisolone.) Alternate Day Therapy Alternate day therapy is a corticosteroid dosing regimen in which twice the usual daily dose of corticoid is administered every other morning.

The purpose of this mode of therapy is to provide the patient requiring long-term pharmacologic dose treatment with the beneficial effects of corticoids while minimizing certain undesirable effects, including pituitary-adrenal suppression, the Cushingoid state, corticoid withdrawal symptoms, and growth suppression in children.

The rationale for this treatment schedule is based on two major premises: (a) the anti-inflammatory or therapeutic effect of corticoids persists longer than their physical presence and metabolic effects and (b) administration of the corticosteroid every other morning allows for re-establishment of more nearly normal hypothalamic-pituitary-adrenal (HPA) activity on the off-steroid day.

A brief review of the HPA physiology may be helpful in understanding this rationale.

Acting primarily through the hypothalamus a fall in free cortisol stimulates the pituitary gland to produce increasing amounts of corticotropin (ACTH) while a rise in free cortisol inhibits ACTH secretion.

Normally the HPA system is characterized by diurnal (circadian) rhythm.

Serum levels of ACTH rise from a low point about 10 pm to a peak level about 6 am.

Increasing levels of ACTH stimulate adrenocortical activity resulting in a rise in plasma cortisol with maximal levels occurring between 2 am and 8 am.

This rise in cortisol dampens ACTH production and in turn adrenocortical activity.

There is a gradual fall in plasma corticoids during the day with lowest levels occurring about midnight.

The diurnal rhythm of the HPA axis is lost in Cushing’s disease, a syndrome of adrenocortical hyperfunction characterized by obesity with centripetal fat distribution, thinning of the skin with easy bruisability, muscle wasting with weakness, hypertension, latent diabetes, osteoporosis, electrolyte imbalance, etc.

The same clinical findings of hyperadrenocorticism may be noted during long-term pharmacologic dose corticoid therapy administered in conventional daily divided doses.

It would appear, then, that a disturbance in the diurnal cycle with maintenance of elevated corticoid values during the night may play a significant role in the development of undesirable corticoid effects.

Escape from these constantly elevated plasma levels for even short periods of time may be instrumental in protecting against undesirable pharmacologic effects.

During conventional pharmacologic dose corticosteroid therapy, ACTH production is inhibited with subsequent suppression of cortisol production by the adrenal cortex.

Recovery time for normal HPA activity is variable depending upon the dose and duration of treatment.

During this time the patient is vulnerable to any stressful situation.

Although it has been shown that there is considerably less adrenal suppression following a single morning dose of prednisolone (10 mg) as opposed to a quarter of that dose administered every 6 hours, there is evidence that some suppressive effect on adrenal activity may be carried over into the following day when pharmacologic doses are used.

Further, it has been shown that a single dose of certain corticosteroids will produce adrenocortical suppression for two or more days.

Other corticoids, including methylprednisolone, hydrocortisone, prednisone, and prednisolone, are considered to be short acting (producing adrenocortical suppression for 1¼ to 1½ days following a single dose) and thus are recommended for alternate day therapy.

The following should be kept in mind when considering alternate day therapy: Basic principles and indications for corticosteroid therapy should apply.

The benefits of alternate day therapy should not encourage the indiscriminate use of steroids.

Alternate day therapy is a therapeutic technique primarily designed for patients in whom long-term pharmacologic corticoid therapy is anticipated.

In less severe disease processes in which corticoid therapy is indicated, it may be possible to initiate treatment with alternate day therapy.

More severe disease states usually will require daily divided high dose therapy for initial control of the disease process.

The initial suppressive dose level should be continued until satisfactory clinical response is obtained, usually four to ten days in the case of many allergic and collagen diseases.

It is important to keep the period of initial suppressive dose as brief as possible particularly when subsequent use of alternate day therapy is intended.

Once control has been established, two courses are available: (a) change to alternate day therapy and then gradually reduce the amount of corticoid given every other day or (b) following control of the disease process reduce the daily dose of corticoid to the lowest effective level as rapidly as possible and then change over to an alternate day schedule.

Theoretically, course (a) may be preferable.

Because of the advantages of alternate day therapy, it may be desirable to try patients on this form of therapy who have been on daily corticoids for long periods of time (e.g., patients with rheumatoid arthritis).

Since these patients may already have a suppressed HPA axis, establishing them on alternate day therapy may be difficult and not always successful.

However, it is recommended that regular attempts be made to change them over.

It may be helpful to triple or even quadruple the daily maintenance dose and administer this every other day rather than just doubling the daily dose if difficulty is encountered.

Once the patient is again controlled, an attempt should be made to reduce this dose to a minimum.

As indicated above, certain corticosteroids, because of their prolonged suppressive effect on adrenal activity, are not recommended for alternate day therapy (e.g., dexamethasone and betamethasone).

The maximal activity of the adrenal cortex is between 2 am and 8 am, and it is minimal between 4 pm and midnight.

Exogenous corticosteroids suppress adrenocortical activity the least, when given at the time of maximal activity (am).

In using alternate day therapy it is important, as in all therapeutic situations to individualize and tailor the therapy to each patient.

Complete control of symptoms will not be possible in all patients.

An explanation of the benefits of alternate day therapy will help the patient to understand and tolerate the possible flare-up in symptoms which may occur in the latter part of the off-steroid day.

Other symptomatic therapy may be added or increased at this time if needed.

In the event of an acute flare-up of the disease process, it may be necessary to return to a full suppressive daily divided corticoid dose for control.

Once control is again established alternate day therapy may be re-instituted.

Although many of the undesirable features of corticosteroid therapy can be minimized by alternate day therapy, as in any therapeutic situation, the physician must carefully weigh the benefit-risk ratio for each patient in whom corticoid therapy is being considered.

Generic Name: MIDAZOLAM HYDROCHLORIDE
Brand Name: Midazolam Hydrochloride
  • Substance Name(s):
  • MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these infants accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

DRUG INTERACTIONS

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

chemical-structure-1.jpg chemical-structure-2.jpg midazolam-chart.jpg

HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Infants born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ) .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

Nursing Mothers Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

2.

Inform your physician if you are pregnant or are planning to become pregnant.

3.

Inform your physician if you are nursing.

4.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

5.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

6.

For pediatric patients, particular care should be taken to assure safe ambulation.

7.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

2.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

3.

Turn the entire unit (bottle and oral dispenser) upside down.

4.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

5.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

6.

The tip of the dispenser may be covered with a tip cap, until time of use.

7.

Close bottle with cap after each use.

8.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

2.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

plunger.jpg image-1.jpg image-2.jpg image-3.jpg

WARNINGS

Hepatic Effects SPORANOX ® has been associated with rare cases of serious hepatotoxicity, including liver failure and death.

Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment.

If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Continued SPORANOX ® use or reinstitution of treatment with SPORANOX ® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.

(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS .) Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX ® and/or other CYP3A4 inhibitors.

Concomitant administration of these drugs with SPORANOX ® is contraindicated.

(See BOXED WARNING , CONTRAINDICATIONS , and PRECAUTIONS: Drug Interactions .) Cardiac Disease SPORANOX ® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

SPORANOX ® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX ® therapy.

These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders.

Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment.

If signs or symptoms of CHF appear during administration of SPORANOX ® Capsules, discontinue administration.

Itraconazole has been shown to have a negative inotropic effect.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented.

In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

SPORANOX ® has been associated with reports of congestive heart failure.

In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

In addition, itraconazole can inhibit the metabolism of calcium channel blockers.

Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of SPORANOX ® and felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , PRECAUTIONS: Drug Interactions , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Interaction potential SPORANOX ® has a potential for clinically important drug interactions.

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.

Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability SPORANOX ® (itraconazole) Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given.

In addition, the topical effects of mucosal exposure may be different between the two formulations.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

DRUG INTERACTIONS

Drug Interactions Effect of SPORANOX ® on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.

Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP).

Consequently, SPORANOX ® has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs.

Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes , respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism).

Reduced concentrations of concomitant drugs may reduce their efficacy.

Table 1 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 1 Drug Interactions with SPORANOX ® that Affect Concomitant Drug Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with SPORANOX ® that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant Drug Alpha Blockers Alfuzosin Silodosin Tamsulosin Not recommended during and 2 weeks after SPORANOX ® treatment.

Analgesics Methadone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fentanyl Not recommended during and 2 weeks after SPORANOX ® treatment.

Alfentanil Buprenorphine (IV and sublingual) Oxycodone Based on clinical drug interaction information with itraconazole.

Sufentanil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Digoxin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antibacterials Bedaquiline Based on 400 mg Bedaquiline once daily for 2 weeks.

Concomitant SPORANOX ® not recommended for more than 2 weeks at any time during bedaquiline treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Clarithromycin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

See also Table 2 .

Trimetrexate Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticoagulants and Antiplatelets Ticagrelor Contraindicated during and 2 weeks after SPORANOX ® treatment.

Apixaban Rivaroxaban Vorapaxar Not recommended during and 2 weeks after SPORANOX ® treatment.

