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olmesartan medoxomil tablet, film coated
FULL PRESCRIBING INFORMATION
WARNING: AVOID USE IN PREGNANCY
When pregnancy is detected, discontinue Benicar as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus [see Warnings and Precautions (5.1)].
1 INDICATIONS AND USAGE
Benicar is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
2 DOSAGE AND ADMINISTRATION
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 (5.3), 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 (5.2)].
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.
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 [see Preparation of Suspension].
Preparation of Suspension (for 200 mL of a 2 mg/mL suspension)
3 DOSAGE FORMS AND STRENGTHS
5 WARNINGS AND PRECAUTIONS
5.1 Fetal/Neonatal Morbidity and Mortality
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue Benicar as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Benicar as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, discontinue Benicar unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
5.2 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.
5.3 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), 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.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
The overall frequency of adverse reactions was not dose-related. Analysis of gender, age and race groups demonstrated no differences between Benicar and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with Benicar and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with Benicar and at a higher incidence versus placebo was dizziness (3% vs. 1%).
The incidence of cough was similar in placebo (0.7%) and Benicar (0.9%) patients.
Other potentially important adverse reactions that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive patients treated with Benicar monotherapy in controlled or open-label trials are listed below.
Facial edema was reported in five patients receiving Benicar. Angioedema has been reported with angiotensin II antagonists.
Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Benicar.
6.2 Post-Marketing Experience
The following adverse reactions have been reported in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: Asthenia, angioedema
7 DRUG INTERACTIONS
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.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Categories C (first trimester) and D (second and third trimesters). There is no clinical experience with the use of Benicar in pregnant women [see Warnings and Precautions (5.1)].
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.
8.4 Pediatric Use
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.
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)].
8.6 Hepatic Impairment
Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
8.7 Renal Impairment
Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min) [see Dosage and Administration (2.1), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].
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.
Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 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 C29H30N6O6 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.
12 CLINICAL PHARMACOLOGY
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 AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An AT2 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 AT1 receptor than for the AT2 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.
Benicar doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of Benicar >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of Benicar to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg Benicar had minimal influence on aldosterone levels and no effect on serum potassium.
Benicar tablets and the suspension formulation prepared from Benicar tablets are bioequivalent [see Dosage and Administration (2.2)].
The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Metabolism and Excretion
Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.
Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).
Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
14 CLINICAL STUDIES
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.
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).
16 HOW SUPPLIED/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:
17 PATIENT COUNSELING INFORMATION
Pregnancy: Female patients of childbearing age should be told about the consequences of second and third trimester exposure to drugs that act on the renin-angiotensin system and they should be told also that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054
Copyright © Daiichi Sankyo, Inc. 2009. All rights reserved.
Revised: 05/2010 Daiichi Sankyo, Inc
Reproduced with permission of U.S. National Library of Medicine
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