Author: druginteractionchecker_lgaiz4

Olmesartan medoxomil 5 MG Oral Tablet [Benicar]

DRUG INTERACTIONS

7 No significant drug interactions were reported in studies in which Benicar was co-administered with digoxin or warfarin in healthy volunteers.

The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH) 3 /Mg(OH) 2 ].

Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.

Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Closely monitor blood pressure, renal function and electrolytes in patients on Benicar and other agents that affect the RAS.

Do not co-administer aliskiren with Benicar in patients with diabetes [see Contraindications (4) ].

Avoid use of aliskiren with Benicar in patients with renal impairment (GFR <60 ml/min).

Colesevelam hydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan.

Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect.

Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3) ] .

NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect (7) .

Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7) .

Colesevelam hydrochloride: Consider administering olmesartan at least 4 hours before colesevelam hydrochloride dose (7)

OVERDOSAGE

10 Limited data are available related to overdosage in humans.

The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs.

If symptomatic hypotension occurs, initiate supportive treatment.

The dialyzability of olmesartan is unknown.

DESCRIPTION

11 Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.

Olmesartan is a selective AT 1 subtype angiotensin II receptor antagonist.

Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4-(1 hydroxy-1-methylethyl)-2-propyl-1-[ p -( o -1H-tetrazol-5-ylphenyl)benzyl]imidazole-5 carboxylate, cyclic 2,3-carbonate.

Its empirical formula is C 29 H 30 N 6 O 6 and its structural formula is: Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.59.

It is practically insoluble in water and sparingly soluble in methanol.

Benicar is available for oral use as film-coated tablets containing 5 mg, 20 mg, or 40 mg of olmesartan medoxomil and the following inactive ingredients: hydroxypropyl cellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, and (5 mg only) yellow iron oxide.

Structural formula for olmesartan medoxomil

CLINICAL STUDIES

14 14.1 Adult Hypertension The antihypertensive effects of Benicar have been demonstrated in seven placebo controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure.

A total of 2693 patients (2145 Benicar; 548 placebo) with essential hypertension were studied.

Benicar once daily lowered diastolic and systolic blood pressure.

The response was dose-related, as shown in the following graph.

A Benicar dose of 20 mg daily produces a trough sitting BP reduction over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting BP reduction over placebo of about 12/7 mmHg.

Benicar doses greater than 40 mg had little additional effect.

The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2 weeks.

Data above are from seven placebo-controlled studies (2145 Benicar patients, 548 placebo patients).

The blood pressure lowering effect was maintained throughout the 24-hour period with Benicar once daily, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%.

The blood pressure lowering effect of Benicar, with and without hydrochlorothiazide, was maintained in patients treated for up to 1 year.

There was no evidence of tachyphylaxis during long-term treatment with Benicar or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1 year of treatment.

The antihypertensive effect of Benicar was similar in men and women and in patients older and younger than 65 years.

The effect was smaller in black patients (usually a low renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers.

Benicar had an additional blood pressure lowering effect when added to hydrochlorothiazide.

There are no trials of Benicar demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

Benicar Dose Response: Placebo-adjusted Reduction in Blood Pressure (mm Hg) 14.2 Pediatric Hypertension The antihypertensive effects of Benicar in the pediatric population were evaluated in a randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years.

The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks.

The etiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort).

Patients who weighed 20 to <35 kg were randomized to 2.5 or 20 mg of Benicar once daily and patients who weighed ≥35 kg were randomized to 5 or 40 mg of Benicar once daily.

At the end of 3 weeks, patients were re-randomized to continuing Benicar or to taking placebo for up to 2 weeks.

During the initial dose-response phase, Benicar significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner.

Overall, the two dose levels of Benicar (low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively.

These reductions in systolic blood pressure included both drug and placebo effect.

During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2 mmHg lower and mean diastolic blood pressure at trough was 2.8 mmHg lower in patients continuing Benicar than in patients withdrawn to placebo.

These differences were statistically different.

As observed in adult populations, the blood pressure reductions were smaller in black patients.

In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of Benicar once daily for three weeks in an open label phase and then were randomized to receiving Benicar or placebo in a double-blind phase.

At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to Benicar; this difference in blood pressure was not statistically significant (95% C.I.

-2 to 7/-1 to 7).

HOW SUPPLIED

16 /STORAGE AND HANDLING Benicar is supplied as yellow, round, film-coated, non-scored tablets containing 5 mg of olmesartan medoxomil, as white, round, film-coated, non-scored tablets containing 20 mg of olmesartan medoxomil, and as white, oval-shaped, film-coated, non-scored tablets containing 40 mg of olmesartan medoxomil.

Tablets are debossed with Sankyo on one side and C12, C14, or C15 on the other side of the 5, 20, and 40 mg tablets, respectively.

Tablets are supplied as follows: 5 mg 20 mg 40 mg Bottle of 30 NDC 51138-211-30 NDC 51138-212-30 NDC 51138-213-30 Storage Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature] .

RECENT MAJOR CHANGES

Boxed Warning 3/2012 Indications and Usage (1) 2/2012 Contraindications (4) 9/2012 Dosage and Administration: Pediatric Hypertension (6 to 16 years of age) (2.2) 2/2012 Warnings and Precautions: Pregnancy (5.1) 3/2012 Morbidity in Infants (5.2) 2/2012

GERIATRIC USE

8.5 Geriatric Use Of the total number of hypertensive patients receiving Benicar in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older.

No overall differences in effectiveness or safety were observed between elderly patients and younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) ] .

DOSAGE FORMS AND STRENGTHS

3 5 mg yellow, round, film-coated, non-scored tablets debossed with Sankyo on one side and C12 on the other side 20 mg white, round, film-coated, non-scored tablets debossed with Sankyo on one side and C14 on the other side 40 mg white, oval-shaped, film-coated, non-scored tablets debossed with Sankyo on one side and C15 on the other side Tablets: 5 mg, 20 mg, and 40 mg (3) .

MECHANISM OF ACTION

12.1 Mechanism of Action Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II).

Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium.

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in vascular smooth muscle.

Its action is, therefore, independent of the pathways for angiotensin II synthesis.

An AT 2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis.

Olmesartan has more than a 12,500-fold greater affinity for the AT 1 receptor than for the AT 2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension.

ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE.

Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin.

Whether this difference has clinical relevance is not yet known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

INDICATIONS AND USAGE

1 Benicar is indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

There are no controlled trials demonstrating risk reduction with Benicar.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

It may be used alone or in combination with other antihypertensive agents.

Benicar is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1) .

PEDIATRIC USE

8.4 Pediatric Use Neonates with a history of in utero exposure to Benicar: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

The antihypertensive effects of Benicar were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see Clinical Studies (14.2) ] .

The pharmacokinetics of Benicar were evaluated in pediatric patients 1 to 16 years of age [see Clinical Pharmacology (12.3) ] .

Benicar was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults.

Benicar has not been shown to be effective for hypertension in children <6 years of age.

Children <1 year of age must not receive Benicar for hypertension [see Warnings and Precautions (5.2) ].

The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development.

RAAS blockade has been shown to lead to abnormal kidney development in very young mice.

Administering drugs that act directly on the renin- angiotensin aldosterone system (RAAS) can alter normal renal development.

PREGNANCY

8.1 Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue Benicar as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue Benicar, unless it is considered lifesaving for the mother.

Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to Benicar for hypotension, oliguria, and hyperkalemia [ see Use in Specific Populations ( 8.4 )] .

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats.

Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Benicar as soon as possible [see Warnings and Precautions ( 5.1 )].

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions ( 5.1 )].

WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue Benicar as soon as possible (5.1) .

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1) .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Avoid fetal (in utero) exposure (5.1) .

Children <1 year of age must not receive Benicar for hypertension (5.2) .

Observe for signs and symptoms of hypotension in volume- or salt-depleted patients with treatment initiation (5.3) .

Monitor for worsening renal function in patients with renal impairment (5.4) .

5.1 Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue Benicar as soon as possible [ see Use in specific Populations ( 8.1 )] .

5.2 Morbidity in Infants Children <1 year of age must not receive Benicar for hypertension.

Drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of immature kidneys [see Use in Specific Populations (8.4) ] .

5.3 Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin aldosterone system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with Benicar.

Initiate treatment under close medical supervision.

If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline [see Dosage and Administration (2.1) ] .

A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.4 Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Benicar.

In patients whose renal function may depend upon the activity of the renin angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

Similar results may be anticipated in patients treated with Benicar [see Dosage and Administration (2.1) , Drug Interactions (7) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported.

There has been no long-term use of Benicar in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Benicar during pregnancy.

Discuss treatment options with women planning to become pregnant.

Patients should be asked to report pregnancies to their physicians as soon as possible.

Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054 Rx Only Copyright © Daiichi Sankyo, Inc.

2009.

All rights reserved.

Repackaged By: Med-Health Pharma, LLC North Las Vegas, NV 89032 SP-60060 Rev06

DOSAGE AND ADMINISTRATION

2 Indication Starting dose Dose Range Adult Hypertension (2.1) 20 mg once daily 20 – 40 mg once daily Pediatric Hypertension (6 – 16 years) (2.2) 20 to <35 kg 10 mg once daily ≥35 kg 20 mg once daily 20 to <35 kg 10 – 20 mg once daily ≥35 kg 20 – 40 mg once daily Benicar may be administered with or without food.

If blood pressure is not controlled by Benicar alone, a diuretic may be added.

Benicar may be administered with other antihypertensive agents.

2.1 Adult Hypertension Dosage must be individualized.

The usual recommended starting dose of Benicar is 20 mg once daily when used as monotherapy in patients who are not volume-contracted.

For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Benicar may be increased to 40 mg.

Doses above 40 mg do not appear to have greater effect.

Twice-daily dosing offers no advantage over the same total dose given once daily.

No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min) or with moderate to marked hepatic dysfunction [see Warnings and Precautions (5.4) , Use in Specific Populations ( 8.5 , 8.6 , 8.7 ) and Clinical Pharmacology (12.3) ] .

For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Benicar under close medical supervision and give consideration to use of a lower starting dose [see Warnings and Precautions (5.3) ] .

Benicar may be administered with or without food.

If blood pressure is not controlled by Benicar alone, a diuretic may be added.

Benicar may be administered with other antihypertensive agents.

2.2 Pediatric Hypertension (6 to 16 years of age) Dosage must be individualized.

For children who can swallow tablets, the usual recommended starting dose of Benicar is 10 mg once daily for patients who weigh 20 to <35 kg (44 to 77 lb), or 20 mg once daily for patients who weigh ≥35 kg.

For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Benicar may be increased to a maximum of 20 mg once daily for patients who weigh <35 kg or 40 mg once daily for patients who weigh ≥35 kg.

Children <1 year of age must not receive Benicar for hypertension.

For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below [see Clinical Pharmacology (12.3) ] .

Follow the suspension preparation instructions below to administer Benicar as a suspension.

Preparation of Suspension (for 200 mL of a 2 mg/mL suspension) Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty Benicar 20 mg tablets and allow to stand for a minimum of 5 minutes.

Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute.

Repeat 1-minute shaking and 1-minute standing for four additional times.

Add 100 mL of Ora-Sweet ® * and 50 mL of Ora-Plus ® * to the suspension and shake well for at least 1 minute.

The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks.

Shake the suspension well before each use and return promptly to the refrigerator.

* Ora-Sweet ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc.

Glipizide XL 10 MG 24 HR Extended Release Oral Tablet

WARNINGS

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY: The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.

This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes.

The study involved 823 patients who were randomly assigned to one of four treatment groups ( Diabetes , 19, SUPP.

2: 747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 1/2 times that of patients treated with diet alone.

A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality.

Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning.

The patient should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

As with any other non-deformable material, caution should be used when administering glipizide extended-release tablets in patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic).

There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable sustained release formulation.

DRUG INTERACTIONS

Drug Interactions: The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents.

When such drugs are administered to a patient receiving glipizide, the patient should be observed closely for hypoglycemia.

When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss of control.

In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol.

However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs.

Certain drugs tend to produce hyperglycemia and may lead to loss of control.

These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

When such drugs are administered to a patient receiving glipizide, the patient should be closely observed for loss of control.

When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycemia.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported.

Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known.

The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers.

All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single daily oral dose for 7 days.

The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%).

In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy volunteers, reductions in glipizide AUC 0-∞ and C max of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide ER.

When glipizide ER was administered 4 hours prior to colesevelam, there was no significant change in glipizide AUC 0-∞ or C max , -4% and 0%, respectively.

Therefore, glipizide ER should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide.

OVERDOSAGE

There is no well-documented experience with glipizide extended-release tablets overdosage in humans.

There have been no known suicide attempts associated with purposeful overdosing with glipizide extended-release tablets.

In nonclinical studies the acute oral toxicity of glipizide was extremely low in all species tested (LD 50 greater than 4 g/kg).

Overdosage of sulfonylureas including glipizide can produce hypoglycemia.

Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns.

Close monitoring should continue until the physician is assured that the patient is out of danger.

Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization.

If hypoglycemic coma is diagnosed or suspected, the patient should be given rapid intravenous injection of concentrated (50%) glucose solution.

This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.

Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.

Clearance of glipizide from plasma may be prolonged in persons with liver disease.

Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.

DESCRIPTION

Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.

The Chemical Abstracts name of glipizide is 1-Cyclohexyl-3-[[ p -[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea.

The molecular formula is C 21 H 27 N 5 O 4 S; the molecular weight is 445.55; the structural formula is shown below: Glipizide is a whitish, odorless powder with a pKa of 5.9.

It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide.

Glipizide extended-release tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use and is designed to deliver 5 mg or 10 mg of glipizide.

Each tablet contains the following inactive ingredients: acetyltributyl citrate, edible black ink, hydroxyethyl cellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A and polyethylene glycol.

The 5 mg tablet also contains FD&C Yellow #6.

structural formula

HOW SUPPLIED

Glipizide Extended-Release Tablets are supplied as 5 mg, and 10 mg round, film-coated tablets and are printed with black ink as follows: 5 mg tablets are orange and printed with WPI and 844 , and are supplied in bottles of 100 (NDC 10370-190-01) and 500 (NDC 10370-190-05).

10 mg tablets are white to off-white and printed with WPI and 845 , and are supplied in bottles of 100 (NDC 10370-191-01) and 500 (NDC 10370-191-05).

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

Protect from moisture and humidity.

Mfd.

for: Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977 U.S.A.

Mfd.

by: Patheon Pharmaceuticals Inc.

Cincinnati, OH 45237 U.S.A.

Issued: December 2014 0S190A-01-85-01

GERIATRIC USE

Geriatric Use: Of the total number of patients in clinical studies of glipizide extended-release tablets, 33 percent were 65 and over.

Approximately 1 to 2 days longer were required to reach steady-state in the elderly.

(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION .)There were no overall differences in effectiveness or safety between younger and older patients, but greater sensitivity of some individuals cannot be ruled out.

As such, it should be noted that elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs.

Hypoglycemia may be difficult to recognize in the elderly.

In addition, in elderly, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.

INDICATIONS AND USAGE

Glipizide extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

PEDIATRIC USE

Pediatric Use: Safety and effectiveness in children have not been established.

PREGNANCY

Pregnancy: Pregnancy Category C: Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg).

This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide.

The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide.

In studies in rats and rabbits no teratogenic effects were found.

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

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

Because recent information suggests that abnormal blood-glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood-glucose levels as close to normal as possible.

Nonteratogenic Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery.

This has been reported more frequently with the use of agents with prolonged half-lives.

If glipizide is used during pregnancy, it should be discontinued at least one month before the expected delivery date.

NUSRING MOTHERS

Nursing Mothers: Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk.

Because the potential for hypoglycemia in nursing infants may exist, 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.

If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

INFORMATION FOR PATIENTS

Information for Patients: Patients should be informed that glipizide extended-release tablets should be swallowed whole.

Patients should not chew, divide or crush tablets.

Patients should be informed of the potential risks and advantages of glipizide extended-release tablets and of alternative modes of therapy.

They should also be informed about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.

Primary and secondary failure also should be explained.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of diabetes mellitus with glipizide extended-release tablets or any other hypoglycemic agent.

Glycemic control should be monitored with hemoglobin A 1C and/or blood-glucose levels to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness.

Home blood-glucose monitoring may also provide useful information to the patient and physician.

Short-term administration of glipizide extended-release tablets may be sufficient during periods of transient loss of control in patients usually controlled on diet.

In general, glipizide extended-release tablets should be given with breakfast.

Recommended Dosing: The usual starting dose of glipizide extended-release tablets as initial therapy is 5 mg per day, given with breakfast.

Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose.

Dosage adjustment should be based on laboratory measures of glycemic control.

While fasting blood-glucose levels generally reach steady-state following initiation or change in glipizide extended-release tablet dosage, a single fasting glucose determination may not accurately reflect the response to therapy.

In most cases, hemoglobin A 1C level measured at three month intervals is the preferred means of monitoring response to therapy.

Hemoglobin A 1C should be measured as glipizide extended-release tablet therapy is initiated and repeated approximately three months later.

If the result of this test suggests that glycemic control over the preceding three months was inadequate, the glipizide extended-release tablet dose may be increased.

Subsequent dosage adjustments should be made on the basis of hemoglobin A 1C levels measured at three month intervals.

If no improvement is seen after three months of therapy with a higher dose, the previous dose should be resumed.

Decisions which utilize fasting blood glucose to adjust glipizide extended-release tablet therapy should be based on at least two or more similar, consecutive values obtained seven days or more after the previous dose adjustment.

Most patients will be controlled with 5 mg to 10 mg taken once daily.

However, some patients may require up to the maximum recommended daily dose of 20 mg.

While the glycemic control of selected patients may improve with doses which exceed 10 mg, clinical studies conducted to date have not demonstrated an additional group average reduction of hemoglobin A 1C beyond what was achieved with the 10 mg dose.

Based on the results of a randomized crossover study, patients receiving immediate release glipizide may be switched safely to glipizide extended-release tablets once-a-day at the nearest equivalent total daily dose.

Patients receiving immediate release glipizide also may be titrated to the appropriate dose of glipizide extended-release tablets starting with 5 mg once daily.

The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section).

Combination Use: When adding other blood-glucose-lowering agents to glipizide extended-release tablets for combination therapy, the agent should be initiated at the lowest recommended dose, and patients should be observed carefully for hypoglycemia.