Cilostazol Dabigatran Warfarin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticonvulsants Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Antidiabetic Drugs Repaglinide Saxagliptin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antihelminthics, Antifungals and Antiprotozoals Isavuconazonium Contraindicated during and 2 weeks after SPORANOX ® treatment.

Praziquantel Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Artemether-lumefantrine Quinine Monitor for adverse reactions.

Antimigraine Drugs Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after SPORANOX ® treatment.

Eletriptan Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary Antineoplastics Irinotecan Contraindicated during and 2 weeks after SPORANOX ® treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Not recommended during and 2 weeks after SPORANOX ® treatment.

Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For idelalisib, see also Table 2 .

Antipsychotics, Anxiolytics and Hypnotics Alprazolam Aripiprazole Buspirone Diazepam Haloperidol Midazolam (IV) Quetiapine Ramelteon Risperidone Suvorexant Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Zopiclone Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lurasidone Midazolam (oral) Pimozide Triazolam Contraindicated during and 2 weeks after SPORANOX ® treatment.

Antivirals Simeprevir Not recommended during and 2 weeks after SPORANOX ® treatment.

Daclatasvir Indinavir Maraviroc Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For indinavir, see also Table 2 .

Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted) Monitor for adverse reactions.

See also Table 2 .

Tenofovir disoproxil fumarate Monitor for adverse reactions.

Beta Blockers Nadolol Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Calcium Channel Blockers Felodipine Nisoldipine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Diltiazem Other dihydropyridines Verapamil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For diltiazem, see also Table 2 .

Cardiovascular Drugs, Miscellaneous Ivabradine Ranolazine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension) Not recommended during and 2 weeks after SPORANOX ® treatment.

For sildenafil and tadalafil, see also Urologic Drugs below.

Bosentan Guanfacine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Contraceptives Dienogest Ulipristal Monitor for adverse reactions.

Diuretics Eplerenone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Cisapride Naloxegol Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aprepitant Loperamide Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Netupitant Monitor for adverse reactions.

Immunosuppressants Everolimus Sirolimus Temsirolimus (IV) Not recommended during and 2 weeks after SPORANOX ® treatment.

Budesonide (inhalation) Budesonide (non-inhalation) Ciclesonide (inhalation) Cyclosporine (IV) Cyclosporine (non-IV) Dexamethasone Fluticasone (inhalation) Fluticasone (nasal) Methylprednisolone Tacrolimus (IV) Tacrolimus (oral) Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lipid-Lowering Drugs Lomitapide Lovastatin Simvastatin Contraindicated during and 2 weeks after SPORANOX ® treatment.

Atorvastatin Monitor for drug adverse reactions.

Concomitant drug dose reduction may be necessary .

Respiratory Drugs Salmeterol Not recommended during and 2 weeks after SPORANOX ® treatment.

SSRIs, Tricyclics and Related Antidepressants Venlafaxine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Urologic Drugs Avanafil Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fesoterodine Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Solifenacin Patients with severe renal or moderate to severe hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Darifenacin Vardenafil Not recommended during and 2 weeks after SPORANOX ® treatment.

Dutasteride Oxybutynin Sildenafil (for erectile dysfunction) Tadalafil (for erectile dysfunction and benign prostatic hyperplasia) Tolterodine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For sildenafil and tadalafil, see also Cardiovascular Drugs above.

Miscellaneous Drugs and Other Substances Colchicine Patients with renal or hepatic impairment: Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Not recommended during and 2 weeks after SPORANOX ® treatment.

Eliglustat CYP2D6 EMs EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs , or CYP2D6 PMs : Contraindicated during and 2 weeks after SPORANOX ® treatment.

CYP2D6 EMs not taking a strong or moderate CYP2D6 inhibitor : Monitor for adverse reactions.

Eliglustat dose reduction may be necessary.

Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Vasopressin Receptor Antagonists Conivaptan Tolvaptan Not recommended during and 2 weeks after SPORANOX ® treatment.

Drug Interactions with SPORANOX ® that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug Antineoplastics Regorafenib Not recommended during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Saccharomyces boulardii Not recommended during and 2 weeks after SPORANOX ® treatment.

Nonsteroidal Anti-Inflammatory Drugs Meloxicam Concomitant drug dose increase may be necessary.

Effect of Other Drugs on SPORANOX ® Itraconazole is mainly metabolized through CYP3A4.

Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole.

Some concomitant drugs have the potential to interact with SPORANOX ® resulting in either increased or sometimes decreased concentrations of SPORANOX ® .

Increased concentrations may increase the risk of adverse reactions associated with SPORANOX ® .

Decreased concentrations may reduce SPORANOX ® efficacy.

Table 2 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 2.

Drug Interactions with Other Drugs that Affect SPORANOX ® Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with Other Drugs that Increase SPORANOX ® Concentrations and May Increase Risk of Adverse Reactions Associated with SPORANOX ® Antibacterials Ciprofloxacin Based on clinical drug interaction information with itraconazole.

Erythromycin Clarithromycin Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

Antineoplastics Idelalisib Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavir Ritonavir Saquinavir Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

For, cobicistat, elvitegravir, indinavir, ritonavir, and saquinavir, see also Table 1 .

Calcium Channel Blockers Diltiazem Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Drug Interactions with Other Drugs that Decrease SPORANOX ® Concentrations and May Reduce Efficacy of SPORANOX ® Antibacterials Isoniazid Rifampicin Not recommended 2 weeks before and during SPORANOX ® treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Anticonvulsants Phenobarbital Phenytoin Not recommended 2 weeks before and during SPORANOX ® treatment.

Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Antivirals Efavirenz Nevirapine Not recommended 2 weeks before and during SPORANOX ® treatment.

Gastrointestinal Drugs Drugs that reduce gastric acidity e.g.

acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 – receptor antagonists and proton pump inhibitors.

Use with caution.

Administer acid neutralizing medicines at least 2 hours before or 2 hours after the intake of SPORANOX ® capsules Miscellaneous Drugs and Other Substances Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Pediatric Population Interaction studies have only been performed in adults.

OVERDOSAGE

Itraconazole is not removed by dialysis.

In the event of accidental overdosage, supportive measures should be employed.

Contact a certified poison control center for the most up to date information on the management of SPORANOX ® Capsules overdosage (1-800-222-1222 or www.poison.org).

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole.

(See ADVERSE REACTIONS .)

DESCRIPTION

SPORANOX ® is the brand name for itraconazole, an azole antifungal agent.

Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers.

It may be represented by the following structural formula and nomenclature: (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 R *,4 S *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one mixture with (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 S *,4 R *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one or (±)-1-[( RS )- sec -butyl]-4-[ p -[4-[ p -[[(2 R ,4 S )-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one Itraconazole has a molecular formula of C 35 H 38 Cl 2 N 8 O 4 and a molecular weight of 705.64.

It is a white to slightly yellowish powder.

It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane.

It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

SPORANOX ® Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of sucrose, maize starch, and purified water).

Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No.

1, FD&C Blue No.

2, D&C Red No.

22 and D&C Red No.

28.

Chemical Structure

CLINICAL STUDIES

Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

HOW SUPPLIED

Product: 63629-1647

GERIATRIC USE

Geriatric Use Clinical studies of SPORANOX ® Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

It is advised to use SPORANOX ® Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks.

In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole.

Several of these reports included concurrent administration of quinidine which is contraindicated (See BOXED WARNING: Drug Interactions , CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions ).

MECHANISM OF ACTION

Mechanism of Action In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

SPORANOX ® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.

SPORANOX ® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

PEDIATRIC USE

Pediatric Use The efficacy and safety of SPORANOX ® have not been established in pediatric patients.

The long-term effects of itraconazole on bone growth in children are unknown.

In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5 times the MRHD).

The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.

At a dosage level of 80 mg/kg/day (10 times the MRHD) over 1 year or 160 mg/kg/day (20 times the MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

PREGNANCY

Pregnancy Teratogenic effects Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (5–20 times the MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10 times the MRHD).

Itraconazole has been shown to cross the placenta in a rat model.

In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

There are no studies in pregnant women.

SPORANOX ® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

SPORANOX ® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

SPORANOX ® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses.

Effective contraception should be continued throughout SPORANOX ® therapy and for 2 months following the end of treatment.

During post-marketing experience, cases of congenital abnormalities have been reported.

(See ADVERSE REACTIONS: Post-marketing Experience .)

NUSRING MOTHERS

Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX ® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant.

The U.S.

Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF .

If signs or symptoms of congestive heart failure occur during administration of SPORANOX ® Capsules, discontinue administration.

When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen.

(See CONTRAINDICATIONS , WARNINGS , PRECAUTIONS.

Drug Interactions , ADVERSE REACTIONS: Post-marketing Experience , and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions Coadministration of the following drugs are contraindicated with SPORANOX ® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor.

In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.

See PRECAUTIONS: Drug Interactions Section for specific examples.

Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs.

For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes , a potentially fatal arrhythmia.

See CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug Interactions Section for specific examples.

