Author: druginteractionchecker_lgaiz4

WARNINGS

Malignancy Patients receiving immunosuppressants, including azathioprine, are at increased risk of developing lymphoma and other malignancies, particularly of the skin.

Physicians should inform patients of the risk of malignancy with azathioprine.

As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors.

The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including azathioprine.

Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels.

Rheumatoid Arthritis Information is available on the risk of malignancy with the use of azathioprine in rheumatoid arthritis (see ADVERSE REACTIONS ).

It has not been possible to define the precise risk of malignancy due to azathioprine.

The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients.

However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine.

Inflammatory Bowel Disease Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with azathioprine.

These cases have had a very aggressive disease course and have been fatal.

The majority of reported cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males.

Some of the patients were treated with azathioprine as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis.

The safety and efficacy of azathioprine for the treatment of Crohn’s disease and ulcerative colitis have not been established.

Cytopenias Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with azathioprine.

Severe bone marrow suppression may also occur.

Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of azathioprine.

Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of azathioprine.

TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing azathioprine toxicity.

2-9 (See PRECAUTIONS : Laboratory Tests ).

Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection.

It is suggested that patients on azathioprine have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary.

Delayed hematologic suppression may occur.

Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression.

Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count.

Serious infections Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients.

Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously.

Reduction of azathioprine dosage and/or use of other drugs should be considered.

Effect on Sperm in Animals Azathioprine has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; 10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

11 Pregnancy Pregnancy Category D .

Azathioprine tablets can cause fetal harm when administered to a pregnant woman.

Azathioprine tablets should not be given during pregnancy without careful weighing of risk versus benefit.

Whenever possible, use of azathioprine tablets in pregnant patients should be avoided.

This drug should not be used for treating rheumatoid arthritis in pregnant women.

12 Azathioprine tablets are teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily).

Abnormalities included skeletal malformations and visceral anomalies.

11 Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine tablets.

In a detailed case report, 13 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy.

At 10 weeks most features were normalized.

DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily.

14 There have been two published reports of abnormal physical findings.

Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy.

15 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus.

The father was on long-term azathioprine therapy.

16 Benefit versus risk must be weighed carefully before use of azathioprine tablets in patients of reproductive potential.

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

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Women of childbearing age should be advised to avoid becoming pregnant.

WARNINGS

– SEE BOXED .

Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high dose methotrexate therapy.

WARNINGS

Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18–24 5 additional cases Decreases Compared to Placebo 25–64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials.

There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.

Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for amitriptyline hydrochloride tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that amitriptyline hydrochloride tablets are not approved for use in treating bipolar depression.

Amitriptyline hydrochloride may block the antihypertensive action of guanethidine or similarly acting compounds.

It should be used with caution in patients with a history of seizures and, because of its atropine-like action, in patients with a history of urinary retention or angle-closure glaucoma.

In patients with angle-closure glaucoma, even average doses may precipitate an attack.

Patients with cardiovascular disorders should be watched closely.

Tricyclic antidepressant drugs, including amitriptyline hydrochloride, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia, and prolongation of the conduction time.

Myocardial infarction and stroke have been reported with drugs of this class.

Close supervision is required when amitriptyline hydrochloride is given to hyperthyroid patients or those receiving thyroid medication.

Amitriptyline hydrochloride may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.

In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage.

Delirium has been reported with concurrent administration of amitriptyline and disulfiram.

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs, including amitriptyline hydrochloride tablets, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Usage in Pregnancy: Pregnancy Category C – Teratogenic effects were not observed in mice, rats, or rabbits when amitriptyline was given orally at doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose*).

Studies in literature have shown amitriptyline to be teratogenic in mice and hamsters when given by various routes of administration at doses of 28 to 100 mg/kg/day (9 to 33 times the maximum recommended human dose), producing multiple malformations.

Another study in the rat reported that an oral dose of 25 mg/kg/day (8 times the maximum recommended human dose) produced delays in ossification of fetal vertebral bodies without other signs of embryotoxicity.

In rabbits, an oral dose of 60 mg/kg/day (20 times the maximum recommended human dose) was reported to cause incomplete ossification of the cranial bones.

Amitriptyline has been shown to cross the placenta.

Although a causal relationship has not been established, there have been a few reports of adverse events, including CNS effects, limb deformities, or developmental delay, in infants whose mothers had taken amitriptyline during pregnancy.

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

Amitriptyline hydrochloride should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers: Amitriptyline is excreted into breast milk.

In one report in which a patient received amitriptyline 100 mg/day while nursing her infant, levels of 83 to 141 ng/mL were detected in the mother’s serum.

