Olmesartan medoxomil 20 MG Oral Tablet

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.