INFORMATION FOR PATIENTS

Information for Patients The topical effects of mucosal exposure may be different between the SPORANOX ® Capsules and Oral Solution.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

SPORANOX ® Capsules should not be used interchangeably with SPORANOX ® Oral Solution.

Instruct patients to take SPORANOX ® Capsules with a full meal.

SPORANOX ® Capsules must be swallowed whole.

Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX ® administration, they should discontinue SPORANOX ® and contact their healthcare provider immediately.

Instruct patients to stop SPORANOX ® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop.

Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.

Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.

Instruct patients that hearing loss can occur with the use of itraconazole.

The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.

Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole.

Advise patients that if they experience these events, they should not drive or use machines.

DOSAGE AND ADMINISTRATION

SPORANOX ® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption.

SPORANOX ® (itraconazole) Capsules must be swallowed whole.

SPORANOX ® Capsules is a different preparation than SPORANOX ® Oral Solution and should not be used interchangeably.

Treatment of Blastomycosis and Histoplasmosis The recommended dose is 200 mg once daily (2 capsules).

If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily.

Doses above 200 mg/day should be given in two divided doses.

Treatment of Aspergillosis A daily dose of 200 to 400 mg is recommended.

Treatment in Life-Threatening Situations In life-threatening situations, a loading dose should be used.

Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment.

Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided.

An inadequate period of treatment may lead to recurrence of active infection.

SPORANOX ® Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Treatment of Onychomycosis Toenails with or without fingernail involvement The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.

Treatment of Onychomycosis Fingernails only The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d.

(400 mg/day) for 1 week.

The pulses are separated by a 3-week period without SPORANOX ® .

Use in Patients with Renal Impairment Limited data are available on the use of oral itraconazole in patients with renal impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS .) Use in Patients with Hepatic Impairment Limited data are available on the use of oral itraconazole in patients with hepatic impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations , WARNINGS , and PRECAUTIONS .)

Generic Name: MIDAZOLAM HYDROCHLORIDE
Brand Name: Midazolam Hydrochloride
  • Substance Name(s):
  • MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these infants accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

DRUG INTERACTIONS

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

chemical-structure-1.jpg chemical-structure-2.jpg midazolam-chart.jpg

HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Infants born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ) .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

Nursing Mothers Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

2.

Inform your physician if you are pregnant or are planning to become pregnant.

3.

Inform your physician if you are nursing.

4.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

5.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

6.

For pediatric patients, particular care should be taken to assure safe ambulation.

7.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

2.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

3.

Turn the entire unit (bottle and oral dispenser) upside down.

4.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

5.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

6.

The tip of the dispenser may be covered with a tip cap, until time of use.

7.

Close bottle with cap after each use.

8.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

2.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

plunger.jpg image-1.jpg image-2.jpg image-3.jpg

WARNINGS

Hepatic Effects SPORANOX ® has been associated with rare cases of serious hepatotoxicity, including liver failure and death.

Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment.

If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Continued SPORANOX ® use or reinstitution of treatment with SPORANOX ® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.

(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS .) Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX ® and/or other CYP3A4 inhibitors.

Concomitant administration of these drugs with SPORANOX ® is contraindicated.

(See BOXED WARNING , CONTRAINDICATIONS , and PRECAUTIONS: Drug Interactions .) Cardiac Disease SPORANOX ® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

SPORANOX ® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX ® therapy.

These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders.

Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment.

If signs or symptoms of CHF appear during administration of SPORANOX ® Capsules, discontinue administration.

Itraconazole has been shown to have a negative inotropic effect.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented.

In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

SPORANOX ® has been associated with reports of congestive heart failure.

In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

In addition, itraconazole can inhibit the metabolism of calcium channel blockers.

Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of SPORANOX ® and felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , PRECAUTIONS: Drug Interactions , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Interaction potential SPORANOX ® has a potential for clinically important drug interactions.

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.

Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability SPORANOX ® (itraconazole) Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given.

In addition, the topical effects of mucosal exposure may be different between the two formulations.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

DRUG INTERACTIONS

Drug Interactions Effect of SPORANOX ® on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.

Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP).

Consequently, SPORANOX ® has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs.

Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes , respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism).

Reduced concentrations of concomitant drugs may reduce their efficacy.

Table 1 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 1 Drug Interactions with SPORANOX ® that Affect Concomitant Drug Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with SPORANOX ® that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant Drug Alpha Blockers Alfuzosin Silodosin Tamsulosin Not recommended during and 2 weeks after SPORANOX ® treatment.

Analgesics Methadone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fentanyl Not recommended during and 2 weeks after SPORANOX ® treatment.

Alfentanil Buprenorphine (IV and sublingual) Oxycodone Based on clinical drug interaction information with itraconazole.

Sufentanil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Digoxin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antibacterials Bedaquiline Based on 400 mg Bedaquiline once daily for 2 weeks.

Concomitant SPORANOX ® not recommended for more than 2 weeks at any time during bedaquiline treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Clarithromycin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

See also Table 2 .

Trimetrexate Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticoagulants and Antiplatelets Ticagrelor Contraindicated during and 2 weeks after SPORANOX ® treatment.

Apixaban Rivaroxaban Vorapaxar Not recommended during and 2 weeks after SPORANOX ® treatment.

Cilostazol Dabigatran Warfarin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticonvulsants Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Antidiabetic Drugs Repaglinide Saxagliptin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antihelminthics, Antifungals and Antiprotozoals Isavuconazonium Contraindicated during and 2 weeks after SPORANOX ® treatment.

Praziquantel Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Artemether-lumefantrine Quinine Monitor for adverse reactions.

Antimigraine Drugs Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after SPORANOX ® treatment.

Eletriptan Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary Antineoplastics Irinotecan Contraindicated during and 2 weeks after SPORANOX ® treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Not recommended during and 2 weeks after SPORANOX ® treatment.

Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For idelalisib, see also Table 2 .

Antipsychotics, Anxiolytics and Hypnotics Alprazolam Aripiprazole Buspirone Diazepam Haloperidol Midazolam (IV) Quetiapine Ramelteon Risperidone Suvorexant Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Zopiclone Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lurasidone Midazolam (oral) Pimozide Triazolam Contraindicated during and 2 weeks after SPORANOX ® treatment.

Antivirals Simeprevir Not recommended during and 2 weeks after SPORANOX ® treatment.

Daclatasvir Indinavir Maraviroc Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For indinavir, see also Table 2 .

Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted) Monitor for adverse reactions.

See also Table 2 .

Tenofovir disoproxil fumarate Monitor for adverse reactions.

Beta Blockers Nadolol Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Calcium Channel Blockers Felodipine Nisoldipine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Diltiazem Other dihydropyridines Verapamil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For diltiazem, see also Table 2 .

Cardiovascular Drugs, Miscellaneous Ivabradine Ranolazine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension) Not recommended during and 2 weeks after SPORANOX ® treatment.

For sildenafil and tadalafil, see also Urologic Drugs below.

Bosentan Guanfacine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Contraceptives Dienogest Ulipristal Monitor for adverse reactions.

Diuretics Eplerenone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Cisapride Naloxegol Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aprepitant Loperamide Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Netupitant Monitor for adverse reactions.

Immunosuppressants Everolimus Sirolimus Temsirolimus (IV) Not recommended during and 2 weeks after SPORANOX ® treatment.

Budesonide (inhalation) Budesonide (non-inhalation) Ciclesonide (inhalation) Cyclosporine (IV) Cyclosporine (non-IV) Dexamethasone Fluticasone (inhalation) Fluticasone (nasal) Methylprednisolone Tacrolimus (IV) Tacrolimus (oral) Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lipid-Lowering Drugs Lomitapide Lovastatin Simvastatin Contraindicated during and 2 weeks after SPORANOX ® treatment.

Atorvastatin Monitor for drug adverse reactions.

Concomitant drug dose reduction may be necessary .

Respiratory Drugs Salmeterol Not recommended during and 2 weeks after SPORANOX ® treatment.

SSRIs, Tricyclics and Related Antidepressants Venlafaxine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Urologic Drugs Avanafil Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fesoterodine Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Solifenacin Patients with severe renal or moderate to severe hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Darifenacin Vardenafil Not recommended during and 2 weeks after SPORANOX ® treatment.

Dutasteride Oxybutynin Sildenafil (for erectile dysfunction) Tadalafil (for erectile dysfunction and benign prostatic hyperplasia) Tolterodine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For sildenafil and tadalafil, see also Cardiovascular Drugs above.

Miscellaneous Drugs and Other Substances Colchicine Patients with renal or hepatic impairment: Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Not recommended during and 2 weeks after SPORANOX ® treatment.

Eliglustat CYP2D6 EMs EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs , or CYP2D6 PMs : Contraindicated during and 2 weeks after SPORANOX ® treatment.

CYP2D6 EMs not taking a strong or moderate CYP2D6 inhibitor : Monitor for adverse reactions.

Eliglustat dose reduction may be necessary.

Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Vasopressin Receptor Antagonists Conivaptan Tolvaptan Not recommended during and 2 weeks after SPORANOX ® treatment.

Drug Interactions with SPORANOX ® that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug Antineoplastics Regorafenib Not recommended during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Saccharomyces boulardii Not recommended during and 2 weeks after SPORANOX ® treatment.

Nonsteroidal Anti-Inflammatory Drugs Meloxicam Concomitant drug dose increase may be necessary.

Effect of Other Drugs on SPORANOX ® Itraconazole is mainly metabolized through CYP3A4.

Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole.

Some concomitant drugs have the potential to interact with SPORANOX ® resulting in either increased or sometimes decreased concentrations of SPORANOX ® .

Increased concentrations may increase the risk of adverse reactions associated with SPORANOX ® .

Decreased concentrations may reduce SPORANOX ® efficacy.

Table 2 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 2.

Drug Interactions with Other Drugs that Affect SPORANOX ® Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with Other Drugs that Increase SPORANOX ® Concentrations and May Increase Risk of Adverse Reactions Associated with SPORANOX ® Antibacterials Ciprofloxacin Based on clinical drug interaction information with itraconazole.

Erythromycin Clarithromycin Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

Antineoplastics Idelalisib Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavir Ritonavir Saquinavir Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

For, cobicistat, elvitegravir, indinavir, ritonavir, and saquinavir, see also Table 1 .

Calcium Channel Blockers Diltiazem Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Drug Interactions with Other Drugs that Decrease SPORANOX ® Concentrations and May Reduce Efficacy of SPORANOX ® Antibacterials Isoniazid Rifampicin Not recommended 2 weeks before and during SPORANOX ® treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Anticonvulsants Phenobarbital Phenytoin Not recommended 2 weeks before and during SPORANOX ® treatment.

Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Antivirals Efavirenz Nevirapine Not recommended 2 weeks before and during SPORANOX ® treatment.

Gastrointestinal Drugs Drugs that reduce gastric acidity e.g.

acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 – receptor antagonists and proton pump inhibitors.

Use with caution.

Administer acid neutralizing medicines at least 2 hours before or 2 hours after the intake of SPORANOX ® capsules Miscellaneous Drugs and Other Substances Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Pediatric Population Interaction studies have only been performed in adults.

OVERDOSAGE

Itraconazole is not removed by dialysis.

In the event of accidental overdosage, supportive measures should be employed.

Contact a certified poison control center for the most up to date information on the management of SPORANOX ® Capsules overdosage (1-800-222-1222 or www.poison.org).

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole.

(See ADVERSE REACTIONS .)

DESCRIPTION

SPORANOX ® is the brand name for itraconazole, an azole antifungal agent.

Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers.

It may be represented by the following structural formula and nomenclature: (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 R *,4 S *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one mixture with (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 S *,4 R *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one or (±)-1-[( RS )- sec -butyl]-4-[ p -[4-[ p -[[(2 R ,4 S )-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one Itraconazole has a molecular formula of C 35 H 38 Cl 2 N 8 O 4 and a molecular weight of 705.64.

It is a white to slightly yellowish powder.

It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane.

It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

SPORANOX ® Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of sucrose, maize starch, and purified water).

Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No.

1, FD&C Blue No.

2, D&C Red No.

22 and D&C Red No.

28.

Chemical Structure

CLINICAL STUDIES

Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

HOW SUPPLIED

Product: 63629-1647

GERIATRIC USE

Geriatric Use Clinical studies of SPORANOX ® Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

It is advised to use SPORANOX ® Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks.

In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole.

Several of these reports included concurrent administration of quinidine which is contraindicated (See BOXED WARNING: Drug Interactions , CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions ).

MECHANISM OF ACTION

Mechanism of Action In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

SPORANOX ® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.

SPORANOX ® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

PEDIATRIC USE

Pediatric Use The efficacy and safety of SPORANOX ® have not been established in pediatric patients.

The long-term effects of itraconazole on bone growth in children are unknown.

In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5 times the MRHD).

The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.

At a dosage level of 80 mg/kg/day (10 times the MRHD) over 1 year or 160 mg/kg/day (20 times the MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

PREGNANCY

Pregnancy Teratogenic effects Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (5–20 times the MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10 times the MRHD).

Itraconazole has been shown to cross the placenta in a rat model.

In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

There are no studies in pregnant women.

SPORANOX ® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

SPORANOX ® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

SPORANOX ® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses.

Effective contraception should be continued throughout SPORANOX ® therapy and for 2 months following the end of treatment.

During post-marketing experience, cases of congenital abnormalities have been reported.

(See ADVERSE REACTIONS: Post-marketing Experience .)

NUSRING MOTHERS

Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX ® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant.

The U.S.

Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF .

If signs or symptoms of congestive heart failure occur during administration of SPORANOX ® Capsules, discontinue administration.

When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen.

(See CONTRAINDICATIONS , WARNINGS , PRECAUTIONS.

Drug Interactions , ADVERSE REACTIONS: Post-marketing Experience , and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions Coadministration of the following drugs are contraindicated with SPORANOX ® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor.

In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.

See PRECAUTIONS: Drug Interactions Section for specific examples.

Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs.

For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes , a potentially fatal arrhythmia.

See CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug Interactions Section for specific examples.

INFORMATION FOR PATIENTS

Information for Patients The topical effects of mucosal exposure may be different between the SPORANOX ® Capsules and Oral Solution.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

SPORANOX ® Capsules should not be used interchangeably with SPORANOX ® Oral Solution.

Instruct patients to take SPORANOX ® Capsules with a full meal.

SPORANOX ® Capsules must be swallowed whole.

Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX ® administration, they should discontinue SPORANOX ® and contact their healthcare provider immediately.

Instruct patients to stop SPORANOX ® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop.

Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.

Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.

Instruct patients that hearing loss can occur with the use of itraconazole.

The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.

Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole.

Advise patients that if they experience these events, they should not drive or use machines.

DOSAGE AND ADMINISTRATION

SPORANOX ® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption.

SPORANOX ® (itraconazole) Capsules must be swallowed whole.

SPORANOX ® Capsules is a different preparation than SPORANOX ® Oral Solution and should not be used interchangeably.

Treatment of Blastomycosis and Histoplasmosis The recommended dose is 200 mg once daily (2 capsules).

If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily.

Doses above 200 mg/day should be given in two divided doses.

Treatment of Aspergillosis A daily dose of 200 to 400 mg is recommended.

Treatment in Life-Threatening Situations In life-threatening situations, a loading dose should be used.

Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment.

Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided.

An inadequate period of treatment may lead to recurrence of active infection.

SPORANOX ® Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Treatment of Onychomycosis Toenails with or without fingernail involvement The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.

Treatment of Onychomycosis Fingernails only The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d.

(400 mg/day) for 1 week.

The pulses are separated by a 3-week period without SPORANOX ® .

Use in Patients with Renal Impairment Limited data are available on the use of oral itraconazole in patients with renal impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS .) Use in Patients with Hepatic Impairment Limited data are available on the use of oral itraconazole in patients with hepatic impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations , WARNINGS , and PRECAUTIONS .)

Generic Name: MIDAZOLAM HYDROCHLORIDE
Brand Name: Midazolam Hydrochloride
  • Substance Name(s):
  • MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these infants accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

DRUG INTERACTIONS

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

chemical-structure-1.jpg chemical-structure-2.jpg midazolam-chart.jpg

HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Infants born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ) .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

Nursing Mothers Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

2.

Inform your physician if you are pregnant or are planning to become pregnant.

3.

Inform your physician if you are nursing.

4.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

5.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

6.

For pediatric patients, particular care should be taken to assure safe ambulation.

7.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

2.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

3.

Turn the entire unit (bottle and oral dispenser) upside down.

4.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

5.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

6.

The tip of the dispenser may be covered with a tip cap, until time of use.

7.

Close bottle with cap after each use.

8.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

2.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

plunger.jpg image-1.jpg image-2.jpg image-3.jpg

WARNINGS

Hepatic Effects SPORANOX ® has been associated with rare cases of serious hepatotoxicity, including liver failure and death.

Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment.

If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Continued SPORANOX ® use or reinstitution of treatment with SPORANOX ® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.

(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS .) Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX ® and/or other CYP3A4 inhibitors.

Concomitant administration of these drugs with SPORANOX ® is contraindicated.

(See BOXED WARNING , CONTRAINDICATIONS , and PRECAUTIONS: Drug Interactions .) Cardiac Disease SPORANOX ® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

SPORANOX ® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX ® therapy.

These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders.

Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment.

If signs or symptoms of CHF appear during administration of SPORANOX ® Capsules, discontinue administration.

Itraconazole has been shown to have a negative inotropic effect.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented.

In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

SPORANOX ® has been associated with reports of congestive heart failure.

In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

In addition, itraconazole can inhibit the metabolism of calcium channel blockers.

Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of SPORANOX ® and felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , PRECAUTIONS: Drug Interactions , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Interaction potential SPORANOX ® has a potential for clinically important drug interactions.

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.

Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability SPORANOX ® (itraconazole) Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given.

In addition, the topical effects of mucosal exposure may be different between the two formulations.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

DRUG INTERACTIONS

Drug Interactions Effect of SPORANOX ® on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.

Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP).

Consequently, SPORANOX ® has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs.

Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes , respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism).

Reduced concentrations of concomitant drugs may reduce their efficacy.

Table 1 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 1 Drug Interactions with SPORANOX ® that Affect Concomitant Drug Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with SPORANOX ® that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant Drug Alpha Blockers Alfuzosin Silodosin Tamsulosin Not recommended during and 2 weeks after SPORANOX ® treatment.

Analgesics Methadone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fentanyl Not recommended during and 2 weeks after SPORANOX ® treatment.

Alfentanil Buprenorphine (IV and sublingual) Oxycodone Based on clinical drug interaction information with itraconazole.

Sufentanil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Digoxin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antibacterials Bedaquiline Based on 400 mg Bedaquiline once daily for 2 weeks.

Concomitant SPORANOX ® not recommended for more than 2 weeks at any time during bedaquiline treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Clarithromycin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

See also Table 2 .

Trimetrexate Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticoagulants and Antiplatelets Ticagrelor Contraindicated during and 2 weeks after SPORANOX ® treatment.

Apixaban Rivaroxaban Vorapaxar Not recommended during and 2 weeks after SPORANOX ® treatment.

Cilostazol Dabigatran Warfarin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticonvulsants Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Antidiabetic Drugs Repaglinide Saxagliptin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antihelminthics, Antifungals and Antiprotozoals Isavuconazonium Contraindicated during and 2 weeks after SPORANOX ® treatment.

Praziquantel Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Artemether-lumefantrine Quinine Monitor for adverse reactions.

Antimigraine Drugs Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after SPORANOX ® treatment.

Eletriptan Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary Antineoplastics Irinotecan Contraindicated during and 2 weeks after SPORANOX ® treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Not recommended during and 2 weeks after SPORANOX ® treatment.

Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For idelalisib, see also Table 2 .

Antipsychotics, Anxiolytics and Hypnotics Alprazolam Aripiprazole Buspirone Diazepam Haloperidol Midazolam (IV) Quetiapine Ramelteon Risperidone Suvorexant Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Zopiclone Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lurasidone Midazolam (oral) Pimozide Triazolam Contraindicated during and 2 weeks after SPORANOX ® treatment.

Antivirals Simeprevir Not recommended during and 2 weeks after SPORANOX ® treatment.

Daclatasvir Indinavir Maraviroc Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For indinavir, see also Table 2 .

Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted) Monitor for adverse reactions.

See also Table 2 .

Tenofovir disoproxil fumarate Monitor for adverse reactions.

Beta Blockers Nadolol Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Calcium Channel Blockers Felodipine Nisoldipine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Diltiazem Other dihydropyridines Verapamil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For diltiazem, see also Table 2 .

Cardiovascular Drugs, Miscellaneous Ivabradine Ranolazine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension) Not recommended during and 2 weeks after SPORANOX ® treatment.

For sildenafil and tadalafil, see also Urologic Drugs below.

Bosentan Guanfacine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Contraceptives Dienogest Ulipristal Monitor for adverse reactions.

Diuretics Eplerenone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Cisapride Naloxegol Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aprepitant Loperamide Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Netupitant Monitor for adverse reactions.

Immunosuppressants Everolimus Sirolimus Temsirolimus (IV) Not recommended during and 2 weeks after SPORANOX ® treatment.

Budesonide (inhalation) Budesonide (non-inhalation) Ciclesonide (inhalation) Cyclosporine (IV) Cyclosporine (non-IV) Dexamethasone Fluticasone (inhalation) Fluticasone (nasal) Methylprednisolone Tacrolimus (IV) Tacrolimus (oral) Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lipid-Lowering Drugs Lomitapide Lovastatin Simvastatin Contraindicated during and 2 weeks after SPORANOX ® treatment.

Atorvastatin Monitor for drug adverse reactions.

Concomitant drug dose reduction may be necessary .

Respiratory Drugs Salmeterol Not recommended during and 2 weeks after SPORANOX ® treatment.

SSRIs, Tricyclics and Related Antidepressants Venlafaxine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Urologic Drugs Avanafil Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fesoterodine Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Solifenacin Patients with severe renal or moderate to severe hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Darifenacin Vardenafil Not recommended during and 2 weeks after SPORANOX ® treatment.

Dutasteride Oxybutynin Sildenafil (for erectile dysfunction) Tadalafil (for erectile dysfunction and benign prostatic hyperplasia) Tolterodine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For sildenafil and tadalafil, see also Cardiovascular Drugs above.

Miscellaneous Drugs and Other Substances Colchicine Patients with renal or hepatic impairment: Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Not recommended during and 2 weeks after SPORANOX ® treatment.

Eliglustat CYP2D6 EMs EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs , or CYP2D6 PMs : Contraindicated during and 2 weeks after SPORANOX ® treatment.

CYP2D6 EMs not taking a strong or moderate CYP2D6 inhibitor : Monitor for adverse reactions.

Eliglustat dose reduction may be necessary.

Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Vasopressin Receptor Antagonists Conivaptan Tolvaptan Not recommended during and 2 weeks after SPORANOX ® treatment.

Drug Interactions with SPORANOX ® that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug Antineoplastics Regorafenib Not recommended during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Saccharomyces boulardii Not recommended during and 2 weeks after SPORANOX ® treatment.

Nonsteroidal Anti-Inflammatory Drugs Meloxicam Concomitant drug dose increase may be necessary.

Effect of Other Drugs on SPORANOX ® Itraconazole is mainly metabolized through CYP3A4.

Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole.

Some concomitant drugs have the potential to interact with SPORANOX ® resulting in either increased or sometimes decreased concentrations of SPORANOX ® .

Increased concentrations may increase the risk of adverse reactions associated with SPORANOX ® .

Decreased concentrations may reduce SPORANOX ® efficacy.

Table 2 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 2.

Drug Interactions with Other Drugs that Affect SPORANOX ® Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with Other Drugs that Increase SPORANOX ® Concentrations and May Increase Risk of Adverse Reactions Associated with SPORANOX ® Antibacterials Ciprofloxacin Based on clinical drug interaction information with itraconazole.

Erythromycin Clarithromycin Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

Antineoplastics Idelalisib Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavir Ritonavir Saquinavir Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

For, cobicistat, elvitegravir, indinavir, ritonavir, and saquinavir, see also Table 1 .

Calcium Channel Blockers Diltiazem Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Drug Interactions with Other Drugs that Decrease SPORANOX ® Concentrations and May Reduce Efficacy of SPORANOX ® Antibacterials Isoniazid Rifampicin Not recommended 2 weeks before and during SPORANOX ® treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Anticonvulsants Phenobarbital Phenytoin Not recommended 2 weeks before and during SPORANOX ® treatment.

Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Antivirals Efavirenz Nevirapine Not recommended 2 weeks before and during SPORANOX ® treatment.

Gastrointestinal Drugs Drugs that reduce gastric acidity e.g.

acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 – receptor antagonists and proton pump inhibitors.

Use with caution.

Administer acid neutralizing medicines at least 2 hours before or 2 hours after the intake of SPORANOX ® capsules Miscellaneous Drugs and Other Substances Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Pediatric Population Interaction studies have only been performed in adults.

OVERDOSAGE

Itraconazole is not removed by dialysis.

In the event of accidental overdosage, supportive measures should be employed.

Contact a certified poison control center for the most up to date information on the management of SPORANOX ® Capsules overdosage (1-800-222-1222 or www.poison.org).

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole.

(See ADVERSE REACTIONS .)

DESCRIPTION

SPORANOX ® is the brand name for itraconazole, an azole antifungal agent.

Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers.

It may be represented by the following structural formula and nomenclature: (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 R *,4 S *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one mixture with (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 S *,4 R *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one or (±)-1-[( RS )- sec -butyl]-4-[ p -[4-[ p -[[(2 R ,4 S )-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one Itraconazole has a molecular formula of C 35 H 38 Cl 2 N 8 O 4 and a molecular weight of 705.64.

It is a white to slightly yellowish powder.

It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane.

It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

SPORANOX ® Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of sucrose, maize starch, and purified water).

Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No.

1, FD&C Blue No.

2, D&C Red No.

22 and D&C Red No.

28.

Chemical Structure

CLINICAL STUDIES

Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

HOW SUPPLIED

Product: 63629-1647

GERIATRIC USE

Geriatric Use Clinical studies of SPORANOX ® Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

It is advised to use SPORANOX ® Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks.

In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole.

Several of these reports included concurrent administration of quinidine which is contraindicated (See BOXED WARNING: Drug Interactions , CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions ).

MECHANISM OF ACTION

Mechanism of Action In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

SPORANOX ® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.

SPORANOX ® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

PEDIATRIC USE

Pediatric Use The efficacy and safety of SPORANOX ® have not been established in pediatric patients.