Refer to the product information supplied with the oral agent for additional information.

When adding glipizide extended-release tablets to other blood-glucose-lowering agents, glipizide extended-release tablets can be initiated at 5 mg.

Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose.

Titration should be based on clinical judgment.

When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced.

Therefore, glipizide ER should be administered at least 4 hours prior to colesevelam.

Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many patients with stable type 2 diabetes receiving insulin may be transferred safely to treatment with glipizide extended-release tablets.

When transferring patients from insulin to glipizide extended-release tablets, the following general guidelines should be considered: For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide extended-release tablet therapy may begin at usual dosages.

Several days should elapse between titration steps.

For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide extended-release tablet therapy may begin at usual dosages.

Subsequent reductions in insulin dosage should depend on individual patient response.

Several days should elapse between titration steps.

During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily.

Patients should be instructed to contact the prescriber immediately if these tests are abnormal.

In some cases, especially when the patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period.

Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide extended-release tablets.

Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide extended-release tablets due to potential overlapping of drug effect.

memantine HCl 14 MG 24HR Extended Release Oral Capsule

DRUG INTERACTIONS

7 7.1 Drugs That Make the Urine Alkaline The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8.

Therefore, alterations of urine pH towards the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects.

Urine pH is altered by diet, drugs (e.g.

carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g.

renal tubular acidosis or severe infections of the urinary tract).

Hence, memantine should be used with caution under these conditions.

7.2 Use with other N-methyl-D-aspartate (NMDA) Antagonists The combined use of NAMENDA XR with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution.

OVERDOSAGE

10 Signs and symptoms most often accompanying overdosage with other formulations of memantine in clinical trials and from worldwide marketing experience, alone or in combination with other drugs and/or alcohol, include agitation, asthenia, bradycardia, confusion, coma, dizziness, ECG changes, increased blood pressure, lethargy, loss of consciousness, psychosis, restlessness, slowed movement, somnolence, stupor, unsteady gait, visual hallucinations, vertigo, vomiting, and weakness.

The largest known ingestion of memantine worldwide was 2 grams in an individual who took memantine in conjunction with unspecified antidiabetic medications.

This person experienced coma, diplopia, and agitation, but subsequently recovered.

One patient participating in a NAMENDA XR clinical trial unintentionally took 112 mg of NAMENDA XR daily for 31 days and experienced an elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count.

Fatal outcome has been very rarely been reported with memantine, and the relationship to memantine was unclear.

Because strategies for the management of overdose are continually evolving, it is advisable to contact a poison control center to determine the latest recommendations for the management of an overdose of any drug.

As in any cases of overdose, general supportive measures should be utilized, and treatment should be symptomatic.

Elimination of memantine can be enhanced by acidification of urine.

DESCRIPTION

11 NAMENDA XR is an orally active NMDA receptor antagonist.

The chemical name for memantine hydrochloride is 1-amino-3,5-dimethyladamantane hydrochloride with the following structural formula: The molecular formula is C 12 H 21 N•HCl and the molecular weight is 215.76.

Memantine HCl occurs as a fine white to off-white powder and is soluble in water.

NAMENDA XR capsules are supplied for oral administration as 7, 14, 21, and 28 mg capsules.

Each capsule contains extended release beads with the labeled amount of memantine HCl and the following inactive ingredients: sugar spheres, polyvinylpyrrolidone, hypromellose, talc, polyethylene glycol, ethylcellulose, ammonium hydroxide, oleic acid, and medium chain triglycerides in hard gelatin capsules.

Structural Formula

CLINICAL STUDIES

14 The effectiveness of NAMENDA XR as a treatment for patients with moderate to severe Alzheimer’s disease was based on the results of a double-blind, placebo-controlled trial.

24-week Study of NAMENDA XR Capsules This was a randomized double-blind clinical investigation in outpatients with moderate to severe Alzheimer’s disease (diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination (MMSE) score ≥ 3 and ≤ 14 at Screening and Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening.

The mean age of patients participating in this trial was 76.5 years with a range of 49-97 years.

Approximately 72% of patients were female and 94% were Caucasian.

Study Outcome Measures The effectiveness of NAMENDA XR was evaluated in this study using the co-primary efficacy parameters of Severe Impairment Battery (SIB) and the Clinician’s Interview-Based Impression of Change (CIBIC-Plus).

The ability of NAMENDA XR to improve cognitive performance was assessed with the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia.

The SIB examines selected aspects of cognitive performance, including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction.

The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.

The ability of NAMENDA XR to produce an overall clinical effect was assessed using a Clinician’s Interview Based Impression of Change that required the use of caregiver information, the CIBIC-Plus.

The CIBIC-Plus is not a single instrument and is not a standardized instrument like the ADCS-ADL or SIB.

Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure.

As such, results from a CIBIC-Plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-Plus evaluations from other clinical trials.

The CIBIC-Plus used in this trial was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral.

It represents the assessment of a skilled clinician using validated scales based on his/her observation during an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated.

The CIBIC-Plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “marked improvement” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.” The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

Study Results In this study, 677 patients were randomized to one of the following 2 treatments: NAMENDA XR 28 mg/day or placebo while still receiving an AChEI (either donepezil, galantamine, or rivastigmine).

Effects on Severe Impairment Battery (SIB) Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups completing the 24 weeks of the study.

At 24 weeks of treatment, the mean difference in the SIB change scores for the NAMENDA XR 28 mg/AChEI-treated (combination therapy) patients compared to the patients on placebo/AChEI (monotherapy) was 2.6 units.

Using an LOCF analysis, NAMENDA XR 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.

Figure 1: Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment.

Figure 2 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of improvement in SIB score shown on the X axis.

The curves show that both patients assigned to NAMENDA XR 28 mg/AChEI and placebo/AChEI have a wide range of responses, but that the NAMENDA XR 28 mg/AChEI group is more likely to show an improvement or a smaller decline.

Figure 2: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores.

Figure 3 shows the time course for the CIBIC-Plus score for patients in the two treatment groups completing the 24 weeks of the study.

At 24 weeks of treatment, the mean difference in the CIBIC-Plus scores for the NAMENDA XR 28 mg/AChEI-treated patients compared to the patients on placebo/AChEI was 0.3 units.

Using an LOCF analysis, NAMENDA XR 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.

Figure 3: Time course of the CIBIC-Plus score for patients completing 24 weeks of treatment.

Figure 4 is a histogram of the percentage distribution of CIBIC-Plus scores attained by patients assigned to each of the treatment groups who completed 24 weeks of treatment.

Figure 4: Distribution of CIBIC-Plus ratings at week 24.

Figure Figure Figure Figure

HOW SUPPLIED

16 /STORAGE AND HANDLING Product: 68151-5755 NDC: 68151-5755-8 1 CAPSULE, EXTENDED RELEASE in a CUP Product: 68151-5829 NDC: 68151-5829-8 1 CAPSULE, EXTENDED RELEASE in a BOTTLE

GERIATRIC USE

8.5 Geriatric Use The majority of people with Alzheimer’s disease are 65 years and older.

In the clinical study of memantine HCl extended-release, the mean age of patients was approximately 77; over 91% of patients were 65 years and older, 67% were 75 years and older, and 14% were at or above 85 years of age.

The efficacy and safety data presented in the clinical trials section were obtained from these patients.

There were no clinically meaningful differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 year old.

DOSAGE FORMS AND STRENGTHS

3 Each capsule contains 7 mg, 14 mg, 21 mg, or 28 mg of memantine HCl.

The 7 mg capsules are a yellow opaque capsule, with “FLI 7 mg” black imprint.

The 14 mg capsules are a yellow cap and dark green opaque body capsule, with “FLI 14 mg” black imprint on the yellow cap.

The 21 mg capsules are a white to off-white cap and dark green opaque body capsule, with “FLI 21 mg” black imprint on the white to off-white cap.

The 28 mg capsules are a dark green opaque capsule, with “FLI 28 mg” white imprint.

NAMENDA XR is available as an extended-release capsule in the following strengths: 7 mg, 14 mg, 21 mg, 28 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer’s disease.

Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels.

There is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer’s disease.

INDICATIONS AND USAGE

1 NAMENDA XR (memantine hydrochloride) extended-release capsules are indicated for the treatment of moderate to severe dementia of the Alzheimer’s type.

NAMENDA XR is an NMDA receptor antagonist indicated for the treatment of moderate to severe dementia of the Alzheimer’s type ( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (ASD), including autism Asperger’s disorder and Pervasive Development Disorder – Not Otherwise Specified (PDD-NOS).

Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age.

Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6.

Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively.

In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53).

In a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158).

The overall safety profile of memantine in pediatric patients was generally consistent with the known safety profile in adults [see Adverse Reactions ( 6.1 )] .

In Study A, the adverse reactions in the memantine group (n=56) that were reported in at least 5% of patients and twice that in the placebo group (N=58) are listed in Table 2 : Table 2: Study A Commonly Reported Adverse Reactions With a Frequency ≥ 5% and Twice That in Placebo a Reported adverse reactions leading to discontinuation in more than one patient in either treatment group.

Adverse Reaction Memantine N=56 Placebo N=58 Cough 8.9% 3.4% Influenza 7.1% 3.4% Rhinorrhea 5.4% 0% Agitation 5.4% 1.7% Discontinuations due to adverse reactions a Aggression 3.6% 1.7% Irritability 1.8% 3.4% The adverse reactions that were reported in at least 5% of patients in the 12-48 week open-label study to identify responders to enroll in Study B are listed in Table 3 : Table 3: 12-48 Week Open Label Lead-In study to Study B Commonly Reported Adverse Reactions With a Frequency ≥ 5% a At least 1% incidence of adverse reactions leading to premature discontinuation.

Adverse Reaction Memantine N=903 Headache 8.0% Nasopharyngitis 6.3% Pyrexia 5.8% Irritability 5.4% Discontinuations due to adverse reactions a Irritability 1.2% Aggression 1.0% In the randomized withdrawal study (Study B), the adverse reaction in patients randomized to placebo (n=160) and reported in at least 5% of patients and twice that of the full-dose memantine treatment group (n=157) was irritability (5.0% vs 2.5%).

In a juvenile animal study, male and female juvenile rats were administered memantine (15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 14 through PND 70.

Body weights were reduced at 45 mg/kg/day.

Delays in sexual maturation were noted in male and female rats at doses ≥ 30 mg/kg/day.

Memantine induced neuronal lesions in several areas of the brain on PND 15 and 17 at doses ≥ 30 mg/kg/day.

Behavioral toxicity (decrease percent of auditory startle habituation) was noted for animals in the 45 mg/kg/day dose group.

The 15 mg/kg/day dose was considered the No-Observed-Adverse-Effect-Level (NOAEL) for this study.

In a second juvenile rat toxicity study, male and female juvenile rats were administered memantine (1, 3, 8, 15, 30, and 45 mg/kg/day) starting on postnatal day (PND) 7 through PND 70.

Due to early memantine-related mortality, the 30 and 45 mg/kg/day dose groups were terminated without further evaluation.

Memantine induced apoptosis or neuronal degeneration in several areas of the brain on PND 8, 10, and 17 at a dose of 15 mg/kg/day.

The NOAEL for apoptosis and neuronal degeneration was 8 mg/kg/day.

Behavioral toxicity (effects on motor activity, auditory startle habituation, and learning and memory) was noted at doses ≥ 3 mg/kg/day during treatment, but was not seen after drug discontinuation.

Therefore, the 1 mg/kg/day dose was considered the NOAEL for the neurobehavioral effect in this study.

PREGNANCY

8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of memantine in pregnant women.

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

Memantine given orally to pregnant rats and pregnant rabbits during the period of organogenesis was not teratogenic up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 6 and 21 times, respectively, the maximum recommended human dose [MRHD] on a mg/m 2 basis).

Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at an oral dose of 18 mg/kg/day in a study in which rats were given oral memantine beginning pre-mating and continuing through the postpartum period.

Slight maternal toxicity and decreased pup weights were also seen at this dose in a study in which rats were treated from day 15 of gestation through the post-partum period.

The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m 2 basis.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether memantine is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when Namenda XR is administered to a nursing mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine ( 5.1 , 7.1 ) 5.1 Genitourinary Conditions Conditions that raise urine pH may decrease the urinary elimination of memantine resulting in increased plasma levels of memantine [see Drug Interactions ( 7.1 )] .

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

To assure safe and effective use of NAMENDA XR, the information and instructions provided in the patient information section should be discussed with patients and caregivers.

Instruct patients and caregivers to take NAMENDA XR only once per day, as prescribed.

Instruct patients and caregivers that NAMENDA XR capsules be swallowed whole.

Alternatively, NAMENDA XR capsules may be opened and sprinkled on applesauce and the entire contents should be consumed.

The capsules should not be divided, chewed or crushed.

Warn patients not to use any capsules of NAMENDA XR that are damaged or show signs of tampering.

If a patient misses a single dose of NAMENDA XR, that patient should not double up on the next dose.

The next dose should be taken as scheduled.

If a patient fails to take NAMENDA XR for several days, dosing should not be resumed without consulting that patient’s healthcare professional.

Advise patients and caregivers that NAMENDA XR may cause headache, diarrhea, and dizziness.

Distributed by: Allergan USA, Inc.

Irvine, CA 92612 Manufactured by: Forest Laboratories Ireland Ltd Licensed from Merz Pharmaceuticals GmbH © 2017 Allergan.

All rights reserved

DOSAGE AND ADMINISTRATION

2 The recommended starting dose of NAMENDA XR is 7 mg once daily; the dose should be increased in 7 mg increments to the recommended maintenance dose of 28 mg once daily; the minimum recommended interval between dose increases is one week ( 2.1 ) Patients with severe renal impairment: the recommended maintenance dose of NAMENDA XR is 14 mg once daily ( 2.3 ) 2.1 Recommended Dosing The dosage of NAMENDA XR shown to be effective in a controlled clinical trial is 28 mg once daily.

The recommended starting dose of NAMENDA XR is 7 mg once daily.

The dose should be increased in 7 mg increments to the recommended maintenance dose of 28 mg once daily.

The minimum recommended interval between dose increases is one week.

The dose should only be increased if the previous dose has been well tolerated.

The maximum recommended dose is 28 mg once daily.

NAMENDA XR can be taken with or without food.

NAMENDA XR capsules can be taken intact or may be opened, sprinkled on applesauce, and thereby swallowed.

The entire contents of each NAMENDA XR capsule should be consumed; the dose should not be divided.

Except when opened and sprinkled on applesauce, as described above, NAMENDA XR should be swallowed whole.

NAMENDA XR capsules should not be divided, chewed, or crushed.

If a patient misses a single dose of NAMENDA XR, that patient should not double up on the next dose.

The next dose should be taken as scheduled.

If a patient fails to take NAMENDA XR for several days, dosing may need to be resumed at lower doses and retitrated as described above.

2.2 Switching from NAMENDA to NAMENDA XR Capsules Patients treated with NAMENDA may be switched to NAMENDA XR capsules as follows: It is recommended that a patient who is on a regimen of 10 mg twice daily of NAMENDA be switched to NAMENDA XR 28 mg once daily capsules the day following the last dose of 10 mg NAMENDA.

There is no study addressing the comparative efficacy of these 2 regimens.

In a patient with severe renal impairment, it is recommended that a patient who is on a regimen of 5 mg twice daily of NAMENDA be switched to NAMENDA XR 14 mg once daily capsules the day following the last dose of 5 mg NAMENDA.

2.3 Dosing in Patients with Renal Impairment In patients with severe renal impairment (creatinine clearance of 5 – 29 mL/min, based on the Cockcroft-Gault equation), the recommended maintenance dose (and maximum recommended dose) is 14 mg/day [see Clinical Pharmacology ( 12.3 )] .

dopamine HCl 3200 MCG/ML per 250 ML Injection

Generic Name: DOPAMINE HYDROCHLORIDE IN DEXTROSE
Brand Name: Dopamine Hydrochloride in Dextrose
  • Substance Name(s):
  • DOPAMINE HYDROCHLORIDE

DRUG INTERACTIONS

7 See Table 1 for clinically significant drug interactions with dopamine.

Table 1: Clinically Significant Drug Interactions with Dopamine Halogenated Anesthetics Clinical Impact: Concomitant use may increase cardiac autonomic irritability and can sensitize the myocardium to the action of dopamine which may lead to ventricular arrhythmias and hypertension.

Intervention: Monitor cardiac rhythm.

Examples: desflurane, enflurane, isoflurane, and sevoflurane.

MAO Inhibitors Clinical Impact: Because dopamine is metabolized by monoamine oxidase (MAO), inhibition of this enzyme prolongs and potentiates the effect of dopamine which may result in severe hypertension and cardiac arrhythmia.

Intervention: Reduce the recommended starting dosage to no greater than one-tenth (1/10) of the recommended dose in patients who have been treated with MAO inhibitors within two to three weeks prior to the administration of Dopamine HCl in Dextrose Injection.

Examples: isocarboxazid, phenelzine, tranylcypromine, rasagiline, selegiline, linezolid.

Tricyclic Antidepressants Clinical Impact: Concomitant use may potentiate the cardiovascular effects of dopamine (e.g., hypertension).

Intervention: Monitor blood pressure.

Examples: amitriptyline, desipramine, doxepin, imipramine, nortriptyline.

Vasopressors Clinical Impact: Concomitant use may result in severe hypertension.

Intervention: Monitor blood pressure.

Examples: norepinephrine, epinephrine, oxytocin.

Halogenated anesthetics : Can sensitize the myocardium to the effects of dopamine and can produce ventricular arrhythmias and hypertension.

( 7 ) MAO inhibitors : Risk of severe hypertension.

Reduce recommended Dopamine HCl in Dextrose Injection dosage.

( 7 ) Tricyclic antidepressants : Risk of hypertension.

Monitor blood pressure.

( 7 ) Vasopressors : Risk of severe hypertension.

Monitor blood pressure.

( 7 )

OVERDOSAGE

10 Manifestations of overdosage include excessive blood pressure elevation.

In the case of accidental overdosage, reduce rate of Dopamine HCl in Dextrose Injection infusion, or temporarily discontinue the Dopamine HCl in Dextrose Injection infusion until the overdosage related adverse reactions resolves.

Since dopamine’s duration of action is short, no additional remedial measures are usually necessary.

If these measures fail to resolve the overdosage related adverse reactions, consider using an alpha-adrenergic blocking agent (e.g., phentolamine).

