Amlodipine besylate and Olmesartan medoxomil

Amlodipine besylate and Olmesartan medoxomil
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]

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Black Box Warning

WARNING: FETAL TOXICITY See full prescribing information for complete Boxed Warning. *When pregnancy is detected, discontinue Azor as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Overview

Amlodipine besylate and Olmesartan medoxomil is an antihypertensive agent that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, dizziness, headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Azor is 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. 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 Azor.

• 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.

• Azor may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.

• Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.

• Data from an 8-week, placebo-controlled, parallel-group factorial study provide estimates of the probability of reaching a blood pressure goal with Azor compared to amlodipine or olmesartan medoxomil monotherapy. The figures below provide estimates of the likelihood of achieving the targeted systolic or diastolic blood pressure goals with Azor 10/40 mg compared with amlodipine or olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling from all available data of that treatment group. The right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures.

• The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 SBP <140 mmHg or <130 mmHg or a DBP <90 mmHg or <80 mmHg) for the high-dose treatment groups evaluated in the study. Azor 5/20 mg, the lowest dose combination treatment group, increases the probability of reaching blood pressure goal compared with the highest dose monotherapies, amlodipine 10 mg and olmesartan medoxomil 40 mg.

• For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 48% likelihood of achieving a goal of <140 mmHg (systolic) and a 51% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with olmesartan medoxomil 40 mg, and about a 46% likelihood of achieving a goal of <140 mmHg (systolic) and a 60% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with amlodipine 10 mg. The likelihood of achieving these same goals increases to 63% (systolic) and 71% (diastolic) on Azor 5/20 mg, and to 68% (systolic) and 85% (diastolic) on Azor 10/40 mg.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Amlodipine besylate and Olmesartan medoxomil in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Amlodipine besylate and Olmesartan medoxomil in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Amlodipine besylate and Olmesartan medoxomil in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Amlodipine besylate and Olmesartan medoxomil in pediatric patients.

Contraindications

Do not co-administer aliskiren with Azor in patients with diabetes.

Warnings

WARNING: FETAL TOXICITY See full prescribing information for complete Boxed Warning. *When pregnancy is detected, discontinue Azor as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

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 Azor as soon as possible [see Use in specific Populations (8.1)].

Hypotension in Volume- or Salt-Depleted Patients

• Olmesartan medoxomil. Symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) may be particularly vulnerable. Initiate treatment with Azor 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. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Vasodilation

• Amlodipine. Since the vasodilation attributable to amlodipine in Azor is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, exercise caution, as with any other peripheral vasodilator, when administering Azor, particularly in patients with severe aortic stenosis.

Patients with Severe Obstructive Coronary Artery Disease

• Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Patients with Congestive Heart Failure

• Amlodipine. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.

Patients with Impaired Renal Function

• Azor. There are no studies of Azor in patients with renal impairment.

• Olmesartan medoxomil. Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. 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 inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with Azor because of the olmesartan medoxomil component.

• 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 olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and Azor.

Patients with Hepatic Impairment

• Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with severely impaired hepatic function, exercise caution when administering Azor to patients with severe hepatic impairment.

• Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients [See Use in Specific Populations (8.6)].

Sprue-like Enteropathy

• Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Azor in cases where no other etiology is identified.

Laboratory Tests

• Azor. There was a greater decrease in hemoglobin and hematocrit in the combination product compared to either component. Other laboratory changes can usually be attributed to either monotherapy component.

• Amlodipine. In post-marketing experience, hepatic enzyme elevations have been reported.

• Olmesartan medoxomil. In post-marketing experience, increased blood creatinine levels and hyperkalemia have been reported.

Adverse Reactions

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.

Azor

• The data described below reflect exposure to Azor in more than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for 1 year. Azor was studied in one placebo-controlled factorial trial. The population had a mean age of 54 years and included approximately 55% males. Seventy-one percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once daily.

• The overall incidence of adverse reactions on therapy with Azor was similar to that seen with corresponding doses of the individual components of Azor, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for Azor and 6.8% for placebo).

Edema

• Edema is a known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil.The placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan medoxomil was added to the 10 mg amlodipine dose.

• Across all treatment groups, the frequency of edema was generally higher in women than men, as has been observed in previous studies of amlodipine.

• Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with Azor at about the same or greater incidence as in patients receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia.

• The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled period.

Initial Therapy

• Analyzing the data described above specifically for initial therapy, it was observed that higher doses of Azor caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of Azor 5/20 mg. No increase in the incidence of syncope or near syncope was observed. The incidences of discontinuation because of any treatment emergent adverse events in the double blind phase are summarized in the table below.

Across all treatment groups, the frequency of edema was generally higher in women than men, as has been observed in previous studies of amlodipine.

Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with Azor at about the same or greater incidence as in patients receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia.

The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled period.

Amlodipine

• Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and about 1% of placebo-treated patients. The most common side effects were headache and edema. The incidence (%) of dose-related side effects was as follows:

• For several adverse experiences that appear to be drug- and dose-related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table;

Olmesartan medoxomil.

• Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo. Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.

• The overall frequency of adverse events was not dose-related. Analysis of gender, age, and race groups demonstrated no differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse event that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs 1%).

Postmarketing Experience

• The following adverse reactions have been identified during post-approval use of the individual components of Azor. 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.

• Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

• Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:

• Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema
• Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy [see Warnings and Precautions (5.8)]
• Musculoskeletal: rhabdomyolysis
• Urogenital System: acute renal failure
• Skin and Appendages: alopecia, pruritus, urticaria

• Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, decrease in time-to-onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).