The long-term effects of itraconazole on bone growth in children are unknown.

In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5 times the MRHD).

The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.

At a dosage level of 80 mg/kg/day (10 times the MRHD) over 1 year or 160 mg/kg/day (20 times the MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

PREGNANCY

Pregnancy Teratogenic effects Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (5–20 times the MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10 times the MRHD).

Itraconazole has been shown to cross the placenta in a rat model.

In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

There are no studies in pregnant women.

SPORANOX ® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

SPORANOX ® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

SPORANOX ® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses.

Effective contraception should be continued throughout SPORANOX ® therapy and for 2 months following the end of treatment.

During post-marketing experience, cases of congenital abnormalities have been reported.

(See ADVERSE REACTIONS: Post-marketing Experience .)

NUSRING MOTHERS

Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX ® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant.

The U.S.

Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF .

If signs or symptoms of congestive heart failure occur during administration of SPORANOX ® Capsules, discontinue administration.

When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen.

(See CONTRAINDICATIONS , WARNINGS , PRECAUTIONS.

Drug Interactions , ADVERSE REACTIONS: Post-marketing Experience , and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions Coadministration of the following drugs are contraindicated with SPORANOX ® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor.

In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.

See PRECAUTIONS: Drug Interactions Section for specific examples.

Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs.

For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes , a potentially fatal arrhythmia.

See CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug Interactions Section for specific examples.

INFORMATION FOR PATIENTS

Information for Patients The topical effects of mucosal exposure may be different between the SPORANOX ® Capsules and Oral Solution.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

SPORANOX ® Capsules should not be used interchangeably with SPORANOX ® Oral Solution.

Instruct patients to take SPORANOX ® Capsules with a full meal.

SPORANOX ® Capsules must be swallowed whole.

Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX ® administration, they should discontinue SPORANOX ® and contact their healthcare provider immediately.

Instruct patients to stop SPORANOX ® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop.

Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.

Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.

Instruct patients that hearing loss can occur with the use of itraconazole.

The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.

Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole.

Advise patients that if they experience these events, they should not drive or use machines.

DOSAGE AND ADMINISTRATION

SPORANOX ® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption.

SPORANOX ® (itraconazole) Capsules must be swallowed whole.

SPORANOX ® Capsules is a different preparation than SPORANOX ® Oral Solution and should not be used interchangeably.

Treatment of Blastomycosis and Histoplasmosis The recommended dose is 200 mg once daily (2 capsules).

If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily.

Doses above 200 mg/day should be given in two divided doses.

Treatment of Aspergillosis A daily dose of 200 to 400 mg is recommended.

Treatment in Life-Threatening Situations In life-threatening situations, a loading dose should be used.

Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment.

Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided.

An inadequate period of treatment may lead to recurrence of active infection.

SPORANOX ® Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Treatment of Onychomycosis Toenails with or without fingernail involvement The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.

Treatment of Onychomycosis Fingernails only The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d.

(400 mg/day) for 1 week.

The pulses are separated by a 3-week period without SPORANOX ® .

Use in Patients with Renal Impairment Limited data are available on the use of oral itraconazole in patients with renal impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS .) Use in Patients with Hepatic Impairment Limited data are available on the use of oral itraconazole in patients with hepatic impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations , WARNINGS , and PRECAUTIONS .)

Generic Name: MIDAZOLAM HYDROCHLORIDE
Brand Name: Midazolam Hydrochloride
  • Substance Name(s):
  • MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these infants accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

DRUG INTERACTIONS

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

chemical-structure-1.jpg chemical-structure-2.jpg midazolam-chart.jpg

HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Infants born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ) .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

Nursing Mothers Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

2.

Inform your physician if you are pregnant or are planning to become pregnant.

3.

Inform your physician if you are nursing.

4.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

5.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

6.

For pediatric patients, particular care should be taken to assure safe ambulation.

7.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

2.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

3.

Turn the entire unit (bottle and oral dispenser) upside down.

4.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

5.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

6.

The tip of the dispenser may be covered with a tip cap, until time of use.

7.

Close bottle with cap after each use.

8.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

2.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

plunger.jpg image-1.jpg image-2.jpg image-3.jpg

WARNINGS

Hepatic Effects SPORANOX ® has been associated with rare cases of serious hepatotoxicity, including liver failure and death.

Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment.

If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Continued SPORANOX ® use or reinstitution of treatment with SPORANOX ® is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.

(See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS .) Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX ® and/or other CYP3A4 inhibitors.

Concomitant administration of these drugs with SPORANOX ® is contraindicated.

(See BOXED WARNING , CONTRAINDICATIONS , and PRECAUTIONS: Drug Interactions .) Cardiac Disease SPORANOX ® Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

SPORANOX ® Capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of SPORANOX ® therapy.

These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders.

Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment.

If signs or symptoms of CHF appear during administration of SPORANOX ® Capsules, discontinue administration.

Itraconazole has been shown to have a negative inotropic effect.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented.

In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

SPORANOX ® has been associated with reports of congestive heart failure.

In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

In addition, itraconazole can inhibit the metabolism of calcium channel blockers.

Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of SPORANOX ® and felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , PRECAUTIONS: Drug Interactions , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Interaction potential SPORANOX ® has a potential for clinically important drug interactions.

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.

Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability SPORANOX ® (itraconazole) Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given.

In addition, the topical effects of mucosal exposure may be different between the two formulations.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

DRUG INTERACTIONS

Drug Interactions Effect of SPORANOX ® on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors.

Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP).

Consequently, SPORANOX ® has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs.

Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes , respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism).

Reduced concentrations of concomitant drugs may reduce their efficacy.

Table 1 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 1 Drug Interactions with SPORANOX ® that Affect Concomitant Drug Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with SPORANOX ® that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant Drug Alpha Blockers Alfuzosin Silodosin Tamsulosin Not recommended during and 2 weeks after SPORANOX ® treatment.

Analgesics Methadone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fentanyl Not recommended during and 2 weeks after SPORANOX ® treatment.

Alfentanil Buprenorphine (IV and sublingual) Oxycodone Based on clinical drug interaction information with itraconazole.

Sufentanil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Digoxin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antibacterials Bedaquiline Based on 400 mg Bedaquiline once daily for 2 weeks.

Concomitant SPORANOX ® not recommended for more than 2 weeks at any time during bedaquiline treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Clarithromycin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

See also Table 2 .

Trimetrexate Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticoagulants and Antiplatelets Ticagrelor Contraindicated during and 2 weeks after SPORANOX ® treatment.

Apixaban Rivaroxaban Vorapaxar Not recommended during and 2 weeks after SPORANOX ® treatment.

Cilostazol Dabigatran Warfarin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Anticonvulsants Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 2 .

Antidiabetic Drugs Repaglinide Saxagliptin Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Antihelminthics, Antifungals and Antiprotozoals Isavuconazonium Contraindicated during and 2 weeks after SPORANOX ® treatment.

Praziquantel Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Artemether-lumefantrine Quinine Monitor for adverse reactions.

Antimigraine Drugs Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after SPORANOX ® treatment.

Eletriptan Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary Antineoplastics Irinotecan Contraindicated during and 2 weeks after SPORANOX ® treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Not recommended during and 2 weeks after SPORANOX ® treatment.

Bortezomib Brentuximab-vedotin Busulfan Erlotinib Gefitinib Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Vandetanib Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For idelalisib, see also Table 2 .

Antipsychotics, Anxiolytics and Hypnotics Alprazolam Aripiprazole Buspirone Diazepam Haloperidol Midazolam (IV) Quetiapine Ramelteon Risperidone Suvorexant Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Zopiclone Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lurasidone Midazolam (oral) Pimozide Triazolam Contraindicated during and 2 weeks after SPORANOX ® treatment.

Antivirals Simeprevir Not recommended during and 2 weeks after SPORANOX ® treatment.

Daclatasvir Indinavir Maraviroc Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For indinavir, see also Table 2 .

Cobicistat Elvitegravir (ritonavir-boosted) Ritonavir Saquinavir (unboosted) Monitor for adverse reactions.

See also Table 2 .

Tenofovir disoproxil fumarate Monitor for adverse reactions.

Beta Blockers Nadolol Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Calcium Channel Blockers Felodipine Nisoldipine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Diltiazem Other dihydropyridines Verapamil Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For diltiazem, see also Table 2 .

Cardiovascular Drugs, Miscellaneous Ivabradine Ranolazine Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aliskiren Riociguat Sildenafil (for pulmonary hypertension) Tadalafil (for pulmonary hypertension) Not recommended during and 2 weeks after SPORANOX ® treatment.

For sildenafil and tadalafil, see also Urologic Drugs below.

Bosentan Guanfacine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Contraceptives Dienogest Ulipristal Monitor for adverse reactions.

Diuretics Eplerenone Contraindicated during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Cisapride Naloxegol Contraindicated during and 2 weeks after SPORANOX ® treatment.

Aprepitant Loperamide Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Netupitant Monitor for adverse reactions.

Immunosuppressants Everolimus Sirolimus Temsirolimus (IV) Not recommended during and 2 weeks after SPORANOX ® treatment.