DESCRIPTION

11 Dopamine Hydrochloride in 5% Dextrose Injection, USP is a sterile, nonpyrogenic, premixed solution of dopamine hydrochloride in 5% dextrose injection for intravenous infusion.

Each 100 mL contains 80 mg (800 mcg/mL), 160 mg (1600 mcg/mL) or 320 mg (3200 mcg/mL) of dopamine HCl; 5 grams of hydrous dextrose, in Water for Injection, and 50 mg of sodium metabisulfite (a stabilizer); pH = 3.8 (2.5 to 4.5), and the following osmolar concentrations: 261, 269, or 286 mOsmol/liter, respectively.

May contain hydrochloric acid and/or sodium hydroxide for pH adjustment.

Dopamine HCl is chemically designated 3, 4-dihydroxyphenethylamine hydrochloride (C 8 H 11 NO 2 ∙ HCl), a white crystalline powder freely soluble in water.

Dopamine HCl has a molecular weight of 189.64 and it has the following structural formula: Dopamine (also referred to as 3-hydroxytyramine) is a naturally occurring endogenous catecholamine.

Dextrose, USP is chemically designated D-glucose monohydrate (C 6 H 12 O 6 ∙ H 2 O), a hexose sugar freely soluble in water.

The molecular weight of dextrose (D-glucose) monohydrate is 198.17 and it has the following structural formula: Water for Injection, USP is chemically designated H 2 O.

Chemical Structure Chemical Structure

HOW SUPPLIED

16 /STORAGE AND HANDLING Dopamine Hydrochloride in 5% Dextrose Injection, USP, is supplied in 250 and 500 mL LifeCare flexible single-dose plastic containers (the solutions are clear to slightly yellow in appearance) as follows.

Each 100 mL contains 5 grams of hydrous dextrose in Water for Injection.

Unit of Sale Total Strength/Total Volume (Concentration) NDC 0409-7809-22 12 in a case 400 mg/250 mL (1600 mcg/mL) NDC 0409-7809-24 12 in a case 800 mg/500 mL (1600 mcg/mL) NDC 0409-7810-22 12 in a case 800 mg/250 mL (3200 mcg/mL) Store at 20°C to 25°C (68°F to 77°F).

[See USP Controlled Room Temperature.] Protect from freezing.

Discard unused portion.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of dopamine 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 start at the low end of the dosing range, reflecting the frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 The following strengths of Dopamine Hydrochloride in 5% Dextrose Injection, USP, are supplied in LifeCare flexible single-dose plastic containers (the solutions are clear to slightly yellow in appearance): 800 mcg/mL (250 or 500 mL) 1600 mcg/mL (250 or 500 mL) 3200 mcg/mL (250 mL) Each 100 mL contains 5 grams of hydrous dextrose in Water for Injection.

Following strengths of Dopamine Hydrochloride in 5% Dextrose Injection, USP, are supplied in LifeCare flexible single-dose plastic containers (each 100 mL contains 5 grams of hydrous dextrose in Water for Injection): ( 3 ) 800 mcg/mL (250 and 500 mL) 1600 mcg/mL (250 and 500 mL) 3200 mcg/mL (250 mL)

MECHANISM OF ACTION

12.1 Mechanism of Action Dopamine is a natural catecholamine formed by the decarboxylation of 3,4-dihydroxyphenylalanine (DOPA).

It is a precursor to norepinephrine in noradrenergic nerves and is also a neurotransmitter in certain areas of the central nervous system, especially in the nigrostriatal tract, and in a few peripheral sympathetic nerves.

Dopamine elicits its pharmacological action by activating dopamine D1 and D2 receptors, beta-1 receptors and alpha-1 receptors.

The activation of different receptors leading to its effects are dependent on dopamine dose.

INDICATIONS AND USAGE

1 Dopamine Hydrochloride in Dextrose Injection is indicated to improve hemodynamic status in patients in distributive shock, or shock due to reduced cardiac output.

Dopamine HCl in Dextrose Injection is a catecholamine indicated to improve hemodynamic status in patients in shock.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use Dopamine HCl infusions have been used in pediatric patients from birth through adolescence.

Most reports in pediatric patients describe dosing that is similar (on a mcg/kg/minute basis) to that used in adults [see Dosage and Administration (2.2) ] .

Except for vasoconstrictive effects caused by inadvertent infusion of dopamine into the umbilical artery, adverse reactions unique to pediatric patients have not been identified, nor have adverse reactions identified in adults been found to be more common in pediatric patients.

PREGNANCY

8.1 Pregnancy Risk Summary There are no human data with dopamine use in pregnant women.

There are risks to the mother and fetus from hypotension associated with shock, which can be fatal if left untreated ( see Clinical Considerations ).

In animal reproduction studies, adverse developmental outcomes were observed with intravenous dopamine HCl administration in pregnant rats during organogenesis at dosages, on a mcg/m 2 basis, of one-third the human starting dosage of 2 mcg/kg/minute (90 mcg/m 2 /minute).

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

All pregnancies carry some risk of birth defect, loss, or other adverse outcomes.

In the U.S.

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

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypotension associated with distributive shock, or shock due to reduced cardiac output are medical emergencies in pregnancy which can be fatal if left untreated.

Delaying treatment in pregnant women with hypotension associated with distributive shock, or shock due to reduced cardiac output may increase the risk of maternal and fetal morbidity and mortality.

Life-sustaining therapy for the pregnant woman should not be withheld due to potential concerns regarding the effects of dopamine on the fetus.

Labor or Delivery Vasopressor drugs, including dopamine, may cause severe maternal hypertension when used concomitantly with some oxytocic drugs [see Drug Interactions (7) ] .

Data Animal Data Animal reproduction studies in rats and rabbits at dopamine HCl dosages up to 6 mg/kg/day intravenously (on a mcg/m 2 basis, one-third and two-thirds, respectively, the human starting dosage of 2 mcg/kg/minute) during organogenesis produced no detectable teratogenic or embryotoxic effects, although maternal toxicity consisting of mortalities, decreased body weight gain, and pharmacotoxic signs were observed in rats.

In a published study, administration of 10 mg/kg/day dopamine HCl (on a mcg/m 2 basis, two-thirds the human starting dosage of 2 mcg/kg/minute) to pregnant rats throughout gestation or for 5 days starting on gestation day 10 or 15 resulted in decreased body weight gain, increased mortality, and slight increase in cataract formation among the offspring.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Tissue ischemia : Severe peripheral and visceral vasoconstriction can occur.

Address hypovolemia prior to use, monitor extremities, and infuse into large vein.

( 5.1 ) Cardiac arrhythmias : Monitor closely.

( 5.2 ) Hypotension after abrupt discontinuation : Gradually reduce infusion rate while expanding blood volume with intravenous fluids.

( 5.3 ) Severe hypersensitivity reactions due to sodium metabisulfite excipient : May cause anaphylaxis including life-threatening or less severe asthmatic episodes in susceptible individuals.

( 5.4 ) 5.1 Tissue Ischemia Administration of dopamine to patients who are hypotensive from hypovolemia can result in severe peripheral and visceral vasoconstriction, decreased renal perfusion and hypouresis, tissue hypoxia, lactic acidosis, and poor systemic blood flow despite “normal” blood pressure.

Address hypovolemia prior to initiating Dopamine HCl in Dextrose Injection [see Dosage and Administration (2.2) ] .

Gangrene of the extremities has occurred in patients with occlusive vascular disease or who received prolonged or high dose infusions.

Monitor for changes to the skin of the extremities in susceptible patients.

Extravasation of Dopamine HCl in Dextrose Injection may cause necrosis and sloughing of surrounding tissue.

To reduce the risk of extravasation, infuse into a large vein [see Dosage and Administration (2.1) ] , check the infusion site frequently for free flow, and monitor for signs of extravasation.

Emergency Treatment of Extravasation To prevent sloughing and necrosis in areas in which extravasation has occurred, infiltrate the ischemic area as soon as possible, using a syringe with a fine hypodermic needle with: 5 to 10 mg of phentolamine mesylate in 10 to 15 mL of 0.9% Sodium Chloride Injection in adults 0.1 to 0.2 mg/kg of phentolamine mesylate up to a maximum of 10 mg per dose in pediatric patients.

Sympathetic blockade with phentolamine causes immediate and conspicuous local hyperemic changes if the area is infiltrated within 12 hours.

5.2 Cardiac Arrhythmias Dopamine may cause arrhythmias.

Monitor patients with arrhythmias and treat appropriately.

5.3 Hypotension after Abrupt Discontinuation Sudden cessation of the infusion rate may result in marked hypotension.

Gradually reduce the infusion rate while expanding blood volume with intravenous fluids.

5.4 Severe Hypersensitivity Reactions due to Sodium Metabisulfite Excipient Dopamine HCl in Dextrose Injection, contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.

The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.

Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Risk of Tissue Damage Advise the patient, family, or caregiver to report signs of extravasation urgently [see Warnings and Precautions (5.1) ].

Cardiac Arrhythmias Advise the patient, family, or caregiver that Dopamine HCl in Dextrose Injection can induce or worsen arrhythmias [see Warnings and Precautions (5.2) ] .

DOSAGE AND ADMINISTRATION

2 Correct hypovolemia, acidosis, and hypoxia prior to use.

( 2.1 ) Administer in a large vein with an infusion pump preferably in an intensive care setting.

( 2.1 ) Recommended starting dosage in adults and pediatric patients is 2 to 5 mcg/kg/minute as a continuous intravenous infusion.

Titrate in 5 to 10 mcg/kg/minute increments based on hemodynamic response and tolerability, up to not more than 50 mcg/kg/minute.

( 2.2 ) See the Full Prescribing Information for important preparation instructions and drug incompatibilities.

( 2.3 ) 2.1 Administration Instructions Correct Hypovolemia, Acidosis, and Hypoxia Address hypovolemia, acidosis, and hypoxia before initiating Dopamine HCl in Dextrose Injection.

If patient does not respond to therapy, suspect occult hypovolemia.

Acidosis may reduce the effectiveness of dopamine [see Warnings and Precautions (5.1) ] .

Administration Dopamine HCl in Dextrose Injection is a premixed infusion solution that does not require dilution prior to intravenous administration.

Administer Dopamine HCl in Dextrose Injection into a large vein [see Warnings and Precautions (5.1) ] with the use of an infusion pump preferably in an intensive care setting.

Remove outer wrap (moisture and oxygen barrier) only when ready to administer the product.

Discard product if outer wrap is damaged (e.g., tears or holes).

Inspect Dopamine HCl in Dextrose Injection for particulate matter and discoloration prior to administration (the solution is clear to slightly yellow).

Do not administer if the solution is darker than slightly yellow or the container is damaged.

Use higher concentration premixed solutions (e.g., 3200 mcg/mL or 1600 mcg/mL strengths) in patients requiring fluid restriction.

Discontinuation When discontinuing Dopamine HCl in Dextrose Injection, gradually reduce the infusion rate while expanding blood volume with intravenous fluids [see Warnings and Precautions (5.3) ].

2.2 Recommended Dosage The recommended starting dosage in adults and pediatric patients is 2 to 5 mcg/kg/minute as a continuous intravenous infusion [see Dosage and Administration (2.3) ] .

Titrate the infusion rate in 5 to 10 mcg/kg/minute increments based on hemodynamic response and tolerability, up to but not more than 50 mcg/kg/minute.

Infusion rates may be calculated using the following formula: Infusion Rate (mL/hour) = [Dose (mcg/kg/minute) × Weight (kg) × 60 (minutes/hour)] Concentration (mcg/mL) Example calculations for infusion rates are as follows: Example 1: for a 60 kg person at the recommended initial dose of 2 mcg/kg/minute using an 800 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/hour) = [2 (mcg/kg/minute) × 60 (kg) × 60 (minutes/hour) ] = 9 (mL/hour) 800 (mcg/mL) Example 2: for a 70 kg person at a dose of 5 mcg/kg/minute using a 3,200 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/hour) = [5 (mcg/kg/minute) × 70 (kg) × 60 (minutes/hour) ] = 6.56 (mL/hour) 3200 (mcg/mL) 2.3 Drug Incompatibilities Dopamine HCl in Dextrose Injection is incompatible with the following products; therefore, avoid simultaneous administration (through the same infusion set): Sodium bicarbonate or other alkalinizing substances, because dopamine is inactivated in alkaline solution.

Blood, because of the risk of pseudoagglutination of red cells Iron salts Do not add additional medications in the premixed infusion solution.

prazosin HCl 5 MG Oral Capsule

Generic Name: PRAZOSIN HYDROCHLORIDE
Brand Name: Prazosin Hydrochloride
  • Substance Name(s):
  • PRAZOSIN HYDROCHLORIDE

WARNINGS

As with all alpha-blockers, prazosin hydrochloride capsules may cause syncope with sudden loss of consciousness.

In most cases, this is believed to be due to an excessive postural hypotensive effect, although occasionally the syncopal episode has been preceded by a bout of severe tachycardia with heart rates of 120‒160 beats per minute.

Syncopal episodes have usually occurred within 30 to 90 minutes of the initial dose of the drug; occasionally, they have been reported in association with rapid dosage increases or the introduction of another antihypertensive drug into the regimen of a patient taking high doses of prazosin hydrochloride capsules.

The incidence of syncopal episodes is approximately 1% in patients given an initial dose of 2 mg or greater.

Clinical trials conducted during the investigational phase of this drug suggest that syncopal episodes can be minimized by limiting the initial dose of the drug to 1 mg, by subsequently increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient’s regimen with caution (see DOSAGE AND ADMINISTRATION ).

Hypotension may develop in patients given prazosin hydrochloride capsules who are also receiving a beta-blocker such as propranolol.

If syncope occurs, the patient should be placed in the recumbent position and treated supportively as necessary.

This adverse effect is self-limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration.

Patients should always be started on the 1 mg capsules of prazosin hydrochloride capsules.

The 2 and 5 mg capsules are not indicated for initial therapy.

More common than loss of consciousness are the symptoms often associated with lowering of the blood pressure, namely, dizziness and lightheadedness.

The patient should be cautioned about these possible adverse effects and advised what measures to take should they develop.

The patient should also be cautioned to avoid situations where injury could result should syncope occur during the initiation of prazosin hydrochloride capsules therapy.

Priapism Prolonged erections and priapism have been reported with alpha-1 blockers including prazosin in post marketing experience.

In the event of an erection that persists longer than 4 hours, seek immediate medical assistance.

If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

DRUG INTERACTIONS

Drug Interactions Prazosin hydrochloride capsules have been administered without any adverse drug interaction in limited clinical experience to date with the following: (1) cardiac glycosides‒digitalis and digoxin; (2) hypoglycemics‒insulin, chlorpropamide, phenformin, tolazamide, and tolbutamide; (3) tranquilizers and sedatives‒chlordiazepoxide, diazepam, and phenobarbital; (4) antigout‒allopurinol, colchicine, and probenecid; (5) antiarrhythmics‒procainamide, propranolol (see WARNINGS however), and quinidine; and (6) analgesics, antipyretics and anti-inflammatories-propoxyphene, aspirin, indomethacin, and phenylbutazone.

Addition of a diuretic or other antihypertensive agent to prazosin hydrochloride capsules have been shown to cause an additive hypotensive effect.

This effect can be minimized by reducing the prazosin hydrochloride capsules dose to 1 to 2 mg three times a day, by introducing additional antihypertensive drugs cautiously, and then by retitrating prazosin hydrochloride capsules based on clinical response.

Concomitant administration of prazosin hydrochloride capsules with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE AND ADMINISTRATION ).

OVERDOSAGE

Accidental ingestion of at least 50 mg of prazosin hydrochloride capsules in a two year old child resulted in profound drowsiness and depressed reflexes.

No decrease in blood pressure was noted.

Recovery was uneventful.

Should overdosage lead to hypotension, support of the cardiovascular system is of first importance.

Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position.

If this measure is inadequate, shock should first be treated with volume expanders.

If necessary, vasopressors should then be used.

Renal function should be monitored and supported as needed.

Laboratory data indicate prazosin hydrochloride capsules are not dialysable because it is protein bound.

DESCRIPTION

Prazosin hydrochloride capsules, USP a quinazoline derivative, is the first of a new chemical class of antihypertensives.

It is the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl) piperazine and its structural formula is: Molecular formula C 19 H 21 N 5 O 4 • HCl It is a white to tan powder, slightly soluble in water and methanol, very slightly soluble in alcohol, practically insoluble in chloroform and acetone and has a molecular weight of 419.87.

Each capsule, for oral use, contains prazosin hydrochloride, USP equivalent (as the polyhydrate) to 1 mg, 2 mg or 5 mg of prazosin.

Inert ingredients in the formulations are: colloidal silicon dioxide, lactose monohydrate, magnesium stearate and microcrystalline cellulose.

The empty gelatin capsules contain black iron oxide, gelatin, red iron oxide, titanium dioxide and yellow iron oxide.

In addition, the 1 mg empty gelatin capsules contain D&C Yellow No.

10 and FD&C Green No.

3; the 2 mg empty gelatin capsules contain D&C Red No.

28, D&C Yellow No.

10, FD&C Blue No.

1 and FD&C Red No.

40; and the 5 mg empty gelatin capsules contain FD&C Blue No.

1.

The imprinting ink also contains ammonium hydroxide, propylene glycol, shellac glaze, simethicone and titanium dioxide.

Prazosin Hydrochloride Structural Formula

HOW SUPPLIED

Prazosin Hydrochloride Capsules, USP are available containing prazosin hydrochloride, USP equivalent to 1 mg, 2 mg, or 5 mg of prazosin.

The 1 mg capsule is a hard-shell gelatin capsule with a dark green opaque cap and a light brown opaque body filled with a white to off-white powder blend.

The capsule is axially printed with MYLAN over 1101 in white ink on both the cap and body.

They are available as follows: NDC 0378-1101-01 bottles of 100 capsules NDC 0378-1101-10 bottles of 1000 capsules The 2 mg capsule is a hard-shell gelatin capsule with a brown opaque cap and a light brown opaque body filled with a white to off-white powder blend.

The capsule is axially printed with MYLAN over 2302 in white ink on both the cap and body.

They are available as follows: NDC 0378-2302-01 bottles of 100 capsules NDC 0378-2302-10 bottles of 1000 capsules The 5 mg capsule is a hard-shell gelatin capsule with a light blue opaque cap and a light brown opaque body filled with a white to off-white powder blend.

The capsule is axially printed with MYLAN over 3205 in white ink on both the cap and body.