Levels of 135 to 151 ng/mL were found in the breast milk, but no trace of the drug could be detected in the infant’s serum.

Because of the potential for serious adverse reactions in nursing infants from amitriptyline, 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.

Usage in Pediatric Patients: In view of the lack of experience with the use of this drug in pediatric patients, it is not recommended at the present time for patients under 12 years of age.

WARNINGS

1.

Cardiac Conduction: Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome.

This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second or third-degree AV block (13 of 3,290 patients or 0.40%).

Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction.

A patient with Prinzmetal’s angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of diltiazem.

(See ADVERSE REACTIONS section.) 2.

Congestive Heart Failure: Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt).

An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt).

Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function.

Experience with the use of diltiazem in combination with beta-blockers in patients with impaired ventricular function is limited.

Caution should be exercised when using this combination.

3.

Hypotension: Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.

4.

Acute Hepatic Injury: Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies.

Such elevations were usually transient and frequently resolved even with continued diltiazem treatment.

In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted.

These reactions tended to occur early after therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy.

The relationship to diltiazem is uncertain in some cases, but probable in some.

(See PRECAUTIONS .)

WARNINGS

Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.

All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.

Patients with known CV disease or risk factors for CV disease may be at greater risk.

To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms.

Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see , GI Effects ).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS ).

Hypertension NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events.

Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.

NSAIDs, including diclofenac potassium tablets, should be used with caution in patients with hypertension.

Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs.

Diclofenac potassium tablets should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal (GI) Effects: Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including diclofenac potassium tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal.

These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic.

Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year.

These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy.

However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding.

Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors.

Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status.

Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration.

Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected.

This should include discontinuation of the NSAID until a serious GI adverse event is ruled out.

For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects Caution should be used when initiating treatment with diclofenac potassium tablets in patients with considerable dehydration.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.

In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly.

Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease No information is available from controlled clinical studies regarding the use of diclofenac in patients with advanced renal disease.

Therefore, treatment with diclofenac potassium tablets is not recommended in these patients with advanced renal disease.

If diclofenac potassium tablet therapy must be initiated, close monitoring of the patient’s renal function is advisable.

Hepatic Effects Elevations of one or more liver tests may occur during therapy with diclofenac potassium.

These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy.

Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients.

Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment.

In a large, open-label, controlled trial of 3,700 patients treated for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks.

Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients.

In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (> 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs.

Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic.

Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac.

Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure.

Some of these reported cases resulted in fatalities or liver transplantation.

Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms.

The optimum times for making the first and subsequent transaminase measurements are not known.

Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.

However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac potassium should be discontinued immediately.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac potassium, the lowest effective dose should be used for the shortest duration possible.

Caution should be exercised in prescribing diclofenac potassium with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur both in patients with the aspirin triad and in patients without known sensitivity to NSAIDs or known prior exposure to diclofenac potassium tablets.

Diclofenac potassium tablets should not be given to patients with the aspirin triad.

This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS , Preexisting Asthma ).

Anaphylaxis-type reactions have been reported with NSAID products, including with diclofenac products, such as diclofenac potassium tablets.

Emergency help should be sought in cases where an anaphylactic reaction occurs.

Skin Reactions NSAIDs, including diclofenac potassium tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

These serious events may occur without warning.

Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy In late pregnancy, as with other NSAIDs, diclofenac potassium tablets should be avoided because they may cause premature closure of the ductus arteriosus.

WARNINGS

NOT FOR INJECTION.

Ofloxacin Ophthalmic Solution should not be injected subconjunctivally, nor should it be introduced directly into the anterior chamber of the eye.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin.

Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching.

A rare occurrence of Stevens-Johnson syndrome, which progressed to toxic epidermal necrolysis, has been reported in a patient who was receiving topical ophthalmic ofloxacin.

If an allergic reaction to ofloxacin occurs, discontinue the drug.

Serious acute hypersensitivity reactions may require immediate emergency treatment.

Oxygen and airway management, including intubation should be administered as clinically indicated.

WARNINGS

Volume and Electrolyte Depletion The dose of bumetanide should be adjusted to the patient’s need.

Excessive doses or too frequent administration can lead to profound water loss, electrolyte depletion, dehydration, reduction in blood volume and circulatory collapse with the possibility of vascular thrombosis and embolism, particularly in elderly patients.

Hypokalemia Hypokalemia can occur as a consequence of bumetanide administration.

Prevention of hypokalemia requires particular attention in the following conditions: patients receiving digitalis and diuretics for congestive heart failure, hepatic cirrhosis and ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, certain diarrheal states, or other states where hypokalemia is thought to represent particular added risks to the patient, i.e., history of ventricular arrhythmias.