Budesonide (inhalation) Budesonide (non-inhalation) Ciclesonide (inhalation) Cyclosporine (IV) Cyclosporine (non-IV) Dexamethasone Fluticasone (inhalation) Fluticasone (nasal) Methylprednisolone Tacrolimus (IV) Tacrolimus (oral) Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Lipid-Lowering Drugs Lomitapide Lovastatin Simvastatin Contraindicated during and 2 weeks after SPORANOX ® treatment.

Atorvastatin Monitor for drug adverse reactions.

Concomitant drug dose reduction may be necessary .

Respiratory Drugs Salmeterol Not recommended during and 2 weeks after SPORANOX ® treatment.

SSRIs, Tricyclics and Related Antidepressants Venlafaxine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Urologic Drugs Avanafil Contraindicated during and 2 weeks after SPORANOX ® treatment.

Fesoterodine Patients with moderate to severe renal or hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Solifenacin Patients with severe renal or moderate to severe hepatic impairment : Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Darifenacin Vardenafil Not recommended during and 2 weeks after SPORANOX ® treatment.

Dutasteride Oxybutynin Sildenafil (for erectile dysfunction) Tadalafil (for erectile dysfunction and benign prostatic hyperplasia) Tolterodine Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

For sildenafil and tadalafil, see also Cardiovascular Drugs above.

Miscellaneous Drugs and Other Substances Colchicine Patients with renal or hepatic impairment: Contraindicated during and 2 weeks after SPORANOX ® treatment.

Other patients : Not recommended during and 2 weeks after SPORANOX ® treatment.

Eliglustat CYP2D6 EMs EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs , or CYP2D6 PMs : Contraindicated during and 2 weeks after SPORANOX ® treatment.

CYP2D6 EMs not taking a strong or moderate CYP2D6 inhibitor : Monitor for adverse reactions.

Eliglustat dose reduction may be necessary.

Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Alitretinoin (oral) Cabergoline Cannabinoids Cinacalcet Ivacaftor Monitor for adverse reactions.

Concomitant drug dose reduction may be necessary.

Vasopressin Receptor Antagonists Conivaptan Tolvaptan Not recommended during and 2 weeks after SPORANOX ® treatment.

Drug Interactions with SPORANOX ® that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant Drug Antineoplastics Regorafenib Not recommended during and 2 weeks after SPORANOX ® treatment.

Gastrointestinal Drugs Saccharomyces boulardii Not recommended during and 2 weeks after SPORANOX ® treatment.

Nonsteroidal Anti-Inflammatory Drugs Meloxicam Concomitant drug dose increase may be necessary.

Effect of Other Drugs on SPORANOX ® Itraconazole is mainly metabolized through CYP3A4.

Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole.

Some concomitant drugs have the potential to interact with SPORANOX ® resulting in either increased or sometimes decreased concentrations of SPORANOX ® .

Increased concentrations may increase the risk of adverse reactions associated with SPORANOX ® .

Decreased concentrations may reduce SPORANOX ® efficacy.

Table 2 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® .

Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ® .

Table 2.

Drug Interactions with Other Drugs that Affect SPORANOX ® Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with Other Drugs that Increase SPORANOX ® Concentrations and May Increase Risk of Adverse Reactions Associated with SPORANOX ® Antibacterials Ciprofloxacin Based on clinical drug interaction information with itraconazole.

Erythromycin Clarithromycin Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

Antineoplastics Idelalisib Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavir Ritonavir Saquinavir Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

For, cobicistat, elvitegravir, indinavir, ritonavir, and saquinavir, see also Table 1 .

Calcium Channel Blockers Diltiazem Monitor for adverse reactions.

SPORANOX ® dose reduction may be necessary.

See also Table 1 .

Drug Interactions with Other Drugs that Decrease SPORANOX ® Concentrations and May Reduce Efficacy of SPORANOX ® Antibacterials Isoniazid Rifampicin Not recommended 2 weeks before and during SPORANOX ® treatment.

Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Anticonvulsants Phenobarbital Phenytoin Not recommended 2 weeks before and during SPORANOX ® treatment.

Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

See also Table 1 .

Antivirals Efavirenz Nevirapine Not recommended 2 weeks before and during SPORANOX ® treatment.

Gastrointestinal Drugs Drugs that reduce gastric acidity e.g.

acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H 2 – receptor antagonists and proton pump inhibitors.

Use with caution.

Administer acid neutralizing medicines at least 2 hours before or 2 hours after the intake of SPORANOX ® capsules Miscellaneous Drugs and Other Substances Lumacaftor/Ivacaftor Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment.

Pediatric Population Interaction studies have only been performed in adults.

OVERDOSAGE

Itraconazole is not removed by dialysis.

In the event of accidental overdosage, supportive measures should be employed.

Contact a certified poison control center for the most up to date information on the management of SPORANOX ® Capsules overdosage (1-800-222-1222 or www.poison.org).

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole.

(See ADVERSE REACTIONS .)

DESCRIPTION

SPORANOX ® is the brand name for itraconazole, an azole antifungal agent.

Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers.

It may be represented by the following structural formula and nomenclature: (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 R *,4 S *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one mixture with (±)-1-[( R *)- sec -butyl]-4-[ p -[4-[ p -[[(2 S *,4 R *)-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one or (±)-1-[( RS )- sec -butyl]-4-[ p -[4-[ p -[[(2 R ,4 S )-2-(2,4-dichlorophenyl)-2-(1 H -1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one Itraconazole has a molecular formula of C 35 H 38 Cl 2 N 8 O 4 and a molecular weight of 705.64.

It is a white to slightly yellowish powder.

It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane.

It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

SPORANOX ® Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of sucrose, maize starch, and purified water).

Inactive ingredients are hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No.

1, FD&C Blue No.

2, D&C Red No.

22 and D&C Red No.

28.

Chemical Structure

CLINICAL STUDIES

Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

HOW SUPPLIED

Product: 63629-1647

GERIATRIC USE

Geriatric Use Clinical studies of SPORANOX ® Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

It is advised to use SPORANOX ® Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks.

In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole.

Several of these reports included concurrent administration of quinidine which is contraindicated (See BOXED WARNING: Drug Interactions , CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions ).

MECHANISM OF ACTION

Mechanism of Action In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

INDICATIONS AND USAGE

SPORANOX ® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms.

Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.

SPORANOX ® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis.

(See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS , and ADVERSE REACTIONS: Post-marketing Experience for more information.) Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status.

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases.

Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients).

The median dose was 200 mg/day.

A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months.

Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients.

The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S.

for patients who either failed or were intolerant of amphotericin B therapy (N=190).

The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population.

Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months.

Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given SPORANOX ® Capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of SPORANOX ® Capsules b.i.d., followed by a 3-week period without SPORANOX ® , which was followed by a second 1-week pulse of 200 mg of SPORANOX ® Capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

PEDIATRIC USE

Pediatric Use The efficacy and safety of SPORANOX ® have not been established in pediatric patients.

The long-term effects of itraconazole on bone growth in children are unknown.

In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5 times the MRHD).

The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.

At a dosage level of 80 mg/kg/day (10 times the MRHD) over 1 year or 160 mg/kg/day (20 times the MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

PREGNANCY

Pregnancy Teratogenic effects Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (5–20 times the MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10 times the MRHD).

Itraconazole has been shown to cross the placenta in a rat model.

In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

There are no studies in pregnant women.

SPORANOX ® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

SPORANOX ® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

SPORANOX ® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses.

Effective contraception should be continued throughout SPORANOX ® therapy and for 2 months following the end of treatment.

During post-marketing experience, cases of congenital abnormalities have been reported.

(See ADVERSE REACTIONS: Post-marketing Experience .)

NUSRING MOTHERS

Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX ® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant.

The U.S.

Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions SPORANOX ® (itraconazole) Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF .

If signs or symptoms of congestive heart failure occur during administration of SPORANOX ® Capsules, discontinue administration.

When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen.

(See CONTRAINDICATIONS , WARNINGS , PRECAUTIONS.

Drug Interactions , ADVERSE REACTIONS: Post-marketing Experience , and CLINICAL PHARMACOLOGY: Special Populations for more information.) Drug Interactions Coadministration of the following drugs are contraindicated with SPORANOX ® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor.

In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors.

See PRECAUTIONS: Drug Interactions Section for specific examples.

Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs.

For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes , a potentially fatal arrhythmia.

See CONTRAINDICATIONS and WARNINGS Sections, and PRECAUTIONS: Drug Interactions Section for specific examples.

INFORMATION FOR PATIENTS

Information for Patients The topical effects of mucosal exposure may be different between the SPORANOX ® Capsules and Oral Solution.

Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

SPORANOX ® Capsules should not be used interchangeably with SPORANOX ® Oral Solution.

Instruct patients to take SPORANOX ® Capsules with a full meal.

SPORANOX ® Capsules must be swallowed whole.

Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX ® administration, they should discontinue SPORANOX ® and contact their healthcare provider immediately.