They are available as follows: NDC 0378-3205-01 bottles of 100 capsules NDC 0378-3205-25 bottles of 250 capsules Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] Protect from moisture and light.

Dispense in a tight, light-resistant container as defined by the USP using a child-resistant closure.

INDICATIONS AND USAGE

Prazosin hydrochloride capsules are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Prazosin hydrochloride capsules can be used alone or in combination with other antihypertensive drugs such as diuretics or beta-adrenergic blocking agents.

PREGNANCY

Usage in Pregnancy Prazosin hydrochloride capsules has been shown to be associated with decreased litter size at birth, 1, 4, and 21 days of age in rats when given doses more than 225 times the usual maximum recommended human dose.

No evidence of drug-related external, visceral, or skeletal fetal abnormalities were observed.

No drug-related external, visceral, or skeletal abnormalities were observed in fetuses of pregnant rabbits and pregnant monkeys at doses more than 225 times and 12 times the usual maximum recommended human dose, respectively.

The use of prazosin and a beta-blocker for the control of severe hypertension in 44 pregnant women revealed no drug-related fetal abnormalities or adverse effects.

Therapy with prazosin was continued for as long as 14 weeks.1 Prazosin has also been used alone or in combination with other hypotensive agents in severe hypertension of pregnancy by other investigators.

No fetal or neonatal abnormalities have been reported with the use of prazosin.2 There are no adequate and well controlled studies which establish the safety of prazosin hydrochloride capsules in pregnant women.

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

NUSRING MOTHERS

Nursing Mothers Prazosin has been shown to be excreted in small amounts in human milk.

Caution should be exercised when prazosin hydrochloride capsules are administered to a nursing woman.

INFORMATION FOR PATIENTS

Information for Patients Dizziness or drowsiness may occur after the first dose of this medicine.

Avoid driving or performing hazardous tasks for the first 24 hours after taking this medicine or when the dose is increased.

Dizziness, lightheadedness, or fainting may occur, especially when rising from a lying or sitting position.

Getting up slowly may help lessen the problem.

These effects may also occur if you drink alcohol, stand for long periods of time, exercise, or if the weather is hot.

While taking prazosin hydrochloride capsules, be careful in the amount of alcohol you drink.

Also, use extra care during exercise or hot weather, or if standing for long periods.

Check with your physician if you have any questions.

DOSAGE AND ADMINISTRATION

The dose of prazosin hydrochloride capsules should be adjusted according to the patient’s individual blood pressure response.

The following is a guide to its administration: Initial Dose 1 mg two or three times a day (see WARNINGS ).

Maintenance Dose Dosage may be slowly increased to a total daily dose of 20 mg given in divided doses.

The therapeutic dosages most commonly employed have ranged from 6 mg to 15 mg daily given in divided doses.

Doses higher than 20 mg usually do not increase efficacy, however a few patients may benefit from further increases up to a daily dose of 40 mg given in divided doses.

After initial titration some patients can be maintained adequately on a twice daily dosage regimen.

Use With Other Drugs When adding a diuretic or other antihypertensive agent, the dose of prazosin hydrochloride capsules should be reduced to 1 mg or 2 mg three times a day and retitration then carried out.

Concomitant administration of prazosin hydrochloride capsules with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension; therefore, PDE-5 inhibitor therapy should be initiated at the lowest dose in patients taking prazosin hydrochloride capsules.

estradiol valerate 3 MG Oral Tablet

Generic Name: ESTRADIOL VALERATE AND ESTRADIOL VALERATE/DIENOGEST
Brand Name: Natazia

DRUG INTERACTIONS

7 Consult the labeling of all concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations .

Drugs or herbal products that induce certain enzymes (for example, CYP3A4) may decrease the effectiveness of COCs or increase breakthrough bleeding.

Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs.

( 7.1 ) 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances diminishing the efficacy of COCs: Dienogest is a substrate of CYP3A4.

Women who take medications that are strong CYP3A4 inducers should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of increased breakthrough bleeding and/or decreased contraceptive efficacy.

Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding.

Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampin, topiramate and products containing St.

John’s wort.

Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure.

Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability.

Multiple dose co-administration of the strong CYP3A4 inducer rifampin with estradiol valerate/dienogest tablets in healthy postmenopausal women led to a decrease in dienogest and estradiol systemic exposure at steady state.

[See Clinical Pharmacology (12.3).] Substances Increasing the Systemic Exposure of COCs (enzyme inhibitors): Concomitant administration of moderate or strong CYP3A4 inhibitors like azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit increase the serum concentrations of both estradiol and dienogest.

In a multiple dose study investigating the effect of CYP3A4 inhibitors (ketoconazole and erythromycin) on Natazia, steady state estradiol and dienogest exposures were increased when co-administered with ketoconazole or erythromycin [see Clinical Pharmacology 12.3] .

Human Immunodeficiency Virus (HIV)/Hepatitis C Virus (HCV) Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors : Significant changes (increase and decrease) in plasma concentrations of estrogen and progestin have been noted in some cases of co-administration of HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors.

Antibiotics : There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids.

7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing ethinyl estradiol may inhibit the metabolism of other compounds.

COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation.

This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.

Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations.

[See Clinical Pharmacology ( 12.3 ).] In vitro studies with human CYP enzymes did not indicate an inhibitory potential of dienogest at clinically relevant concentrations.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs.

7.3 Interference with Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7.2 )].

OVERDOSAGE

10 There have been no reports of serious ill effects from overdose, including ingestion by children.

Overdosage may cause withdrawal bleeding in females and nausea.

DESCRIPTION

11 Natazia (estradiol valerate and estradiol valerate/dienogest) tablets provide an oral contraceptive regimen consisting of 26 active film-coated tablets that contain the active ingredients specified for each tablet below, followed by two inert film-coated tablets: • 2 dark yellow tablets each containing 3 mg estradiol valerate • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets each containing 1 mg estradiol valerate • 2 white tablets (inert) Natazia also contains the excipients lactose monohydrate, maize starch, maize starch pre-gelatinized, povidone 25, magnesium stearate, hypromellose, macrogol 6000, talc, titanium dioxide, and ferric oxide pigment, yellow, or ferric oxide pigment, red.

The empirical formula of estradiol valerate is C 23 H 32 O 3 and the chemical structure is: Estradiol Valerate The chemical name of estradiol valerate is Estra-1,3,5(10)-triene-3,17-diol(17ß)-,17-pentanoate.

The empirical formula of dienogest is C 20 H 25 NO 2 and the chemical structure is: Dienogest The chemical name of dienogest is (17α)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile.

Chemical Strcuture EV Dienogest Chemical Structure

CLINICAL STUDIES

14 14.1 Oral Contraceptive Clinical Trials The study conducted in North America (U.S.

and Canada) was a multicenter, open-label, single-arm, unintended pregnancy study.

There were 490 healthy subjects between 18 and 35 years of age (mean age: 25.1 years) who were treated for up to 28 cycles of 28 days each.

The racial demographic of enrolled women was: Caucasian (76%), Hispanic (13%), African-American (7%), Asian (3%), and Other (1%).

The weight range for treated women was 40 to 100 kg (mean weight: 62.5 kg) and the BMI range was 14 to 30 kg/m 2 (mean BMI: 23.3 kg/m 2 ).

Of treated women, 15% discontinued the study treatment due to an adverse event, 13% were lost to follow up, 10% withdrew their consent, 8% discontinued due to other reason, 1% discontinued due to protocol deviation, and 1% discontinued due to pregnancy.

The study conducted in Europe (Germany, Austria and Spain) was a multicenter, open-label, single-arm contraceptive reliability study.

There were 1,377 healthy subjects between 18 and 50 years of age (mean age: 30.3 years) who were treated for 20 cycles of 28 days each.

The racial demographic of enrolled women was predominantly Caucasian (99.2%).

The weight range for treated women was 38 to 98 kg (mean weight: 63.8 kg) and the BMI range was 15 to 31.8 kg/m 2 (mean BMI: 22.8 kg/m 2 ).

Of treated women, 10% discontinued the study treatment due to an adverse event, 5% discontinued due to other reason, 2% were lost to follow up, 2% discontinued due to protocol deviation, 2% withdrew their consent, and 1% discontinued due to pregnancy.

The Pearl Index (PI) was the primary efficacy endpoint used to assess contraceptive reliability and was assessed in each of the two studies, assuming all subjects were at risk of pregnancy in all medication cycles unless back-up contraception was documented.

The PI is based on pregnancies that occurred after the onset of treatment and within 7 days after the last pill intake.

Cycles in which conception did not occur, but which included the use of back-up contraception, were not included in the calculation of the PI.

The PI also includes patients who did not take the drug correctly.

The estimated PI for the North American study is 1.64 and the estimated PI for the European study is 1.04.

The Kaplan-Meier method was also used to calculate the contraceptive failure rate.

The summary of the Pearl Indexes and cumulative contraceptive failure rates are provided in Table 2: Table 2 Summary of the Pearl Indexes and the Cumulative Contraceptive Failure Rates Study Age Group Relative Treatment Exposure Cycles Total treatment exposure time without back-up contraception Number of Pregnancies within 13 Cycles and 7 Days after Last Treatment Pearl Index Upper Limit of 95% CI Contraceptive Failure Rate at the End of First Year North America 18–35 3,969 5 1.64 3.82 0.016 Europe 18–35 11,275 9 1.04 1.97 0.010 14.2 Heavy Menstrual Bleeding Clinical Trials The efficacy and safety of Natazia were evaluated in two multi-regional, multicenter, double-blind, randomized, placebo-controlled clinical trials.

Study 308960 was performed in the United States and Canada and Study 308961 was performed in Australia and 9 European countries.

The studies were identical in design.

The studies enrolled women, 18 years of age or older, with a diagnosis of dysfunctional uterine bleeding characterized as heavy, prolonged and/or frequent bleeding without organic pathology.

Heavy menstrual bleeding (HMB) was defined as menstrual blood loss of 80 mL or more in at least 2 bleeding episodes.

The diagnosis of HMB was documented through the collection of used sanitary protection (pads and tampons) to quantify blood loss assessed by the alkaline hematin method.

Overall, about 85% of the subjects qualified for the study because they had heavy menstrual bleeding symptoms.

A total of 421 women with a mean age of 38.2 and a mean BMI of 25.5 were randomized to the two clinical studies, for a total of 269 women in the Natazia group and 152 women in the placebo group, and treated for seven 28-day cycles.

Approximately 81% were Caucasian, 13% were Black, and 6% were Hispanic or Asian or Other.

The primary efficacy variable was the proportion of subjects who were completely relieved of symptoms, which was defined by the number of subjects with the absence of any dysfunctional bleeding symptom and who met up to 8 strictly defined criteria for success during the 90-day efficacy assessment phase.

In Study 308960, the proportion of the intent-to-treat subjects with complete symptom relief was 29.2% in the Natazia group compared to 2.9% in the placebo group.

In Study 308961, the proportion of the intent-to-treat subjects with complete symptom relief was 29.5% in the Natazia group compared to 1.2% in the placebo group.

In both studies, Natazia was effective in treating the symptoms of HMB in the subset of women who entered the study with symptoms specific to HMB.

Among patients with HMB, menstrual blood loss (MBL) was statistically significantly reduced in the group treated with Natazia compared with placebo (p<0.0001 for both studies).

Evaluating data based on 28-day cycles, the median menstrual blood volume at Cycle 7 was reduced from the baseline median by 90% in one trial and 87% in the other.

For women treated with placebo, the median menstrual blood volume at Cycle 7 was reduced from the baseline median by 14% and 32% in the two trials, respectively.

Figures 1 and 2 display the MBL volume by cycle and by study.

Figure 2: Median Menstrual Blood Loss Volume by Cycle (Study 308960) Figure 3: Median Menstrual Blood Loss Volume by Cycle (Study 308961) Figure 1 Figure 2

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Natazia (estradiol valerate and estradiol valerate/dienogest) tablets are available in packages of three blister packs (NDC 50419-409-03).

The active and inert film-coated tablets are rounded with biconvex faces, one side is embossed with a regular hexagon shape with the letters DD or DJ or DH or DN or DT.

Each blister pack (28 film-coated tablets) contains in the following order: • 2 round biconvex dark yellow film-coated tablets with embossed “DD” in a regular hexagon on one side each containing 3 mg estradiol valerate • 5 round biconvex medium red film-coated tablets with embossed “DJ” in a regular hexagon on one side each containing 2 mg estradiol valerate and 2 mg dienogest • 17 round biconvex light yellow film-coated tablets with embossed “DH” in a regular hexagon on one side each containing 2 mg estradiol valerate and 3 mg dienogest • 2 round biconvex dark red film-coated tablets with embossed “DN” in a regular hexagon on one side each containing 1 mg estradiol valerate • 2 white round biconvex white film-coated tablets with embossed “DT” in a regular hexagon on one side (inert) 16.2 Storage Store at 25º C (77º F); excursions permitted to 15–30 o C (59–86 o F) [see USP Controlled Room Temperature] .

RECENT MAJOR CHANGES

Warnings and Precautions ( 5.2 ) 4/2022

GERIATRIC USE

8.5 Geriatric Use Natazia has not been studied in postmenopausal women and is not indicated in this population.

DOSAGE FORMS AND STRENGTHS

3 Natazia (estradiol valerate and estradiol valerate/dienogest) tablets are available in blister packs.

Each blister pack contains 28 round, biconvex, film-coated tablets in the following order: • 2 dark yellow tablets, with an embossed “DD” in a regular hexagon on one side, each containing 3 mg estradiol valerate • 5 medium red tablets, with an embossed “DJ” in a regular hexagon on one side, each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets, with an embossed “DH” in a regular hexagon on one side, each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets, with an embossed “DN” in a regular hexagon on one side, each containing 1 mg estradiol valerate • 2 white tablets (inert), with an embossed “DT” in a regular hexagon on one side Natazia consists of 28 film-coated, unscored tablets in the following order ( 3 ): • 2 dark yellow tablets each containing 3 mg estradiol valerate • 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest • 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest • 2 dark red tablets each containing 1 mg estradiol valerate • 2 white tablets (inert)

MECHANISM OF ACTION

12.1 Mechanism of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation.

Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation.

INDICATIONS AND USAGE

1 • Natazia is an estrogen/progestin COC indicated for use by women to prevent pregnancy.

( 1 ) • Treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception.

( 1.2 ) • The efficacy of Natazia in women with a body mass index (BMI) of >30 kg/m 2 has not been evaluated.

( 1 , 8.8 ) 1.1 Oral Contraception Natazia ® is indicated for use by women to prevent pregnancy.

The efficacy of Natazia in women with a body mass index (BMI) of > 30 kg/m 2 has not been evaluated.

1.2 Heavy Menstrual Bleeding Natazia is also indicated for the treatment of heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception [see Clinical Studies ( 14.2 )].

PEDIATRIC USE

8.4 Pediatric Use Safety and efficacy of Natazia have been established in women of reproductive age.

Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older.

Use of this product before menarche is not indicated.

PREGNANCY

8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy.

Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy.

The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy.

COCs should not be used during pregnancy to treat threatened or habitual abortion.

Women who do not breastfeed may start COCs no earlier than four weeks postpartum.

NUSRING MOTHERS

8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child.

Estrogen-containing COCs can reduce milk production in breastfeeding mothers.

This is less likely to occur once breastfeeding is well-established; however, it can occur at any time in some women.

Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk.

BOXED WARNING

WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use.

This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked.

For this reason, COCs should not be used by women who are over 35 years of age and smoke.

[See Contraindications ( 4 ).] WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning.

• Women over 35 years old who smoke should not use Natazia.

( 4 ) • Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use.

( 4 )

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Vascular risks : Stop Natazia if a thrombotic event occurs.

Stop Natazia at least 4 weeks before and through 2 weeks after major surgery.

Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding.

( 5.1 ) • Liver disease : Discontinue Natazia if jaundice occurs.

( 5.3 ) • High blood pressure : Do not prescribe Natazia for women with uncontrolled hypertension or hypertension with vascular disease.

( 5.4 ) • Carbohydrate and lipid metabolic effects : Monitor prediabetic and diabetic women taking Natazia.

Consider an alternate contraceptive method for women with uncontrolled dyslipidemia.

( 5.6 ) • Headache : Evaluate significant change in headaches and discontinue Natazia if indicated.

( 5.7 ) • Uterine bleeding : Evaluate irregular bleeding or amenorrhea.

( 5.8 ) • CYP3A4 induction : Women taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St.

John’s wort) should not choose Natazia as their oral contraceptive due to the possibility of decreased contraceptive efficacy.

( 5.13 , 7.1 ) 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Natazia if an arterial or venous thrombotic event (VTE) occurs.

The use of COCs increases the risk of venous thromboembolism.

However, pregnancy increases the risk of venous thromboembolism as much or more than the use of COCs.

The risk of VTE in women using COCs has been estimated to be 3 to 9 per 10,000 woman-years.

The risk of VTE is highest during the first year of use.

Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-COC users, is greatest during the first 6 months of COC use.

Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.

Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events.

The risk of thromboembolic disease due to oral contraceptives gradually disappears after COC use is discontinued.

If feasible, stop Natazia at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism.

Start Natazia no earlier than 4 weeks after delivery, in women who are not breastfeeding.

The risk of postpartum thromboembolism decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week.

COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), hypertensive women who also smoke.

COCs also increase the risk for stroke in women with other underlying risk factors.

Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.

Stop Natazia if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.

Evaluate for retinal vein thrombosis immediately.

[See Adverse Reactions ( 6 ).] 5.2 Malignant Neoplasms Breast Cancer Natazia is contraindicated in females who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see Contraindications ( 4 )].

Epidemiology studies have not found a consistent association between use of combined oral contraceptives (COCs) and breast cancer risk.

Studies do not show an association between ever (current or past) use of COCs and risk of breast cancer.

However, some studies report a small increase in the risk of breast cancer among current or recent users (<6 months since last use) and current users with longer duration of COC use [see Adverse Reactions ( 6.2 )] .

Cervical Cancer Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia.

However, there is controversy about the extent to which these findings may be due to differences in sexual behavior and other factors.

5.3 Liver Disease Discontinue Natazia if jaundice develops.

Steroid hormones may be poorly metabolized in patients with impaired liver function.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded.

Hepatic adenomas are associated with COC use.

An estimate of the attributable risk is 3.3 cases/100,000 COC users.

Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage.

Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users.

However, the attributable risk of liver cancers in COC users is less than one case per million users.

Oral contraceptive-related cholestasis may occur in women with a history of pregnancy-related cholestasis.

Women with a history of COC-related cholestasis may have the condition recur with subsequent COC use.

5.4 High Blood Pressure For women with well-controlled hypertension, monitor blood pressure and stop Natazia if blood pressure rises significantly.

Women with uncontrolled hypertension or hypertension with vascular disease should not use COCs.

An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use.

The incidence of hypertension increases with increasing concentration of progestin.

5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users.

5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Natazia.

COCs may decrease glucose tolerance in a dose-related fashion.

Consider alternative contraception for women with uncontrolled dyslipidemia.

A small proportion of women will have adverse lipid changes while on COCs.

Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

5.7 Headache If a woman taking Natazia develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Natazia if indicated.

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

5.8 Bleeding Irregularities Breakthrough bleeding and spotting sometimes occur in patients on COCs, especially during the first three months of use.

If bleeding persists or occurs after previously regular cycles, check for causes such as pregnancy or malignancy.

If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC.

Women who are not pregnant and use Natazia, may experience amenorrhea.

Based on patient diaries, amenorrhea occurs in approximately 16% of cycles in women using Natazia.

Pregnancy should be ruled out in the event of amenorrhea occurring in two or more consecutive cycles.

Some women may encounter amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent.

Based on patient diaries from three clinical trials evaluating the safety and efficacy of Natazia for contraception, 10-23% of women experienced intracyclic bleeding per cycle.

5.9 COC Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.

Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy.

Oral contraceptive use should be discontinued if pregnancy is confirmed.

The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see Use in Specific Populations ( 8.1 )] .

5.10 Depression Women with a history of depression should be carefully observed and Natazia discontinued if depression recurs to a serious degree .

5.11 Interference with Laboratory Tests The use of COCs may change the results of some laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins.

Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentrations of thyroid-binding globulin increase with use of COCs [see Clinical Pharmacology ( 12.3 )] .

5.12 Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated healthcare.

5.13 Drug Interactions Women who take medications that are strong cytochrome P450 3A4 (CYP3A4) inducers (for example, carbamazepine, phenytoin, rifampicin, and St.

John’s wort) should not choose Natazia as their oral contraceptive while using these inducers and for at least 28 days after discontinuation of these inducers due to the possibility of decreased contraceptive efficacy [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )].

5.14 Other Conditions In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum.

Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See “FDA-approved patient labeling (Patient Information).” • Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs.

• Counsel patients that the increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4 week or greater pill-free interval) the same or a different COC.

• Counsel patients that Natazia does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

• Counsel patients on Warnings and Precautions associated with COCs.

• Inform patients that Natazia is not indicated during pregnancy.

If pregnancy occurs during treatment with Natazia, instruct the patient to stop further intake.

• Counsel patients to take one tablet daily by mouth at the same time every day in the exact order noted on the blister.

Instruct patients what to do in the event pills are missed.

See What Should I Do if I Miss any Pills section in FDA-Approved Patient Labeling.

• Counsel women who are taking strong CYP3A4 inducers (for example, carbamazepine, phenytoin, rifampicin, and St.

John’s wort) not to choose Natazia as their oral contraceptive due to the possibility of decreased contraceptive efficacy.

• Counsel patients to use a back-up or alternative method of contraception when weak or moderate enzyme inducers are used with Natazia.

• Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce breast milk production.

This is less likely to occur if breastfeeding is well established.

• Counsel any patient who starts COCs postpartum, and who has not yet had a period, to use an additional method of contraception until she has taken Natazia for 9 consecutive days.

• Counsel patients that amenorrhea may occur.

Rule out pregnancy in the event of amenorrhea in two or more consecutive cycles.

DOSAGE AND ADMINISTRATION

2 • Take one tablet daily by mouth at the same time every day.

( 2.1 ) • Tablets must be taken in the order directed on the blister pack.

( 2.1 ) • Do not skip or delay intake by more than 12 hours.

( 2.1 ) 2.1 How to Take Natazia To achieve maximum contraceptive effectiveness, Natazia must be taken exactly as directed.

Take one tablet by mouth at the same time every day.

Tablets must be taken in the order directed on the blister pack.

Tablets should not be skipped or intake delayed by more than 12 hours.

For patient instructions for missed pills, see FDA-Approved Patient Labeling.

2.2 How to Start Natazia Instruct the patient to begin taking Natazia on Day 1 of her menstrual cycle (that is, the first day of her menstrual bleeding).

See FDA-Approved Patient Labeling .

Instruct the patient to use a non-hormonal contraceptive as back-up during the first 9 days.

For postpartum women who do not breastfeed or after a second trimester abortion, start Natazia no earlier than 4 weeks postpartum due to the increased risk of thromboembolism.

If the patient starts on Natazia postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken Natazia for 9 consecutive days.

The possibility of ovulation and conception prior to initiation of medication should also be considered.

If the patient is switching from a combination hormonal method such as: • Another pill • Vaginal ring • Patch • Instruct her to take the first dark yellow pill on the first day of her withdrawal bleed.

She should not continue taking the pills from her previous birth control pack.

If she does not have a withdrawal bleed, rule out pregnancy before starting Natazia.

• If she previously used a vaginal ring or transdermal patch, she should start using Natazia on the day the ring or patch is removed.

• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.

If the patient is switching from a progestin-only method such as a: • Progestin-only pill • Implant • Intrauterine system • Injection • Instruct her to take the first dark yellow pill on the day she would have taken her next progestin-only pill or on the day of removal of her implant or intrauterine system or on the day when she would have had her next injection.

• Instruct the patient to use a non-hormonal back-up method such as a condom or spermicide for the first 9 days.

2.3 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting or diarrhea occurs within 3-4 hours after taking a colored tablet, this can be regarded as a missed tablet.

Amitiza 8 MCG Oral Capsule

DRUG INTERACTIONS

7 Based upon the results of in vitro human microsome studies, there is low likelihood of drug–drug interactions.

In vitro studies using human liver microsomes indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lubiprostone.

Further in vitro studies indicate microsomal carbonyl reductase may be involved in the extensive biotransformation of lubiprostone to the metabolite M3 (See Pharmacokinetics [12.3] .).

Additionally, in vitro studies in human liver microsomes demonstrate that lubiprostone does not inhibit cytochrome P450 isoforms 3A4, 2D6, 1A2, 2A6, 2B6, 2C9, 2C19, or 2E1, and in vitro studies of primary cultures of human hepatocytes show no induction of cytochrome P450 isoforms 1A2, 2B6, 2C9, and 3A4 by lubiprostone.

No drug–drug interaction studies have been performed.

Based on the available information, no protein binding–mediated drug interactions of clinical significance are anticipated.

OVERDOSAGE

10 There have been two confirmed reports of overdosage with Amitiza.

The first report involved a 3-year-old child who accidentally ingested 7 or 8 capsules of 24 mcg of Amitiza and fully recovered.

The second report was a study patient who self-administered a total of 96 mcg of Amitiza per day for 8 days.

The patient experienced no adverse reactions during this time.

Additionally, in a Phase 1 cardiac repolarization study, 38 of 51 patients given a single oral dose of 144 mcg of Amitiza (6 times the highest recommended dose) experienced an adverse event that was at least possibly related to the study drug.

Adverse reactions that occurred in at least 1% of these patients included the following: nausea (45%), diarrhea (35%), vomiting (27%), dizziness (14%), headache (12%), abdominal pain (8%), flushing/hot flash (8%), retching (8%), dyspnea (4%), pallor (4%), stomach discomfort (4%), anorexia (2%), asthenia (2%), chest discomfort (2%), dry mouth (2%), hyperhidrosis (2%), and syncope (2%).

DESCRIPTION

11 Amitiza (lubiprostone) is chemically designated as (–)-7-[(2 R ,4a R ,5 R ,7a R )-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[ b ]pyran-5-yl]heptanoic acid.

The molecular formula of lubiprostone is C 20 H 32 F 2 O 5 with a molecular weight of 390.46 and a chemical structure as follows: Lubiprostone drug substance occurs as white, odorless crystals or crystalline powder, is very soluble in ether and ethanol, and is practically insoluble in hexane and water.

Amitiza is available as an imprinted, oval, soft gelatin capsule in two strengths.

Pink capsules contain 8 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, ferric oxide, titanium dioxide, and purified water.

Orange capsules contain 24 mcg of lubiprostone and the following inactive ingredients: medium-chain triglycerides, gelatin, sorbitol, FD&C Red #40, D&C Yellow #10, and purified water.

image of chemical structure

CLINICAL STUDIES

14 14.1 Chronic Idiopathic Constipation Dose-finding Study A dose-finding, double-blinded, parallel-group, placebo-controlled, Phase 2 study was conducted in patients with chronic idiopathic constipation.

Following a 2-week baseline/washout period, patients (N = 127) were randomized to receive placebo (n = 33), Amitiza 24 mcg/day (24 mcg once daily; n = 29), Amitiza 48 mcg/day (24 mcg twice daily; n = 32), or Amitiza 72 mcg/day (24 mcg three times daily; n = 33) for 3 weeks.

Patients were chosen for participation based on their need for relief of constipation, which was defined as less than 3 spontaneous bowel movements (SBMs) per week.

The primary efficacy variable was the daily average number of SBMs.

The study demonstrated that all patients who took Amitiza experienced a noticeable improvement in clinical response.

Based on the efficacy analysis, there was no statistically significant improvement in the clinical response beyond a total daily dose of 24 mcg during treatment weeks 2 and 3 (Figure 1).

Figure 1: Weekly Mean (± Standard Error) Spontaneous Bowel Movements (Dose-finding Study) Efficacy Studies Two double-blinded, placebo-controlled studies of identical design were conducted in patients with chronic idiopathic constipation.

Chronic idiopathic constipation was defined as, on average, less than 3 SBMs per week along with one or more of the following symptoms of constipation for at least 6 months prior to randomization: 1) very hard stools for at least a quarter of all bowel movements; 2) sensation of incomplete evacuation following at least a quarter of all bowel movements; and 3) straining with defecation at least a quarter of the time.

Following a 2-week baseline/washout period, a total of 479 patients (mean age 47.2 [range 20–81] years; 88.9% female; 80.8% Caucasian, 9.6% African American, 7.3% Hispanic, 1.5% Asian; 10.9% ≥ 65 years of age) were randomized and received Amitiza 24 mcg twice daily (48 mcg/day) or placebo twice daily for 4 weeks.

The primary endpoint of the studies was SBM frequency.

The studies demonstrated that patients treated with Amitiza had a higher frequency of SBMs during Week 1 than the placebo patients.

In both studies, results similar to those in Week 1 were also observed in Weeks 2, 3, and 4 of therapy (Table 3).

Table 3: Spontaneous Bowel Movement Frequency Rates1 (Efficacy Studies) Trial Study Arm Baseline Mean ± SD Median Week 1 Mean ± SD Median Week 2 Mean ± SD Median Week 3 Mean ± SD Median Week 4 Mean ± SD Median Week 1 Change from Baseline Mean ± SD Median Week 4 Change from Baseline Mean ± SD Median Placebo 1.6 ± 1.3 1.5 3.5 ± 2.3 3.0 3.2 ± 2.5 3.0 2.8 ± 2.2 2.0 2.9 ± 2.4 2.3 1.9 ± 2.2 1.5 1.3 ± 2.5 1.0 Study 1 Amitiza 24 mcg Twice Daily 1.5 ± 0.8 1.5 5.7 ± 4.4 5.0 5.1 ± 4.1 4.0 5.3 ± 4.9 5.0 5.3 ± 4.7 4.0 4.3 ± 4.3 3.5 3.9 ± 4.6 3.0 Placebo 1.5 ± 0.8 1.5 4.0 ± 2.7 3.5 3.6 ± 2.7 3.0 3.4 ± 2.8 3.0 3.5 ± 2.9 3.0 2.5 ± 2.6 1.5 1.9 ± 2.7 1.5 Study 2 Amitiza 24 mcg Twice Daily 1.3 ± 0.9 1.5 5.9 ± 4.0 5.0 5.0 ± 4.2 4.0 5.6 ± 4.6 5.0 5.4 ± 4.8 4.3 4.6 ± 4.1 3.8 4.1 ± 4.8 3.0 1 Frequency rates are calculated as 7 times (number of SBMs) / (number of days observed for that week).

In both studies, Amitiza demonstrated increases in the percentage of patients who experienced SBMs within the first 24 hours after administration when compared to placebo (56.7% vs.

36.9% in Study 1 and 62.9% vs.

31.9% in Study 2, respectively).

Similarly, the time to first SBM was shorter for patients receiving Amitiza than for those receiving placebo.

Signs and symptoms related to constipation, including abdominal bloating, abdominal discomfort, stool consistency, and straining, as well as constipation severity ratings, were also improved with Amitiza versus placebo.

The results were consistent in subpopulation analyses for gender, race, and elderly patients (≥ 65 years of age).

Following 4 weeks of treatment with Amitiza 24 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect.

Long-term Studies Three open-labeled, long-term clinical safety and efficacy studies were conducted in patients with chronic idiopathic constipation receiving Amitiza 24 mcg twice daily.

These studies comprised 871 patients (mean age 51.0 [range 19–86] years; 86.1% female; 86.9% Caucasian, 7.3% African American, 4.5% Hispanic, 0.7% Asian; 18.4% ≥ 65 years of age) who were treated for 6–12 months (24–48 weeks).

Patients provided regular assessments of abdominal bloating, abdominal discomfort, and constipation severity.

These studies demonstrated that Amitiza decreased abdominal bloating, abdominal discomfort, and constipation severity over the 6–12-month treatment periods.

image of figure 1 14.2 Irritable Bowel Syndrome with Constipation Efficacy Studies Two double-blinded, placebo-controlled studies of similar design were conducted in patients with IBS-C.

IBS was defined as abdominal pain or discomfort occurring over at least 6 months with two or more of the following: 1) relieved with defecation; 2) onset associated with a change in stool frequency; and 3) onset associated with a change in stool form.

Patients were sub-typed as having IBS-C if they also experienced two of three of the following: 1) less than 3 spontaneous bowel movements per week, 2) greater than 25% hard stools, and 3) greater than 25% spontaneous bowel movements associated with straining.

Following a 4-week baseline/washout period, a total of 1154 patients (mean age 46.6 [range 18–85] years; 91.6% female; 77.4% Caucasian, 13.2% African American, 8.5% Hispanic, 0.4% Asian; 8.3% greater than or equal to 65 years of age) were randomized and received Amitiza 8 mcg twice daily (16 mcg/day) or placebo twice daily for 12 weeks.

The primary efficacy endpoint was assessed weekly utilizing the patient’s response to a global symptom relief question based on a 7-point, balanced scale (“significantly worse” to “significantly relieved”): “How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week compared to how you felt before you entered the study?” The primary efficacy analysis was a comparison of the proportion of “overall responders” in each arm.

A patient was considered an “overall responder” if the criteria for being designated a “monthly responder” were met in at least 2 of the 3 months on study.

A “monthly responder” was defined as a patient who had reported “significantly relieved” for at least 2 weeks of the month or at least “moderately relieved” in all 4 weeks of that month.

During each monthly evaluation period, patients reporting “moderately worse” or “significantly worse” relief, an increase in rescue medication use, or those who discontinued due to lack of efficacy, were deemed non-responders.

The percentage of patients in Study 1 qualifying as an “overall responder” was 13.8% in the group receiving Amitiza 8 mcg twice daily compared to 7.8% of patients receiving placebo twice daily.

In Study 2, 12.1% of patients in the Amitiza 8 mcg group were “overall responders” versus 5.7% of patients in the placebo group.

In both studies, the treatment differences between the placebo and Amitiza groups were statistically significant.

Results in men: The two randomized, placebo-controlled, double-blinded studies comprised 97 (8.4%) male patients, which is insufficient to determine whether men with IBS-C respond differently to Amitiza from women.

Study 1 also assessed the rebound effect from the withdrawal of Amitiza.

Following 12 weeks of treatment with Amitiza 8 mcg twice daily, withdrawal of Amitiza did not result in a rebound effect.

HOW SUPPLIED

16 /STORAGE AND HANDLING Amitiza is available as an oval, soft gelatin capsule containing 8 mcg or 24 mcg of lubiprostone with “SPI” printed on one side.

Amitiza is available as follows: 8-mcg pink capsule Bottles of 60 ( NDC 54868-6153-0 ) 24-mcg orange capsule Bottles of 60 ( NDC 54868-5971-0 ) Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F).

PROTECT FROM EXTREME TEMPERATURES.

GERIATRIC USE

8.5 Geriatric Use Chronic Idiopathic Constipation The efficacy of Amitiza in the elderly (≥ 65 years of age) subpopulation was consistent with the efficacy in the overall study population.

Of the total number of constipated patients treated in the dose-finding, efficacy, and long-term studies of Amitiza, 15.5% were ≥ 65 years of age, and 4.2% were ≥ 75 years of age.

Elderly patients taking Amitiza (any dosage) experienced a lower incidence rate of associated nausea compared to the overall study population taking Amitiza (18% vs.

29%, respectively).

Irritable Bowel Syndrome with Constipation The safety profile of Amitiza in the elderly (≥ 65 years of age) subpopulation (8.0% were ≥ 65 years of age and 1.8% were ≥ 75 years of age) was consistent with the safety profile in the overall study population.

Clinical studies of Amitiza did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.

DOSAGE FORMS AND STRENGTHS

3 Amitiza is available as an oval, gelatin capsule containing 8 mcg or 24 mcg of lubiprostone.

8-mcg capsules are pink and are printed with “SPI” on one side 24-mcg capsules are orange and are printed with “SPI” on one side Gelatin capsules: 8 mcg and 24 mcg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Lubiprostone is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum.

Lubiprostone acts by specifically activating ClC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A–independent fashion.

By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with chronic idiopathic constipation.

Patch clamp cell studies in human cell lines have indicated that the majority of the beneficial biological activity of lubiprostone and its metabolites is observed only on the apical (luminal) portion of the gastrointestinal epithelium.

Additionally, activation of ClC-2 by lubiprostone has been shown to stimulate recovery of mucosal barrier function via the restoration of tight junction protein complexes in ex vivo studies of ischemic porcine intestine.