• The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months.

• Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.

Drug Interactions

Drug Interactions with Azor

• The pharmacokinetics of amlodipine and olmesartan medoxomil are not altered when the drugs are co-administered.

• No drug interaction studies have been conducted with Azor and other drugs, although studies have been conducted with the individual amlodipine and olmesartan medoxomil components of Azor, as described below, and no significant drug interactions have been observed.

Drug Interactions with Amlodipine

• In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Effect of Other Agents on Amlodipine

• Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
• Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
• Maalox® (antacid): Co-administration of the antacid Maalox® with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
• Sildenafil: A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Effect of Amlodipine on Other Agents

• Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin.
• Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
• Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
• Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
• Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Drug Interactions with Olmesartan Medoxomil

• 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.

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

• The bioavailability of olmesartan medoxomil 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.

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 Azor and other agents that affect the RAS.

• Do not co-administer aliskiren with Azor in patients with diabetes.
• Avoid use of aliskiren with Azor in patients with renal impairment (GFR <60 ml/min).

Use with 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.

Lithium

• Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including AZOR. Monitor serum lithium levels during concomitant use.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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 Azor 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 Azor, 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 Azor for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations(8.4)].

• Olmesartan. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

• Amlodipine. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg). However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Amlodipine besylate and Olmesartan medoxomil in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Amlodipine besylate and Olmesartan medoxomil during labor and delivery.

Nursing Mothers

• It is not known whether the amlodipine or olmesartan medoxomil components of Azor are 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.

Pediatric Use

Neonates with a history of in utero exposure to Azor:

• 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 safety and effectiveness of Azor in pediatric patients have not been established.

• Amlodipine. The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.

• Olmesartan medoxomil. Safety and effectiveness of olmesartan medoxomil in pediatric patients have not been established.

Geriatic Use

• Of the total number of subjects in the double-blind clinical study of Azor, 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.

• Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients ≥75 years old is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in patients ≥75 years old.

• Amlodipine. Reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required.

• Olmesartan medoxomil. Of the total number of hypertensive patients receiving olmesartan medoxomil 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.

Gender

There is no FDA guidance on the use of Amlodipine besylate and Olmesartan medoxomil with respect to specific gender populations.

Race

Black Patients

• Of the total number of subjects in the double-blind clinical study of Azor, 25% (481/1940) were black patients. Azor was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.

Renal Impairment

• There are no studies of Azor in patients with renal impairment.

• Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.

• Olmesartan medoxomil. Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, 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).

Hepatic Impairment

• There are no studies of Azor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment. Use caution when administering Azor to patients with severe hepatic impairment.

• Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients with hepatic impairment is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Amlodipine besylate and Olmesartan medoxomil in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Amlodipine besylate and Olmesartan medoxomil in patients who are immunocompromised.

Administration and Monitoring

Administration

General Considerations:

• The side effects of olmesartan medoxomil are generally rare and apparently independent of dose. Those of amlodipine are generally dose-dependent (mostly edema).

• Maximum antihypertensive effects are attained within 2 weeks after a change in dose.

• Azor may be taken with or without food.

• Azor may be administered with other antihypertensive agents.

• Dosage may be increased after 2 weeks. The maximum recommended dose of Azor is 10/40 mg.

Replacement Therapy:

• Azor may be substituted for its individually titrated components.

• When substituting for individual components, the dose of one or both of the components can be increased if blood pressure control has not been satisfactory.

Add-on Therapy:

• Azor may be used to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with olmesartan medoxomil (or another angiotensin receptor blocker) alone.

Initial Therapy:

• The usual starting dose of Azor is 5/20 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum dose of one 10/40 mg tablet once daily as needed to control blood pressure.

• Initial therapy with Azor is not recommended in patients ≥75 years old or with hepatic impairment.

Monitoring

• Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy.
• Monitor blood pressure, renal function and electrolytes in patients on Azor and other agents that affect the RAS.
• Monitor serum lithium levels during concomitant use.

IV Compatibility

There is limited information regarding the compatibility of Amlodipine besylate and Olmesartan medoxomil and IV administrations.

Overdosage

• There is no information on overdosage with Azor in humans.

• Amlodipine. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.

• Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.

• If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

• Olmesartan medoxomil. 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 should occur, supportive treatment should be initiated. The dialyzability of olmesartan is unknown.

Pharmacology

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Mechanism of Action in the drug label.

Structure

• Azor provided as a tablet for oral administration, is a combination of the calcium channel blocker (CCB) amlodipine besylate and the angiotensin II receptor blocker (ARB) olmesartan medoxomil.

• The amlodipine besylate component of Azor is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25CIN2O5•C6H6O3S.

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

• The olmesartan medoxomil component of Azor is chemically described 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.

• The structural formula for amlodipine besylate is:

The structural formula for olmesartan medoxomil is:

• Azor contains amlodipine besylate, a white to off-white crystalline powder, and olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder. The molecular weights of amlodipine besylate and olmesartan medoxomil are 567.1 and 558.59, respectively. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol.

• Each tablet of Azor also contains the following inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coatings contain polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (5/40 mg, 10/20 mg, 10/40 mg tablets), iron oxide red (10/20 mg and 10/40 mg tablets), and iron oxide black (10/20 mg tablets).

Pharmacodynamics

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Clinical Studies in the drug label.

How Supplied

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil How Supplied in the drug label.

Storage

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Storage in the drug label.

Images

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Patient Counseling Information

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Amlodipine besylate and Olmesartan medoxomil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Amlodipine besylate and Olmesartan medoxomil Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.