Instruct patients to stop SPORANOX ® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop.

Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools.

Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions.

Instruct patients that hearing loss can occur with the use of itraconazole.

The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur.

Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole.

Advise patients that if they experience these events, they should not drive or use machines.

DOSAGE AND ADMINISTRATION

SPORANOX ® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption.

SPORANOX ® (itraconazole) Capsules must be swallowed whole.

SPORANOX ® Capsules is a different preparation than SPORANOX ® Oral Solution and should not be used interchangeably.

Treatment of Blastomycosis and Histoplasmosis The recommended dose is 200 mg once daily (2 capsules).

If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily.

Doses above 200 mg/day should be given in two divided doses.

Treatment of Aspergillosis A daily dose of 200 to 400 mg is recommended.

Treatment in Life-Threatening Situations In life-threatening situations, a loading dose should be used.

Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment.

Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided.

An inadequate period of treatment may lead to recurrence of active infection.

SPORANOX ® Capsules and SPORANOX ® Oral Solution should not be used interchangeably.

Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Treatment of Onychomycosis Toenails with or without fingernail involvement The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.

Treatment of Onychomycosis Fingernails only The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d.

(400 mg/day) for 1 week.

The pulses are separated by a 3-week period without SPORANOX ® .

Use in Patients with Renal Impairment Limited data are available on the use of oral itraconazole in patients with renal impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS .) Use in Patients with Hepatic Impairment Limited data are available on the use of oral itraconazole in patients with hepatic impairment.

Caution should be exercised when this drug is administered in this patient population.

(See CLINICAL PHARMACOLOGY: Special Populations , WARNINGS , and PRECAUTIONS .)

Generic Name: MIDAZOLAM HYDROCHLORIDE
Brand Name: Midazolam Hydrochloride
  • Substance Name(s):
  • MIDAZOLAM HYDROCHLORIDE

WARNINGS

Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function.

Midazolam HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry).

Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately.

The immediate availability of specific reversal agents (flumazenil) is highly recommended.

Vital signs should continue to be monitored during the recovery period.

Because midazolam can depress respiration [see CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam was used in combination with other central nervous system depressants.

These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients.

Consideration should be given to the possibility of paradoxical reaction.

Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding.

Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect.

Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency.

Debilitation and Comorbidity Considerations Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered.

Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam.

Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction.

Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see CLINICAL PHARMACOLOGY] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

Gross tests of recovery from the effects of midazolam HCl syrup [see CLINICAL PHARMACOLOGY] cannot be relied upon to predict reaction time under stress.

It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer.

Particular care should be taken to assure safe ambulation.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these infants accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

DRUG INTERACTIONS

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration.

Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors.

When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation.

Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome.

The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol.

Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION] .

No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics).

Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam.

These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam.

Caution is advised when midazolam HCl syrup is used concomitantly with these drugs.

Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions] .

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies.

Although clinical studies have not been performed, phenobarbital is expected to have the same effect.

Caution is advised when administering midazolam HCl syrup to patients receiving these medications and if necessary dose adjustments should be considered.

OVERDOSAGE

Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma.

In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia.

Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur.

In severe overdosage cases, patients may develop respiratory depression and coma.

Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see WARNINGS: Dependence and Withdrawal Reactions).

Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

Management of Overdose In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency.

The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy.

Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus).

If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage.

See the flumazenil injection Prescribing Information.

Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

DESCRIPTION

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration.

Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions.

Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride.

Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ·HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with artificial bitterness modifier, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, mixed fruit flavor, sodium benzoate, sodium citrate, sorbitol, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid.

Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring.

The amount of open-ring form is dependent upon the pH of the solution.

At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound.

At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such.

The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions.

As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6.

Above pH 5, at least 99% of the mixture is present in the closed-ring form.

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HOW SUPPLIED

Midazolam HCl Syrup is supplied as a clear, red to purplish-red, mixed fruit flavored syrup containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL; each amber glass bottle of 118 mL of syrup is supplied with 1 press-in bottle adapter, 4 single-use, graduated, oral dispensers and 4 tip caps; 10 x bottle of 2.5 mL is supplied with 10 single-use, graduated, oral dispensers and 10 tip caps.

NDC 0574-0150-04 Bottle of 118 mL.

NDC 0574-0150-25 10 x Bottle of 2.5 mL.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.]

GERIATRIC USE

Geriatric Use The safety and efficacy of this product have not been fully studied in geriatric patients.

Therefore, there are no available data on a safe dosing regimen.

One study in geriatric subjects, using midazolam 7.5 mg as a premedicant prior to general anesthesia, noted a 60% incidence of hypoxemia (pO 2 <90% for over 30 seconds) at sometime during the operative procedure versus 15% for the nonpremedicated group.

Until further information is available it is recommended that this product should not be used in geriatric patients.

Use in Patients With Heart Disease Following oral administration of 7.5 mg of midazolam to adult patients with congestive heart failure, the half-life of midazolam was 43% higher than in control subjects.

One study suggests that hypercarbia or hypoxia following premedication with oral midazolam might pose a risk to children with congenital heart disease and pulmonary hypertension, although there are no known reports of pulmonary hypertensive crisis that had been triggered by premedication.

In the study, 22 children were premedicated with oral midazolam (0.75 mg/kg) or IM morphine plus scopolamine prior to elective repair of congenital cardiac defects.

Both premedication regimens increased PtcCO 2 and decreased SpO 2 and respiratory rates preferentially in patients with pulmonary hypertension.

INDICATIONS AND USAGE

Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

PEDIATRIC USE

Pediatric Use Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam Hydrochloride Syrup 2 mg/mL, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis.

Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss.

Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data.

[See WARNINGS; Pediatric Neurotoxicity, PRECAUTIONS; Pregnancy, and Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

PREGNANCY

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary Infants born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ) .

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates.

Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.

Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal.

Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ) .

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18).

Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21).

All doses produced ataxia.

The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring.

The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus.

In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human.

The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits ( see WARNINGS, Pediatric Neurotoxicity, PRECAUTIONS, Pediatric Use, and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ).

Nursing Mothers Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam HCl syrup and any potential adverse effects on the breastfed infant from midazolam HCl syrup or from the underlying maternal condition.

Clinical Considerations Infants exposed to midazolam HCl syrup through breast milk should be monitored for sedation, poor feeding and poor weight gain.

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

BOXED WARNING

WARNINGS Personnel and Equipment for Monitoring and Depression Midazolam HCl syrup has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings.

Midazolam HCl syrup has been associated with reports of respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, most often when used concomitantly with other central nervous system depressants.

Midazolam HCl syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

Monitor patients for respiratory depression and sedation [see WARNINGS, PRECAUTIONS/Drug Interactions] .

INFORMATION FOR PATIENTS

Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1.

Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment.

2.

Inform your physician if you are pregnant or are planning to become pregnant.

3.

Inform your physician if you are nursing.

4.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound.

The decision as to when patients who have received midazolam HCl syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized.

5.

Midazolam HCl syrup should not be taken in conjunction with grapefruit juice.

6.

For pediatric patients, particular care should be taken to assure safe ambulation.

7.

Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy).

Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy (see Precautions, Pregnancy ).

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed.

Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant (see Precautions, Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients.

Midazolam HCl syrup is not intended for chronic administration.

Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians’ and dentists’ offices that can provide for continuous monitoring of respiratory and cardiac function.

Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS] .

For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Continuous monitoring of respiratory and cardiac function is required.

Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional.

Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

Patient response to sedative agents, and resultant respiratory status, is variable.

Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions] .

This is especially true in pediatric patients.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities.

Further recommendations include appropriate presedation fasting.

Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression.

Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring.

When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased.

For appropriate patient monitoring, see WARNINGS and : Monitoring.

The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg.

In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS] .

The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg.

A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical.

For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants.

As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup.

In obese pediatric patients, the dose should be calculated based on ideal body weight.

Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

USE OF ORAL DISPENSERS AND PIBA 1.

Remove the cap.

2.

Before inserting the tip of the oral dispenser into bottle adapter, push the plunger completely down toward the tip of the oral dispenser.

Insert tip firmly into opening of the bottle adapter.

3.

Turn the entire unit (bottle and oral dispenser) upside down.

4.

Pull the plunger out slowly until the desired amount of medication is withdrawn into the oral dispenser.

5.

Turn the entire unit right side up and remove the oral dispenser slowly from the bottle.

6.

The tip of the dispenser may be covered with a tip cap, until time of use.

7.

Close bottle with cap after each use.

8.

Dispense directly into mouth.

Do not mix with any liquid (such as grapefruit juice) prior to dispensing.

INSERTION OF PRESS-IN BOTTLE ADAPTER (PIBA) 1.

Remove the cap and push bottle adapter into neck of bottle.

2.

Close the bottle tightly with cap.

This will assure the proper seating of the bottle adapter in the bottle.

DISPOSAL OF MIDAZOLAM HCl SYRUP The disposal of Schedule IV controlled substances must be consistent with State and Federal Regulations.

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