INDICATIONS AND USAGE

1 Enter section text here Amitiza is a chloride channel activator indicated for: Treatment of chronic idiopathic constipation in adults (1.1) Treatment of irritable bowel syndrome with constipation in women ≥ 18 years old (1.2) 1.1 Chronic Idiopathic Constipation Amitiza ® is indicated for the treatment of chronic idiopathic constipation in adults.

1.2 Irritable Bowel Syndrome with Constipation Amitiza is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in women ≥ 18 years old.

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been studied.

PREGNANCY

8.1 Pregnancy Teratogenic effects: Pregnancy Category C.

[See Warnings and Precautions (5.1) .] Teratology studies with lubiprostone have been conducted in rats at oral doses up to 2000 mcg/kg/day (approximately 332 times the recommended human dose, based on body surface area), and in rabbits at oral doses of up to 100 mcg/kg/day (approximately 33 times the recommended human dose, based on body surface area).

Lubiprostone was not teratogenic in rats or rabbits.

In guinea pigs, lubiprostone caused fetal loss at repeated doses of 10 and 25 mcg/kg/day (approximately 2 and 6 times the highest recommended human dose, respectively, based on body surface area) administered on days 40 to 53 of gestation.

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

However, during clinical testing of Amitiza, six women became pregnant.

Per protocol, Amitiza was discontinued upon pregnancy detection.

Four of the six women delivered healthy babies.

The fifth woman was monitored for 1 month following discontinuation of study drug, at which time the pregnancy was progressing as expected; the patient was subsequently lost to follow-up.

The sixth pregnancy was electively terminated.

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

If a woman is or becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether lubiprostone is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from lubiprostone, 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Enter section text here Women who could become pregnant should have a negative pregnancy test prior to beginning therapy and should be capable of complying with effective contraceptive measures (8.1) Use during pregnancy only if the potential benefit justifies the potential risk to the fetus (5.1) Patients may experience nausea; concomitant administration of food may reduce this symptom (5.2) Do not prescribe for patients that have severe diarrhea (5.3) Patients taking Amitiza may experience dyspnea within an hour of first dose.

This symptom generally resolves within 3 hours, but may recur with repeat dosing (5.4) Evaluate patients with symptoms suggestive of mechanical gastrointestinal obstruction prior to initiating treatment with Amitiza (5.5) 5.1 Pregnacy The safety of Amitiza in pregnancy has not been evaluated in humans.

In guinea pigs, lubiprostone has been shown to have the potential to cause fetal loss.

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

Women who could become pregnant should have a negative pregnancy test prior to beginning therapy with Amitiza and should be capable of complying with effective contraceptive measures.

See Use in Specific Populations ( 8.1 ).

5.2 Nausea Patients taking Amitiza may experience nausea.

If this occurs, concomitant administration of food with Amitiza may reduce symptoms of nausea.

See Adverse Reactions ( 6.1 ).

5.3 Diarrhea Amitiza should not be prescribed to patients that have severe diarrhea.

Patients should be aware of the possible occurrence of diarrhea during treatment.

Patients should be instructed to inform their physician if severe diarrhea occurs.

See Adverse Reactions ( 6.1 ).

5.4 Dyspnea In clinical trials conducted to study Amitiza in treatment of chronic idiopathic constipation and IBS-C there were reports of dyspnea.

This was reported at 2.5% of the treated chronic idiopathic constipation population and at 0.4% in the treated IBS-C population.

Although not classified as serious adverse events, some patients discontinued treatment on study because of this event.

There have been postmarketing reports of dyspnea when using Amitiza 24 mcg.

Most have not been characterized as serious adverse events, but some patients have discontinued therapy because of dyspnea.

These events have usually been described as a sensation of chest tightness and difficulty taking in a breath, and generally have an acute onset within 30–60 minutes after taking the first dose.

They generally resolve within a few hours after taking the dose, but recurrence has been frequently reported with subsequent doses.

5.5 Bowel Obstruction In patients with symptoms suggestive of mechanical gastrointestinal obstruction, the treating physician should perform a thorough evaluation to confirm the absence of such an obstruction prior to initiating therapy with Amitiza.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Enter section text here 17.1 Dosing Instructions Amitiza should be taken twice daily with food and water to reduce potential symptoms of nausea.

The capsule should be taken once in the morning and once in the evening daily as prescribed.

The capsule should be swallowed whole and should not be broken apart or chewed.

Physicians and patients should periodically assess the need for continued therapy.

Patients on treatment who experience severe nausea, diarrhea, or dyspnea should inform their physician.

Patients taking Amitiza may experience dyspnea within an hour of the first dose.

This symptom generally resolves within 3 hours, but may recur with repeat dosing.

Chronic Idiopathic Constipation Patients should take a single 24 mcg capsule of Amitiza twice daily with food and water.

Irritable Bowel Syndrome with Constipation Patients should take a single 8 mcg capsule of Amitiza twice daily with food and water.

Marketed by: Sucampo Pharma Americas, Inc.

Bethesda, MD 20814 and Takeda Pharmaceuticals America, Inc.

Deerfield, IL 60015 Amitiza ® is a registered trademark of Sucampo Pharmaceuticals, Inc.

Relabeling of “Additional Barcode” by: Physicians Total Care, Inc.

Tulsa, OK 74146

DOSAGE AND ADMINISTRATION

2 Amitiza should be taken twice daily orally with food and water.

Physicians and patients should periodically assess the need for continued therapy.

Chronic idiopathic constipation 24 mcg taken twice daily orally with food and water (2.1) Irritable bowel syndrome with constipation 8 mcg taken twice daily orally with food and water (2.2) 2.1 Chronic Idiopathic Constipation 24 mcg twice daily orally with food and water.

2.2 Irritable Bowel Syndrome with Constipation 8 mcg twice daily orally with food and water.

Cimetidine 400 MG Oral Tablet

Generic Name: CIMETIDINE
Brand Name: Cimetidine
  • Substance Name(s):
  • CIMETIDINE

DRUG INTERACTIONS

Drug Interactions Cimetidine tablets, apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline, and metronidazole, thereby delaying elimination and increasing blood levels of these drugs.

Clinically significant effects have been reported with the warfarin anticoagulants; therefore, close monitoring of prothrombin time is recommended, and adjustment of the anticoagulant dose may be necessary when cimetidine tablets are administered concomitantly.

Interaction with phenytoin, lidocaine, and theophylline has also been reported to produce adverse clinical effects.

However, a crossover study in healthy subjects receiving either 300 mg 4 times daily or 800 mg at bedtime of cimetidine tablets concomitantly with a 300 mg twice-daily dose of theophylline extended-release tablets demonstrated less alteration in steady-state theophylline peak serum levels with the 800 mg at bedtime regimen, particularly in subjects aged 54 years and older.

Data beyond 10 days are not available.

(Note: All patients receiving theophylline should be monitored appropriately, regardless of concomitant drug therapy.) Dosage of the drugs mentioned above and other similarly metabolized drugs, particularly those of low therapeutic ratio or in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping the concomitant administration of cimetidine tablets to maintain optimum therapeutic blood levels.

Alteration of pH may affect absorption of certain drugs (e.g., ketoconazole).

If these products are needed, they should be given at least 2 hours before cimetidine administration.

Additional clinical experience may reveal other drugs affected by the concomitant administration of cimetidine tablets.

OVERDOSAGE

Studies in animals indicate that toxic doses are associated with respiratory failure and tachycardia that may be controlled by assisted respiration and the administration of a beta-blocker.

Reported acute ingestions orally of up to 20 grams have been associated with transient adverse effects similar to those encountered in normal clinical experience.

The usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring, and supportive therapy should be employed.

There have been reports of severe CNS symptoms, including unresponsiveness, following ingestion of between 20 and 40 grams of cimetidine, and extremely rare reports following concomitant use of multiple CNS-active medications and ingestion of cimetidine at doses less than 20 grams.

An elderly, terminally ill dehydrated patient with organic brain syndrome receiving concomitant antipsychotic agents and 4,800 mg of cimetidine intravenously over a 24-hour period experienced mental deterioration with reversal on discontinuation of cimetidine.

There have been two deaths in adults who were reported to have ingested over 40 grams orally on a single occasion.

DESCRIPTION

Cimetidine is a histamine H 2 -receptor antagonist.

Chemically it is N” -cyano- N -methyl- N’ -[2-[[(5-methyl-1 H -imidazol-4-yl)methyl]thio]-ethyl]guanidine.

Its structural formula is: Cimetidine contains an imidazole ring, and is chemically related to histamine.

Cimetidine has a bitter taste and characteristic odor.

Solubility Characteristics Cimetidine is soluble in alcohol, slightly soluble in water, very slightly soluble in chloroform and insoluble in ether.

Each tablet, for oral administration, contains 200 mg, 300 mg, 400 mg or 800 mg cimetidine, USP.

Inactive ingredients are: croscarmellose sodium, crospovidone, hypromellose, lecithin, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, pregelatinized starch (corn), sodium alginate, sodium lauryl sulfate, titanium dioxide, triacetin, vanillin, FD&C Blue No.

1 Aluminum Lake, FD&C Yellow No.

6 Aluminum Lake and D&C Yellow No.

10 Aluminum Lake.

Structural Formula

CLINICAL STUDIES

CLINICAL TRIALS Duodenal Ulcer Cimetidine tablets have been shown to be effective in the treatment of active duodenal ulcer and, at reduced dosage, in maintenance therapy following healing of active ulcers.

Active Duodenal Ulcer Cimetidine tablets accelerate the rate of duodenal ulcer healing.

Healing rates reported in U.S.

and foreign controlled trials with cimetidine tablets are summarized below, beginning with the regimen providing the lowest nocturnal dose.

Table 3.

Duodenal Ulcer Healing Rates with Various Dosage Regimens of Cimetidine Tablets Averages from controlled clinical trials.

Regimen 300 mg 4 times daily 400 mg twice daily 800 mg at bedtime 1600 mg at bedtime Week 4 68% 73% 80% 86% Week 6 80% 80% 89% – Week 8 – 92% 94% – A U.S., double-blind, placebo-controlled, dose-ranging study demonstrated that all once-daily at bedtime regimens of cimetidine tablets were superior to placebo in ulcer healing and that 800 mg of cimetidine tablets at bedtime healed 75% of patients at 4 weeks.

The healing rate with 800 mg at bedtime was significantly superior to 400 mg at bedtime (66%) and not significantly different from 1600 mg at bedtime (81%).

In the U.S.

dose-ranging trial, over 80% of patients receiving 800 mg of cimetidine tablets at bedtime experienced nocturnal pain relief after one day.

Relief from daytime pain was reported in approximately 70% of patients after 2 days.

As with ulcer healing, the 800 mg dose at bedtime was superior to 400 mg at bedtime and not different from 1,600 mg at bedtime.

In foreign, double-blind studies with 800 mg of cimetidine tablets at bedtime, 79% to 85% of patients were healed at 4 weeks.

While short-term treatment with cimetidine tablets can result in complete healing of the duodenal ulcer, acute therapy will not prevent ulcer recurrence after cimetidine tablets have been discontinued.

Some follow-up studies have reported that the rate of recurrence once therapy was discontinued was slightly higher for patients healed on cimetidine tablets than for patients healed on other forms of therapy; however, the patients treated with cimetidine tablets generally had more severe disease.

Maintenance Therapy in Duodenal Ulcer Treatment with a reduced dose of cimetidine tablets have been proven effective as maintenance therapy following healing of active duodenal ulcers.

In numerous placebo-controlled studies conducted worldwide, the percent of patients with observed ulcers at the end of 1 year’s therapy with 400 mg of cimetidine tablets at bedtime was significantly lower (10% to 45%) than in patients receiving placebo (44% to 70%).

Thus, from 55% to 90% of patients were maintained free of observed ulcers at the end of 1 year with 400 mg of cimetidine tablets at bedtime.

Factors such as smoking, duration and severity of disease, gender, and genetic traits may contribute to variations in actual percentages.

Trials of other anti-ulcer therapy, whether placebo-controlled, positive-controlled or open, have demonstrated a range of results similar to that seen with cimetidine tablets.

Active Benign Gastric Ulcer Cimetidine tablets have been shown to be effective in the short-term treatment of active benign gastric ulcer.

In a multicenter, double-blind U.S.

study, patients with endoscopically confirmed benign gastric ulcer were treated with 300 mg of cimetidine tablets 4 times a day or with placebo for 6 weeks.

Patients were limited to those with ulcers ranging from 0.5 to 2.5 cm in size.

Endoscopically confirmed healing at 6 weeks was seen in significantly* more patients treated with cimetidine tablets than in patients receiving placebo, as shown below: Table 4.

Rate of Endoscopically Confirmed Gastric Ulcer Healing Cimetidine Tablets (300 mg, 4 times daily) Placebo Week 2 14/63 (22%) 7/63 (11%) Total at week 6 43/65 (66%) p < 0.05 30/67 (45%) In a similar multicenter U.S.

study of the 800 mg bedtime oral regimen, the endoscopically confirmed healing rates were: Table 5.

Rate of Endoscopically Confirmed Gastric Ulcer Healing Cimetidine Tablets (800 mg at bedtime) Placebo Total at week 6 63/83 (76%) p = 0.005 44/80 (55%) Similarly, in worldwide double-blind clinical studies, endoscopically evaluated benign gastric ulcer healing rates were consistently higher with cimetidine tablets than with placebo.

Gastroesophageal Reflux Disease In 2 multicenter, double-blind, placebo-controlled studies in patients with gastroesophageal reflux disease (GERD) and endoscopically proven erosions and/or ulcers, cimetidine tablets were significantly more effective than placebo in healing lesions.

The endoscopically confirmed healing rates were: Table 6.

Rate of Endoscopically Confirmed Healing of Erosions and/or Ulcers Trial Cimetidine Tablets (800 mg twice daily) Cimetidine Tablets (400 mg 4 times daily) Placebo p-Value (800 mg twice daily vs.

placebo) 1 Week 6 45% 52% 26% 0.02 Week 12 60% 66% 42% 0.02 2 Week 6 50% 20% <0.01 Week 12 67% 36% <0.01 In these trials cimetidine tablets were superior to placebo by most measures in improving symptoms of day- and night-time heartburn, with many of the differences statistically significant.

The 4 times-daily regimen was generally somewhat better than the twice-daily regimen where these were compared.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome): Cimetidine tablets significantly inhibited gastric acid secretion and reduced occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis, and multiple endocrine adenomas.

Use of cimetidine tablets were also followed by healing of intractable ulcers.

HOW SUPPLIED

Cimetidine Tablets, USP are available containing 200 mg, 300 mg, 400 mg or 800 mg of cimetidine, USP.

The 200 mg tablets are green, film-coated, five-sided, house-shaped, unscored tablets debossed with M on one side and 53 on the other side.

They are available as follows: NDC 0378-0053-01 bottles of 100 tablets The 300 mg tablets are green, film-coated, five-sided, house-shaped, unscored tablets debossed with M on one side and 317 on the other side.

They are available as follows: NDC 0378-0317-01 bottles of 100 tablets The 400 mg tablets are green, film-coated, five-sided, house-shaped, partially scored tablets debossed with M on one side and 372 on the other side.

They are available as follows: NDC 0378-0372-01 bottles of 100 tablets The 800 mg tablets are green, film-coated, oval, partially scored tablets debossed with M 541 across the partial score.

They are available as follows: NDC 0378-0541-01 bottles of 100 tablets Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Revised: 7/2019 CIM:R14

INDICATIONS AND USAGE

Cimetidine tablets are indicated in: 1.

Short-term treatment of active duodenal ulcer.

Most patients heal within 4 weeks and there is rarely reason to use cimetidine tablets at full dosage for longer than 6 to 8 weeks (see DOSAGE AND ADMINISTRATION: Duodenal Ulcer ).

Concomitant antacids should be given as needed for relief of pain.

However, simultaneous administration of cimetidine tablets and antacids is not recommended, since antacids have been reported to interfere with the absorption of cimetidine.

2.

Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of active ulcer.

Patients have been maintained on continued treatment with cimetidine tablets 400 mg at bedtime for periods of up to 5 years.

3.

Short-term treatment of active benign gastric ulcer.

There is no information concerning usefulness of treatment periods of longer than 8 weeks.

4.

Erosive gastroesophageal reflux (GERD).

Erosive esophagitis diagnosed by endoscopy.

Treatment is indicated for 12 weeks for healing of lesions and control of symptoms.

The use of cimetidine tablets beyond 12 weeks has not been established (see DOSAGE AND ADMINISTRATION: GERD ).

5.

The treatment of pathological hypersecretory conditions (i.e., Zollinger-Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas).

PEDIATRIC USE

Pediatric Use Clinical experience in children is limited.

Therefore, therapy with cimetidine tablets cannot be recommended for children under 16, unless, in the judgement of the physician, anticipated benefits outweigh the potential risks.

In very limited experience, doses of 20 to 40 mg/kg/day have been used.

PREGNANCY

Pregnancy Teratogenic Effects.

Pregnancy Category B Reproduction studies have been performed in rats, rabbits and mice at doses up to 40 times the normal human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cimetidine tablets.

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

Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

Nursing Mothers Cimetidine is secreted in human milk and, as a general rule, nursing should not be undertaken while a patient is on a drug.

DOSAGE AND ADMINISTRATION

Duodenal Ulcer Active Duodenal Ulcer Clinical studies have indicated that suppression of nocturnal acid is the most important factor in duodenal ulcer healing (see CLINICAL PHARMACOLOGY: Antisecretory Activity: Acid Secretion ).

This is supported by recent clinical trials (see CLINICAL TRIALS: Duodenal Ulcer: Active Duodenal Ulcer ).

Therefore, there is no apparent rationale, except for familiarity with use, for treating with anything other than a once-daily at bedtime dosage regimen.

In a U.S.

dose-ranging study of 400 mg at bedtime, 800 mg at bedtime and 1600 mg at bedtime, a continuous dose-response relationship for ulcer healing was demonstrated.

However, 800 mg at bedtime is the dose of choice for most patients, as it provides a high healing rate (the difference between 800 mg at bedtime and 1,600 mg at bedtime being small), maximal pain relief, a decreased potential for drug interactions (see PRECAUTIONS: Drug Interactions ) and maximal patient convenience.

Patients unhealed at 4 weeks, or those with persistent symptoms, have been shown to benefit from 2 to 4 weeks of continued therapy.

It has been shown that patients who both have an endoscopically demonstrated ulcer larger than 1.0 cm and are also heavy smokers (i.e., smoke 1 pack of cigarettes or more per day) are more difficult to heal.

