Amlodipine Besylate and Olmesartan Medoxomil: Package Insert and Label Information

AMLODIPINE BESYLATE AND OLMESARTAN MEDOXOMIL- amlodipine besylate and olmesartan medoxomil tablet, film coated
Accord Healthcare Inc.

WARNING-FETAL TOXICITY

  • When pregnancy is detected, discontinue amlodipine and olmesartan medoxomil tablets 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).

1 INDICATIONS AND USAGE

Amlodipine and olmesartan medoxomil tablets are 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 amlodipine and olmesartan medoxomil tablets.

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.

Amlodipine and olmesartan medoxomil tablets 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 [see Clinical Studies (14.1)] provide estimates of the probability of reaching a blood pressure goal with amlodipine and olmesartan medoxomil tablets 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 amlodipine and olmesartan medoxomil tablets 10 mg/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.

Figure 1: Probability of Achieving Systolic Blood Pressure (SBP) <140 mmHg at Week 8 With LOCF

Figure 1: Probability of Achieving Systolic Blood Pressure (SBP) <140 mmHg at Week 8 With LOCF

Figure 2: Probability of Achieving Diastolic Blood Pressure (DBP) &amp;amp;amp;amp;amp;amp;amp;lt;90 mmHg at Week 8 With LOCF

Figure 2: Probability of Achieving Diastolic Blood Pressure (DBP) <90 mmHg at Week 8 With LOCF

Figure 3: Probability of Achieving Systolic Blood Pressure (SBP) &amp;amp;amp;amp;amp;amp;amp;lt;130 mmHg at Week 8 With LOCF

Figure 3: Probability of Achieving Systolic Blood Pressure (SBP) <130 mmHg at Week 8 With LOCF

Figure 4: Probability of Achieving Diastolic Blood Pressure (DBP) &amp;amp;amp;amp;amp;amp;amp;lt;80 mmHg at Week 8 With LOCF

Figure 4: Probability of Achieving Diastolic Blood Pressure (DBP) <80 mmHg at Week 8 With LOCF

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. Amlodipine and olmesartan medoxomil tablets 5 mg/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 amlodipine and olmesartan medoxomil tablets 5 mg/20 mg, and to 68% (systolic) and 85% (diastolic) on amlodipine and olmesartan medoxomil tablets 10 mg/40 mg.

2 DOSAGE AND ADMINISTRATION

The usual starting dose of amlodipine and olmesartan medoxomil tablets 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 [see Clinical Studies (14.1)].

Dosage may be increased after 2 weeks. The maximum recommended dose of amlodipine and olmesartan medoxomil tablets is 10/40 mg.

3 DOSAGE FORMS AND STRENGTHS

Amlodipine and olmesartan medoxomil tablets are formulated for oral administration in the following strength combinations:

5 mg/20 mg white, round, bevel-edged, film-coated tablets, debossed with “OA1” on one side and plain on other side.

10 mg/20 mg grayish-orange, round, bevel-edged, film-coated tablets debossed with “OA2” on one side and plain on other side.

5 mg/40 mg cream, round, bevel-edged, film-coated tablets debossed with “OA3” on one side and plain on other side.

10 mg/40 mg brownish-red, round, bevel-edged, film-coated tablets debossed with “OA4” on one side and plain on other side.

4 CONTRAINDICATIONS

Do not co-administer aliskiren with amlodipine and olmesartan medoxomil tablets in patients with diabetes [see Drug Interactions (7.2)].

5 WARNINGS AND PRECAUTIONS

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 amlodipine and olmesartan medoxomil tablets as soon as possible [see Use in specific Populations (8.1)] .

5.2 Hypotension in Volume- or Salt-Depleted Patients

Olmesartan medoxomil . In 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) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with amlodipine and olmesartan medoxomil tablets 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.

Amlodipine . Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

5.3 Increased Angina or Myocardial Infarction

Amlodipine . 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.

5.4 Patients with Impaired Renal Function

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 amlodipine and olmesartan medoxomil tablets because of the olmesartan medoxomil component [see Drug Interactions (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 olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and amlodipine and olmesartan medoxomil tablets.

5.5 Patients with Hepatic Impairment

Amlodipine . 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 amlodipine and olmesartan medoxomil tablets is 5 mg/20 mg; therefore, initial therapy with amlodipine and olmesartan medoxomil tablets is not recommended in hepatically impaired patients [see Use in Specific Populations (8.6) ].

Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t ½ ) is 56 hours in patients with severely impaired hepatic function, titrate slowly when administering to patients with severe hepatic impairment.

5.6 Sprue-like Enteropathy

Olmesartan medoxomil . 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 amlodipine and olmesartan medoxomil tablets in cases where no other etiology is identified.

5.7 Electrolyte Imbalances

Olmesartan medoxomil . Amlodipine and olmesartan medoxomil tablets contain olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

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.

Amlodipine and olmesartan medoxomil tablets

The data described below reflect exposure to amlodipine and olmesartan medoxomil tablets in more than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for 1 year. Amlodipine and olmesartan medoxomil tablets were studied in one placebo-controlled factorial trial [see Clinical Trials(14.1)] . 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 mg/20 mg to 10 mg/40 mg orally once daily.

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

Placebo-Subtracted Incidence of Edema During the Double-Blind Treatment Period
* 12.3%=actual placebo incidence
Olmesartan Medoximil
Placebo 20 mg 40 mg
Placebo * -2.4% 6.2%
Almodopine 5 mg 0.7% 5.7% 6.2%
10 mg 24.5% 13.3% 11.2%

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

There was a greater decrease in hemoglobin and hematocrit in patients treated with amlodipine and olmesartan medoxomil tablets as compared to patients receiving either component.

Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with amlodipine and olmesartan medoxomil tablets 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 amlodipine and olmesartan medoxomil tablets caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of amlodipine and olmesartan medoxomil tablets 5 mg/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.

Discontinuation for any Treatment Emergent Adverse Event 1
Olmesartan Medoximil
Placebo 10 mg 20 mg 40 mg
Placebo 4.9% 4.3% 5.6% 3.1%
Almodopine 5 mg 3.7% 0.0% 1.2% 3.7%
10 mg 5.5% 6.8% 2.5% 5.6%

1 Hypertension is counted as treatment failure and not as treatment emergent adverse event. N=160 to 163 subjects per treatment group.

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:

Adverse Event

Placebo N=520

2.5 mg N=275

5.0 mg N=296

10.0 mg N=268

Edema 0.6 1.8 3.0 10.8
Dizziness 1.5 1.1 3.4 3.4
Flushing 0.0 0.7 1.4 2.6
Palpitation 0.6 0.7 1.4 4.5

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:

Adverse Event

Placebo

Amlodipine

Male=% (N=914)

Female=% (N=336)

Male=% (N=1218)

Female=% (N=512)

Edema 1.4 5.1 5.6 14.6
Flushing 0.3 0.9 1.5 4.5
Palpitation 0.9 0.9 1.4 3.3
Somnolence 0.8 0.3 1.3 1.6

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%).

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