In patients with hepatic cirrhosis and ascites, sudden alterations of electrolyte balance may precipitate hepatic encephalopathy and coma.

Treatment in such patients is best initiated in the hospital with small doses and careful monitoring of the patient’s clinical status and electrolyte balance.

Supplemental potassium and/or spironolactone may prevent hypokalemia and metabolic alkalosis in these patients.

Ototoxicity In cats, dogs and guinea pigs, bumetanide has been shown to produce ototoxicity.

In these test animals bumetanide was 5 to 6 times more potent than furosemide and, since the diuretic potency of bumetanide is about 40 to 60 times furosemide, it is anticipated that blood levels necessary to produce ototoxicity will rarely be achieved.

The potential exists, however, and must be considered a risk of intravenous therapy, especially at high doses, repeated frequently in the face of renal excretory function impairment.

Potentiation of aminoglycoside ototoxicity has not been tested for bumetanide.

Like other members of this class of diuretics, bumetanide probably shares this risk.

Allergy to Sulfonamides Patients allergic to sulfonamides may show hypersensitivity to bumetanide.

Thrombocytopenia Since there have been rare spontaneous reports of thrombocytopenia from postmarketing experience, patients should be observed regularly for possible occurrence of thrombocytopenia.

WARNINGS

Flavoxate hydrochloride should be given cautiously in patients with suspected glaucoma.

WARNINGS

Withdrawal: Patients should be instructed not to discontinue therapy without consulting their physician.

Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.

The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations.

Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal.

When discontinuing therapy with clonidine hydrochloride tablets, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology.

An excessive rise in blood pressure following discontinuation of clonidine hydrochloride tablets therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine.

If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of clonidine hydrochloride tablets.

Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication.

WARNINGS

See BOXED WARNING .

1.

Cardiovascular disorders An increased risk of pulmonary embolism, deep vein thrombosis (DVT), stroke, and myocardial infarction has been reported with estrogen plus progestin therapy.

Should any of these occur or be suspected, estrogen with progestin therapy should be discontinued immediately.

Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (for example, personal history or family history of venous thromboembolism [VTE], obesity, and systemic lupus erythematosus) should be managed appropriately.

a.

Stroke In the Women’s Health Initiative (WHI) estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years).

The increase in risk was demonstrated after the first year and persisted.

(See CLINICAL STUDIES .) Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

b.

Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction [MI], silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women-years).

An increase in relative risk was demonstrated in year 1 and a trend toward decreasing relative risk was reported in years 2 through 5.

(See CLINICAL STUDIES .) In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study [HERS]), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit.

During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease.

There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand, three hundred and twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II.

Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall.

Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II, and overall.

c.

Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and pulmonary embolism [PE]) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years).

Statistically significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women-years) were also demonstrated.

The increase in VTE risk was demonstrated during the first year and persisted.

(See CLINICAL STUDIES .) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

If feasible, estrogens with progestins should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

2.

Malignant neoplasms a.

Breast Cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the Women’s Health Initiative (WHI) substudy of daily CE (0.625 mg) plus MPA (2.5 mg).

After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA.

In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.

The relative risk of invasive breast cancer was 1.24 (95 percent nCI, 1.01-1.54), and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo.

Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for estrogen plus progestin compared with placebo.

Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo.

In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group.

Metastatic disease was rare, with no apparent difference between the two groups.

Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

(See CLINICAL STUDIES .) Consistent with the WHI clinical trials, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use.

The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping).

Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy.

However, these studies have not generally found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations.

In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

b.

Endometrial Cancer An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus.

The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose.

Most studies show no significant increased risk associated with the use of estrogens for less than 1 year.

The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen plus progestin therapy is important.

Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.

There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Adding a progestin to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

c.

Ovarian Cancer The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer.

After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent nCI, 0.77 – 3.24).

The absolute risk for CE plus MPA versus placebo was 4 versus 3 cases per 10,000 women-years.

In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer.

However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.

3.

Probable dementia In the estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.

In the WHIMS estrogen plus progestin ancillary study, after an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia.

The relative risk of probable dementia for estrogen plus progestin versus placebo was 2.05 (95 percent CI, 1.21-3.48).

The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years.

It is unknown whether these findings apply to younger postmenopausal women.

(See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use .) 4.

Vision abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogen.

Discontinue estrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or migraine.

If examination reveals papilledema or retinal vascular lesions, estrogen plus progestin therapy should be permanently discontinued.