There is some evidence which suggests that more rapid healing can be achieved in this subpopulation with 1,600 mg of cimetidine tablets at bedtime.

While early pain relief with either 800 mg at bedtime or 1,600 mg at bedtime is equivalent in all patients, 1,600 mg at bedtime provides an appropriate alternative when it is important to ensure healing within 4 weeks for this subpopulation.

Alternatively, approximately 94% of all patients will also heal in 8 weeks with 800 mg of cimetidine tablets at bedtime.

Other regimens of cimetidine tablets in the United States which have been shown to be effective are: 300 mg 4 times daily, with meals and at bedtime, the original regimen with which U.S.

physicians have the most experience, and 400 mg twice daily, in the morning and at bedtime (see CLINICAL TRIALS: Duodenal Ulcer: Active Duodenal Ulcer ).

Concomitant antacids should be given as needed for relief of pain.

However, simultaneous administration of cimetidine tablets and antacids is not recommended, since antacids have been reported to interfere with the absorption of cimetidine.

While healing with cimetidine tablets often occurs during the first week or two, treatment should be continued for 4 to 6 weeks unless healing has been demonstrated by endoscopic examination.

Maintenance Therapy for Duodenal Ulcer In those patients requiring maintenance therapy, the recommended adult oral dose is 400 mg at bedtime.

Active Benign Gastric Ulcer The recommended adult oral dosage for short-term treatment of active benign gastric ulcer is 800 mg at bedtime, or 300 mg 4 times a day with meals and at bedtime.

Controlled clinical studies were limited to 6 weeks of treatment (see CLINICAL TRIALS ).

A dose of 800 mg at bedtime is the preferred regimen for most patients based upon convenience and reduced potential for drug interactions.

Symptomatic response to cimetidine tablets does not preclude the presence of a gastric malignancy.

It is important to follow gastric ulcer patients to assure rapid progress to complete healing.

Erosive Gastroesophageal Reflux Disease (GERD) The recommended adult oral dosage for the treatment of erosive esophagitis that has been diagnosed by endoscopy is 1,600 mg daily in divided doses (800 mg twice daily or 400 mg 4 times daily) for 12 weeks.

The use of cimetidine tablets beyond 12 weeks has not been established.

Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome) Recommended adult oral dosage: 300 mg 4 times a day with meals and at bedtime.

In some patients it may be necessary to administer higher doses more frequently.

Doses should be adjusted to individual patient needs, but should not usually exceed 2,400 mg per day and should continue as long as clinically indicated.

Dosage Adjustment for Patients with Impaired Renal Function Patients with severely impaired renal function have been treated with cimetidine tablets.

However, such usage has been very limited.

On the basis of this experience the recommended dosage is 300 mg every 12 hours orally.

Should the patient’s condition require, the frequency of dosing may be increased to every 8 hours or even further with caution.

In severe renal failure, accumulation may occur and the lowest frequency of dosing compatible with an adequate patient response should be used.

When liver impairment is also present, further reductions in dosage may be necessary.

Hemodialysis reduces the level of circulating cimetidine tablets.

Ideally, the dosage schedule should be adjusted so that the timing of a scheduled dose coincides with the end of hemodialysis.

Propranolol Hydrochloride 60 MG Oral Tablet

Generic Name: PROPRANOLOL HYDROCHLORIDE
Brand Name: Propranolol Hydrochloride
  • Substance Name(s):
  • PROPRANOLOL HYDROCHLORIDE

WARNINGS

Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy.

Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and the patient should be cautioned against interruption or cessation of therapy without the physician’s advice.

If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of angina pectoris.

Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease who are given propranolol for other indications.

Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS ).

Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS ).

Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure.

Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed.

Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.

In Patients without a History of Heart Failure, continued use of beta blockers can, in some cases, lead to cardiac failure.

Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers.

Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors.

Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics.

In these patients, it may be more difficult to adjust the dosage of insulin.

Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation for surgery.

Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency.

Thyrotoxicosis Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism.

Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm.

Propranolol may change thyroid-function tests, increasing T 4 and reverse T 3 and decreasing T 3 .

Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker.

In one case, this result was reported after an initial dose of 5 mg propranolol.

Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed.

In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure.

DRUG INTERACTIONS

Drug Interactions Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes Because propranolol’s metabolism involves multiple pathways in the cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration with drugs that are metabolized by, or effect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see Drug Interactions under PRECAUTIONS ).

Substrates or Inhibitors of CYP2D6 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir.

No interactions were observed with either ranitidine or lansoprazole.

Substrates or Inhibitors of CYP1A2 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP1A2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan.

Substrates or Inhibitors of CYP2C19 Blood levels and/or toxicity of propranolol may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide.

No interaction was observed with omeprazole.

Inducers of Hepatic Drug Metabolism Blood levels of propranolol may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital.

Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of propranolol, resulting in decreased plasma concentrations.

Cardiovascular Drugs Antiarrhythmics The AUC of propafenone is increased by more than 200% by co-administration of propranolol.

The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two‑three fold increased blood concentration and greater degrees of clinical beta-blockade.

The metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations.

Calcium Channel Blockers The mean C max and AUC of propranolol are increased, respectively, by 50% and 30% by co‑administration of nisoldipine and by 80% and 47%, by co‑administration of nicardipine.

The mean C max and AUC of nifedipine are increased by 64% and 79%, respectively, by co‑administration of propranolol.

Propranolol does not affect the pharmacokinetics of verapamil and norverapamil.

Verapamil does not affect the pharmacokinetics of propranolol.

Non-Cardiovascular Drugs Migraine Drugs Administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (AUC increased by 56% and C max by 37%) or rizatriptan (the AUC and C max were increased by 67% and 75%, respectively).

Theophylline Co-administration of theophylline with propranolol decreases theophylline oral clearance by 30% to 52%.

Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites.

Diazepam does not alter the pharmacokinetics of propranolol.

The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.

Neuroleptic Drugs Co-administration of long-acting propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.

Co-administration of chlorpromazine with propranolol resulted in a 70% increase in propranolol plasma level.

Anti-Ulcer Drugs Co-administration of propranolol with cimetidine, a non-specific CYP450 inhibitor, increased propranolol AUC and C max by 46% and 35%, respectively.

Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in propranolol concentrations.

Co-administration of metoclopramide with the long-acting propranolol did not have a significant effect on propranolol’s pharmacokinetics.

Lipid Lowering Drugs Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.

Co-administration of propranolol with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics.

Propranolol did not have an effect on the pharmacokinetics of fluvastatin.

Warfarin Concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.

Alcohol Concomitant use of alcohol may increase plasma levels of propranolol.

OVERDOSAGE

Propranolol is not significantly dialyzable.

In the event of overdosage or exaggerated response, the following measures should be employed: General: If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration.

Supportive Therapy: Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately.

Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose.

Glucagon should be administered as 50-150 mcg/kg intravenously followed by continuous drip of 1-5 mg/hour for positive chronotropic effect.

Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful.

Epinephrine, however, may provoke uncontrolled hypertension.

Bradycardia can be treated with atropine or isoproterenol.

Serious bradycardia may require temporary cardiac pacing.

The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored.

Isoproterenol and aminophylline may be used for bronchospasm.

DESCRIPTION

Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-.

Its molecular and structural formulae are: Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol.

Its molecular weight is 295.80.

Propranolol hydrochloride is available as 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg tablets for oral administration.

This is the formula for Propranolol Hydrochloride.

The inactive ingredients contained in propranolol hydrochloride tablets, USP are: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow #10 (10 mg, 40 mg and 80 mg tablets), FD&C Blue #1 (20 mg tablet), FD&C Blue #2 (40 mg tablet), FD&C Red #40 (60 mg tablet), FD&C Yellow #6 (10 mg and 80 mg tablets), magnesium stearate, and microcrystalline cellulose.

HOW SUPPLIED

Propranolol Hydrochloride Tablets, USP, 10 mg are orange, round, convex, scored tablets, debossed “54” bisect “82” on one side and debossed “V” on the reverse side.

They are available as follows: Bottles of 100: 0603-5482-21 Bottles of 1000: 0603-5482-32 Propranolol Hydrochloride Tablets, USP, 20 mg are blue, round, flat faced, beveled edge, scored tablets, debossed “54” bisect “83” on one side and debossed “V” on the reverse side.

They are available as follows: Bottles of 100: 0603-5483-21 Bottles of 1000: 0603-5483-32 Propranolol Hydrochloride Tablets, USP, 40 mg are green, round, convex, scored tablets, debossed “54” bisect “84” on one side and debossed “V” on the reverse side.

They are available as follows: Bottles of 100: 0603-5484-21 Bottles of 1000: 0603-5484-32 Propranolol Hydrochloride Tablets, USP, 60 mg are pink, round, convex, scored tablets, debossed “54” bisect “85” on one side and debossed “V” on the reverse side.

They are available as follows: Bottles of 100: 0603-5485-21 Propranolol Hydrochloride Tablets, USP, 80 mg are yellow, round, convex, scored tablets, debossed “54” bisect “86” on one side and debossed “V” on the reverse side.

They are available as follows: Bottles of 100: 0603-5486-21 Bottles of 500: 0603-5486-28 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a well-closed, light-resistant container as defined in the USP.

Protect from light.

GERIATRIC USE

Geriatric In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the clearance of S(-)-enantiomer of propranolol was decreased in the elderly.

Additionally, the half-life of both the R(+)- and S(-)-propranolol were prolonged in the elderly compared with the young (11 hours vs.

5 hours).

Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side-chain oxidation).

Conjugation capacity remains unchanged.

In a study of 32 patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP-ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation).

No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG-conjugation).

MECHANISM OF ACTION

Mechanism of Action The mechanism of the antihypertensive effect of propranolol has not been established.

Factors that may contribute to the antihypertensive action include: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain.

Although total peripheral resistance may increase initially, it readjusts to or below the pretreatment level with chronic use of propranolol.

Effects of propranolol on plasma volume appear to be minor and somewhat variable.

In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction.

Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period.

The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity.

Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action.

In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential.

The significance of the membrane action in the treatment of arrhythmias is uncertain.

The mechanism of the antimigraine effect of propranolol has not been established.

Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.

The specific mechanism of propranolol’s antitremor effects has not been established, but beta-2 (noncardiac) receptors may be involved.

A central effect is also possible.

Clinical studies have demonstrated that propranolol is of benefit in exaggerated physiological and essential (familial) tremor.

INDICATIONS AND USAGE

Hypertension Propranolol hydrochloride tablets, USP are indicated in the management of hypertension.

It may be used alone or used in combination with other antihypertensive agents, particularly a thiazide diuretic.

Propranolol hydrochloride tablets, USP are not indicated in the management of hypertensive emergencies.

Angina Pectoris Due to Coronary Atherosclerosis Propranolol hydrochloride tablets, USP are indicated to decrease angina frequency and increase exercise tolerance in patients with angina pectoris.

Atrial Fibrillation Propranolol hydrochloride tablets, USP are indicated to control ventricular rate in patients with atrial fibrillation and a rapid ventricular response.

Myocardial Infarction Propranolol hydrochloride tablets, USP are indicated to reduce cardiovascular mortality in patients who have survived the acute phase of myocardial infarction and are clinically stable.

Migraine Propranolol hydrochloride tablets, USP are indicated for the prophylaxis of common migraine headache.

The efficacy of propranolol in the treatment of a migraine attack that has started has not been established, and propranolol is not indicated for such use.

Essential Tremor Propranolol hydrochloride tablets, USP are indicated in the management of familial or hereditary essential tremor.

Familial or essential tremor consists of involuntary, rhythmic, oscillatory movements, usually limited to the upper limbs.

It is absent at rest, but occurs when the limb is held in a fixed posture or position against gravity and during active movement.

Propranolol hydrochloride tablets, USP cause a reduction in the tremor amplitude, but not in the tremor frequency.

Propranolol hydrochloride tablets, USP are not indicated for the treatment of tremor associated with Parkinsonism.

Hypertrophic Subaortic Stenosis Propranolol hydrochloride tablets, USP improve NYHA functional class in symptomatic patients with hypertrophic subaortic stenosis.

Pheochromocytoma Propranolol hydrochloride tablets, USP are indicated as an adjunct to alpha-adrenergic blockade to control blood pressure and reduce symptoms of catecholamine-secreting tumors.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established.

Bronchospasm and congestive heart failure have been reported coincident with the administration of propranolol therapy in pediatric patients.

PREGNANCY

Pregnancy: Pregnancy Category C In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation.

At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths).

Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose).

No evidence of embryo or neonatal toxicity was noted.

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

Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy.

Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression.

Adequate facilities for monitoring such infants at birth should be available.

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

NUSRING MOTHERS

Nursing Mothers Propranolol is excreted in human milk.

Caution should be exercised when propranolol is administered to a nursing woman.

INACTIVE INGREDIENTS

The inactive ingredients contained in propranolol hydrochloride tablets, USP are: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow #10 (10 mg, 40 mg and 80 mg tablets), FD&C Blue #1 (20 mg tablet), FD&C Blue #2 (40 mg tablet), FD&C Red #40 (60 mg tablet), FD&C Yellow #6 (10 mg and 80 mg tablets), magnesium stearate, and microcrystalline cellulose.

DOSAGE AND ADMINISTRATION

General Because of the variable bioavailability of propranolol, the dose should be individualized based on response.

Hypertension The usual initial dosage is 40 mg propranolol hydrochloride twice daily, whether used alone or added to a diuretic.

Dosage may be increased gradually until adequate blood pressure control is achieved.

The usual maintenance dosage is 120 mg to 240 mg per day.

In some instances a dosage of 640 mg a day may be required.

The time needed for full antihypertensive response to a given dosage is variable and may range from a few days to several weeks.

While twice-daily dosing is effective and can maintain a reduction in blood pressure throughout the day, some patients, especially when lower doses are used, may experience a modest rise in blood pressure toward the end of the 12-hour dosing interval.

This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day.

If control is not adequate, a larger dose, or 3‑times‑daily therapy may achieve better control.

Angina Pectoris Total daily doses of 80 mg to 320 mg propranolol hydrochloride, when administered orally, twice a day, three times a day, or four times a day, have been shown to increase exercise tolerance and to reduce ischemic changes in the ECG.

If treatment is to be discontinued, reduce dosage gradually over a period of several weeks.

(See WARNINGS .) Atrial Fibrillation The recommended dose is 10 mg to 30 mg propranolol hydrochloride three or four times daily before meals and at bedtime.

Myocardial Infarction In the Beta-Blocker Heart Attack Trial (BHAT), the initial dose was 40 mg t.i.d., with titration after 1 month to 60 mg to 80 mg t.i.d.

as tolerated.

The recommended daily dosage is 180 mg to 240 mg propranolol hydrochloride per day in divided doses.

Although a t.i.d.

regimen was used in the BHAT and a q.i.d.

regimen in the Norwegian Multicenter Trial, there is a reasonable basis for the use of either a t.i.d.

or b.i.d.

regimen (see PHARMACODYNAMICS AND CLINICAL EFFECTS ).

The effectiveness and safety of daily dosages greater than 240 mg for prevention of cardiac mortality have not been established.

However, higher dosages may be needed to effectively treat coexisting diseases such as angina or hypertension (see above).

Migraine The initial dose is 80 mg propranolol hydrochloride daily in divided doses.

The usual effective dose range is 160 mg to 240 mg per day.

The dosage may be increased gradually to achieve optimum migraine prophylaxis.

If a satisfactory response is not obtained within four to six weeks after reaching the maximum dose, propranolol hydrochloride therapy should be discontinued.

It may be advisable to withdraw the drug gradually over a period of several weeks.

Essential Tremor The initial dosage is 40 mg propranolol hydrochloride twice daily.

Optimum reduction of essential tremor is usually achieved with a dose of 120 mg per day.

Occasionally, it may be necessary to administer 240 mg to 320 mg per day.

Hypertrophic Subaortic Stenosis The usual dosage is 20 mg to 40 mg propranolol hydrochloride three or four times daily before meals and at bedtime.

Pheochromocytoma The usual dosage is 60 mg propranolol hydrochloride daily in divided doses for three days prior to surgery as adjunctive therapy to alpha-adrenergic blockade.

For the management of inoperable tumors, the usual dosage is 30 mg daily in divided doses as adjunctive therapy to alpha-adrenergic blockade.

Xopenex Concentrate 1.25 MG in 0.5 ML Inhalant Solution

Generic Name: LEVALBUTEROL HYDROCHLORIDE
Brand Name: Xopenex
  • Substance Name(s):
  • LEVALBUTEROL HYDROCHLORIDE

DRUG INTERACTIONS

7 Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect.

( 7.1 ) Beta-blockers: May block bronchodilatory effects of beta-agonists and produce severe bronchospasm.

Patients with asthma should not normally be treated with beta-blockers.

( 7.2 ) Diuretic: May worsen electrocardiographic changes or hypokalemia associated with diuretic may worsen.

Consider monitoring potassium levels.

( 7.3 ) Digoxin: May decrease serum digoxin levels.

Consider monitoring digoxin levels.

( 7.4 ) Monoamine oxidase inhibitors (MAOs) or tricyclic antidepressants: May potentiate effect of albuterol on the cardiovascular system.

( 7.5 ) 7.1 Short-Acting Bronchodilators Avoid concomitant use of other short-acting sympathomimetic bronchodilators or epinephrine in patients being treated with XOPENEX Inhalation Solution.

If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

7.2 Beta-blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-adrenergic agonists such as XOPENEX Inhalation Solution, but may produce severe bronchospasm in asthmatic patients.

Therefore, patients with asthma should not normally be treated with beta-blockers.

However, under certain circumstances, e.g., prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma.

In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

7.3 Diuretics The ECG changes or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop and thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.

Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non-potassium-sparing diuretics.

Consider monitoring potassium levels.

7.4 Digoxin Mean decreases of 16% and 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of racemic albuterol, respectively, to normal volunteers who had received digoxin for 10 days.

The clinical significance of these findings for patients with obstructive airway disease who are receiving XOPENEX Inhalation Solution and digoxin on a chronic basis is unclear.

Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and XOPENEX Inhalation Solution.

7.5 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants XOPENEX Inhalation Solution should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of levalbuterol on the vascular system may be potentiated.

Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

OVERDOSAGE

10 The expected symptoms with overdosage are those of excessive beta-adrenergic receptor stimulation and/or occurrence or exaggeration of any of the symptoms listed under Adverse Reactions ( 6 ) , e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness.

Hypokalemia also may occur.

As with all sympathomimetic medications, cardiac arrest and even death may be associated with the abuse of XOPENEX Inhalation Solution.

Treatment consists of discontinuation of XOPENEX Inhalation Solution together with appropriate symptomatic therapy.

The judicious use of a cardio selective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm.

There is insufficient evidence to determine if dialysis is beneficial for overdosage of XOPENEX Inhalation Solution.

DESCRIPTION

11 XOPENEX Inhalation Solution Concentrate is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol.

Levalbuterol HCl is a relatively selective beta 2 -adrenergic receptor agonist [see Clinical Pharmacology ( 12 ) ].

The chemical name for levalbuterol HCl is (R)-α 1 -[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows: The molecular weight of levalbuterol HCl is 275.8, and its empirical formula is C 13 H 21 NO 3 •HCl.

It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.

Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.

XOPENEX Inhalation Solution Concentrate is supplied in 0.5 mL unit-dose vials that must be diluted with normal saline before administration by nebulization.

Each 0.5 mL unit-dose vial contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and hydrochloric acid to adjust the pH to 4.0 (3.3 to 4.5).

Chemical Structure

CLINICAL STUDIES

14 Adults and Adolescents ≥12 Years Old The safety and efficacy of XOPENEX Inhalation Solution were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV 1 60% of predicted).

Approximately half of the patients were also receiving inhaled corticosteroids.

Patients were randomized to receive XOPENEX 0.63 mg, XOPENEX 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb ® portable compressor.

Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) was used on an as-needed basis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV 1 , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29.

On both day 1 (see Figure 1 ) and day 29 (see Figure 2 ), 1.25 mg of XOPENEX demonstrated the largest mean percent change from baseline FEV 1 compared with the other active treatments.

A dose of 0.63 mg of XOPENEX and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV 1 on both day 1 and day 29.

Figure 1: Mean Percent Change from Baseline FEV 1 on Day 1, Adults and Adolescents ≥12 years old Figure 2: Mean Percent Change from Baseline FEV 1 on Day 29, Adults and Adolescents ≥12 years old The mean time to onset of a 15% increase in FEV 1 over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment.

The mean duration of effect, as measured by a >15% increase from baseline FEV 1 , was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment.

In some patients, the duration of effect was as long as 8 hours.

Figure 1 Figure 2 Children 6 to 11 Years Old A multicenter, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV 1 73% of predicted) (n=316).

Following a 1-week placebo run-in, subjects were randomized to XOPENEX (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb ® 3000 compressor.

Efficacy, as measured by mean peak percent change from baseline FEV 1 , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21.

Time profile FEV 1 curves for day 1 and day 21 are shown in Figure 3 and Figure 4 , respectively.

The onset of effect (time to a 15% increase in FEV 1 over test-day baseline) and duration of effect (maintenance of a >15% increase in FEV 1 over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.

Figure 3: Mean Percent Change from Baseline FEV 1 on Day 1, Children 6 to 11 Years of Age Figure 4: Mean Percent Change from Baseline FEV 1 on Day 21, Children 6 to 11 Years of Age Figure 3 Figure 4

HOW SUPPLIED

16 /STORAGE AND HANDLING XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate ( foil pouch label color red ) is supplied in 0.5 mL unit-dose, low-density polyethylene (LDPE) vials as a clear, colorless, sterile, preservative-free, aqueous solution.

Each vial contains 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl) and is available in cartons of 30 (NDC 17478-171-30) individually pouched vials.

XOPENEX Inhalation Solution is also available in 3 mL vials in three different strengths of levalbuterol: 0.31 mg (NDC 17478-172-24), 0.63 mg (NDC 17478-173-24), and 1.25 mg (NDC 17478-174-24).

Store XOPENEX Inhalation Solution Concentrate in the protective foil pouch at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature].

Protect from light and excessive heat.

Open the foil pouch just prior to administration.

Once the foil pouch is opened, the contents of the vial should be used immediately.

Discard any vial if the solution is not colorless.

Dilute XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate with sterile normal saline before administration by nebulization.

GERIATRIC USE

8.5 Geriatric Use Clinical studies of XOPENEX Inhalation Solution did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

Only 5 patients 65 years of age and older were treated with XOPENEX Inhalation Solution in a 4-week clinical study [see Clinical Pharmacology ( 12 ) and Clinical Studies ( 14 ) ] (n=2 for 0.63 mg and n=3 for 1.25 mg).

In these patients, bronchodilation was observed after the first dose on day 1 and after 4 weeks of treatment.

In general, patients 65 years of age and older should be started at a dose of 0.63 mg of XOPENEX Inhalation Solution.

If clinically warranted due to insufficient bronchodilator response, the dose of XOPENEX Inhalation Solution may be increased in elderly patients as tolerated, in conjunction with frequent clinical and laboratory monitoring, to the maximum recommended daily dose [see Dosage and Administration ( 2 ) ].

DOSAGE FORMS AND STRENGTHS

3 Inhalation Solution Concentrate: 0.5 mL unit-dose vials containing 1.25 mg of levalbuterol that must be diluted before use.

XOPENEX Inhalation Solution Concentrate is available in cartons of 30 individually pouched vials.

Inhalation Solution Concentrate (unit-dose vial for nebulization): 1.25 mg/0.5 mL Dilute before use.

( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3´, 5´-adenosine monophosphate (cyclic AMP).

The increase in cyclic AMP is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation.

Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles.

Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges.

While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are beta 2 -adrenergic receptors.

The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 ) ].

However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

INDICATIONS AND USAGE

1 XOPENEX (levalbuterol HCl) Inhalation Solution Concentrate is indicated for the treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

XOPENEX (levalbuterol hydrochloride) Inhalation Solution Concentrate is a beta 2 -adrenergic agonist indicated for: Treatment or prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airway disease.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use Pediatric Patients 6 Years of Age and Older The safety and efficacy of XOPENEX Inhalation Solution have been established in pediatric patients 6 years of age and older in an adequate and well-controlled clinical trial [see Adverse Reactions ( 6 ) and Clinical Studies ( 14 ) ].

Pediatric Patients less than 6 Years of Age XOPENEX Inhalation Solution is not indicated for pediatric patients less than 6 years of age.

Clinical trials with XOPENEX Inhalation Solution in this age group failed to meet the primary efficacy endpoint and demonstrated an increased number of asthma-related adverse reactions following chronic XOPENEX treatment.

XOPENEX Inhalation Solution was studied in 379 pediatric patients less than 6 years of age with asthma or reactive airway disease – (291patients 2 to 5 years of age, and 88 patients from birth to less than 2 years of age).

Efficacy and safety data for XOPENEX Inhalation Solution in this age group are primarily available from one 3-week, multicenter, randomized, double-blind, placebo-controlled study (Study 1) in 211 pediatric patients between the ages of 2 and 5 years, of whom 119 received XOPENEX Inhalation Solution.

Over the 3 week treatment period, there were no significant treatment differences in the Pediatric Asthma Questionnaire (PAQ) total score between groups receiving XOPENEX Inhalation Solution 0.31 mg, XOPENEX Inhalation Solution 0.63 mg, racemic albuterol, and placebo.

Additional safety data following chronic dosing is available from a 4-week, multicenter, randomized, modified-blind, placebo-controlled study (Study 2) of 196 patients between the ages of birth and 3 years, of whom 63 received open-label XOPENEX Inhalation Solution.

In these two studies, treatment-emergent asthma exacerbations or asthma-related adverse reactions and treatment discontinuations due to asthma occurred at a higher frequency in XOPENEX Inhalation-treated subjects compared to control ( Table 5 ).

Other adverse reactions were consistent with those observed in the clinical trial population of patients 6 years of age and older [see Adverse Reactions ( 6.1 )].

Table 5.

Asthma-related Adverse Reactions in 3- and 4-Week Clinical Trials in Children Birth to <6 Years of Age *Asthma exacerbation defined as worsening of asthma symptoms or pulmonary function that required any of the following: emergency department visit, hospitalization, therapeutic intervention with oral or parenteral steroids, unscheduled clinic visit to treat acute asthma symptoms **Includes the following Preferred Terms (whether considered by the investigator to be related or unrelated to drug): asthma, cough, hypoxia, status asthmaticus, tachypnea Asthma Exacerbations* n (%) Treatment Discontinuations due to Asthma n (%) Asthma-related Adverse Reactions** n (%) Study 1 XOPENEX 0.31 mg, n=58 6 (10) 4 (7) — XOPENEX 0.63 mg, n=51 7 (14) 6 (12) — Racemic albuterol, n=52 3 (6) 2 (4) — Placebo, n=50 2 (4) 2 (4) — Study 2 XOPENEX 0.31 mg, n=63 — 2 (3) 6 (10) Levalbuterol HFA inhalation aerosol, n=65 — 1 (2) 8 (12) Placebo, n=68 — 0 3 (4)

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medication, including XOPENEX during pregnancy.

To enroll in MotherToBaby Pregnancy Studies’ Asthma & Pregnancy Study or for more information about the registry, call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-study/asthma.

Risk Summary There are no adequate and well-controlled studies of XOPENEX Inhalation Solution Concentrate in pregnant women.

There are clinical considerations with the use of XOPENEX Inhalation Solution Concentrate in pregnant women [see Clinical Considerations ].

Following oral administration of levalbuterol HCl to pregnant rabbits, there was no evidence of teratogenicity at doses up to 25 mg/kg/day [approximately 108 times the maximum recommended human daily inhalation dose (MRHDID) of levalbuterol HCl for adults on a mg/m 2 basis]; however, racemic albuterol sulfate was teratogenic in mice (cleft palate) and rabbits (cranioschisis) at doses slightly higher than the human therapeutic range ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated populations(s) are unknown.

In the U.S.

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

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate.

Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control.

Labor or Delivery Because of the potential for beta-adrenergic agonists to interfere with uterine contractility, the use of XOPENEX Inhalation Solution for the treatment of bronchospasm during labor should be restricted to those patients for whom the benefits clearly outweigh the risk.

XOPENEX Inhalation Solution has not been approved for the management of preterm labor.

The benefit-risk ratio when XOPENEX is administered for tocolysis has not been established.

Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including racemic albuterol.

Data Animal Data The oral administration of levalbuterol HCl to pregnant New Zealand White rabbits during the period of organogenesis found no evidence of teratogenicity at doses up to 25 mg/kg/day (approximately 108 times the MRHDID of levalbuterol HCl for adults on a mg/m 2 basis).

In a rat development study, racemic albuterol sulfate administered by inhalation did not produce any teratogenic effects at exposure approximately 63 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg).

However, other developmental studies with the racemic albuterol sulfate, did result in teratogenic effects in mice and rabbits at doses slightly higher than the human therapeutic range.

In a rabbit developmental study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 215 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 50 mg/kg).

In a mouse developmental study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure approximately 0.3 times the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg/day) and in 10 of 108 (9.3%) fetuses at approximately 3 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg/day).

Similar effects were not observed at approximately 0.03 times the MRHDID for adults on a mg/m 2 basis at maternal dose of 0.025 mg/kg/day (i.e., less than the therapeutic dose).

Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Life-threatening paradoxical bronchospasm may occur.

Discontinue XOPENEX Inhalation Solution immediately and treat with alternative therapy.

( 5.1 ) Need for more doses of XOPENEX Inhalation Solution than usual may be a sign of deterioration of asthma and requires reevaluation of treatment.

( 5.2 ) XOPENEX Inhalation Solution is not a substitute for corticosteroids.

( 5.3 ) Cardiovascular effects may occur.

Consider discontinuation of XOPENEX Inhalation Solution if these effects occur.

Use with caution in patients with underlying cardiovascular disorders.

( 5.4 ) Excessive use may be fatal.

Do not exceed recommended dose.

( 5.5 ) Immediate hypersensitivity reactions may occur.

Discontinue XOPENEX Inhalation Solution immediately.

( 5.6 ) Hypokalemia and changes in blood glucose may occur.

( 5.7 , 5.8 ) 5.1 Paradoxical Bronchospasm XOPENEX Inhalation Solution can produce paradoxical bronchospasm, which may be life-threatening.

If paradoxical bronchospasm occurs, XOPENEX Inhalation Solution should be discontinued immediately and alternative therapy instituted.

It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new vial.

5.2 Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer.

If the patient needs more doses of XOPENEX Inhalation Solution than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

5.3 Use of Anti-Inflammatory Agents XOPENEX Inhalation Solution is not a substitute for corticosteroids.

The use of beta-adrenergic agonist alone may not be adequate to control asthma in many patients.

Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.

5.4 Cardiovascular Effects XOPENEX Inhalation Solution, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients, as measured by heart rate, blood pressure, and symptoms.

Although such effects are uncommon after administration of XOPENEX Inhalation Solution at recommended doses, if they occur, the drug may need to be discontinued.

In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the t-wave, prolongation of the QTc interval, and ST segment depression.

The clinical significance of these findings is unknown.

Therefore, XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.5 Do Not Exceed Recommended Dose Do not exceed the recommended dose.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma.

The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.

5.6 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of levalbuterol or racemic albuterol.

Reactions have included urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving XOPENEX Inhalation Solution.

5.7 Coexisting Conditions XOPENEX Inhalation Solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmias; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines.

Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after the use of any beta-adrenergic bronchodilator.

Changes in blood glucose may occur.

Large doses of intravenous racemic albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.8 Hypokalemia As with other beta-adrenergic agonist medications, XOPENEX Inhalation Solution may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects.

The decrease is usually transient, not requiring supplementation.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information and Instructions for Using XOPENEX Inhalation Solution Concentrate ).

Patients should be given the following information: Hypersensitivity Query patients about previously experienced hypersensitivity to levalbuterol or racemic albuterol and counsel patients to report any hypersensitivity reactions to their physician.

Frequency of Use Inform patients not to increase the dose or use XOPENEX Inhalation Solution more frequently than recommended without consulting their physician.

If patients find that treatment with XOPENEX Inhalation Solution becomes less effective for symptomatic relief, symptoms become worse, or they need to use the product more frequently than usual, they should seek medical attention immediately.

Paradoxical Bronchospasm Inform patients that XOPENEX Inhalation Solution can produce paradoxical bronchospasm.

Instruct patients to discontinue XOPENEX Inhalation Solution if paradoxical bronchospasm occurs.

Concomitant Drug Use Inform patients using XOPENEX Inhalation Solution, that other inhaled drugs and asthma medications should be taken only as directed by their physician.

Common Adverse Reactions Advise patients of the common adverse reactions of treatment with XOPENEX Inhalation Solution include palpitations, chest pain, fast heart rate, headache, dizziness, tremor and nervousness.

Pregnancy Advise patients who are pregnant or nursing to contact their physician about the use of XOPENEX Inhalation Solution.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medication, including XOPENEX, during pregnancy.

To enroll in the Asthma & Pregnancy Study or for more information about the registry, call 1-877-311-8972 or visit www.mothertobaby.org/ongoing-study/asthma [see Use in Specific Populations ( 8.1 ) ].

General Information on Storage and Use Advise patients to dilute XOPENEX Inhalation Solution Concentrate with sterile normal saline before administration by nebulization.

Advise patients how to store XOPENEX Inhalation Solution Concentrate.

Store in the foil pouch between 20°C to 25°C (68°F to 77°F) protected from light and excessive heat.

Do not use after the expiration date stamped on the container.

Open the foil pouch just prior to administration.

Once the foil pouch is opened, use the contents of the vial immediately.

Discard any vial if the solution is not colorless.

Advise patients not to mix XOPENEX Inhalation Solution with other drugs in a nebulizer.

AKORN Distributed by: Akorn, Inc.

Lake Forest, IL 60045 Manufactured for: Oak Pharmaceuticals, Inc.

For customer service, call 1-800-932-5676.

To report adverse events, call 1-800-932-5676.

For medical information, call 1-800-932-5676.

XOPENEX is a registered trademark of Sunovion Pharmaceuticals Inc.

and is used under license.

XPA0N December 2018 PHARMACIST — DETACH HERE AND GIVE LEAFLET TO PATIENT ————————————————————————————————————

DOSAGE AND ADMINISTRATION

2 XOPENEX Inhalation Solution Concentrate is for oral inhalation only.

Dilute with sterile normal saline before administration.

Administer by nebulization using with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.

Do not exceed recommended dose.

For dosages less than 1.25 mg, the non-concentrate (i.e., XOPENEX Inhalation Solution, 3 mL) formulation must be used.

FOR ORAL INHALATION ONLY ( 2 ) Dilute XOPENEX (levalbuterol hydrochloride) Inhalation Solution Concentrate with sterile normal saline before administration by nebulization.

Children 6 to 11 years old: 0.31 mg administered three times a day, by nebulization.

Routine dosing should not exceed 0.63 mg three times a day.

( 2 ) Adults and Adolescents ≥ 12 years old: 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.

The maximum recommended dose is 1.25 mg three times a day.

( 2 ) For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor.

( 2 ) Children 6 to 11 years old: The recommended dosage of XOPENEX Inhalation Solution for patients 6 to 11 years old is 0.31 mg administered three times a day, by nebulization.

Routine dosing should not exceed 0.63 mg three times a day.

Adults and Adolescents ≥ 12 years old: The recommended starting dosage of XOPENEX Inhalation Solution for patients 12 years of age and older is 0.63 mg administered three times a day, every 6 to 8 hours, by nebulization.

Patients 12 years of age and older with more severe asthma or patients who do not respond adequately to a dose of 0.63 mg of XOPENEX Inhalation Solution may benefit from a dosage of 1.25 mg three times a day.

Patients receiving the highest dose of XOPENEX Inhalation Solution should be monitored closely for adverse systemic effects, and the risks of such effects should be balanced against the potential for improved efficacy.

The use of XOPENEX Inhalation Solution can be continued as medically indicated to help control recurring bouts of bronchospasm.

During this time, most patients gain optimal benefit from regular use of the inhalation solution.

If a previously effective dosage regimen fails to provide the usual response this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

The drug compatibility (physical and chemical), efficacy, and safety of XOPENEX Inhalation Solution when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of XOPENEX Inhalation Solution have been established in clinical trials when administered using the PARI LC Jet™ and PARI LC Plus™ nebulizers, and the PARI Master ® Dura-Neb ® 2000 and Dura-Neb ® 3000 compressors.

The safety and efficacy of XOPENEX Inhalation Solution when administered using other nebulizer systems have not been established.