Amlodipine Besylate: Package Insert and Label Information

AMLODIPINE BESYLATE- amlodipine besylate tablet
Marlex Pharmaceuticals Inc

1 INDICATIONS AND USAGE

1.1 Hypertension

Amlodipine Besylate Tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including amlodipine besylate.

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

1.2 Coronary Artery Dis eas e (CAD)

Chronic Stable Angina

Amlodipine besylate tablets are indicated for the symptomatic treatment of chronic stable angina. Amlodipine besylate tablets may be used alone or in combination with other antianginal agents.

Vasospastic Angina (Prinzmetal’s or Variant Angina)

Amlodipine besylate tablets are indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine besylate tablets may be used as monotherapy or in combination with other antianginal agents.

Angiographically Documented CAD

In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, amlodipine besylate tablets are indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

2 DOSAGE AND A DMINISTRATION

2.1 Adults

The usual initial antihypertensive oral dose of amlodipine besylate tablets is 5 mg once daily, and the maximum dose is 10 mg once daily.

Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily and this dose may be used when adding amlodipine besylate tablets to other antihypertensive therapy.

Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

Angina: The recommended dose for chronic stable or vasospastic angina is 5–10 mg, with the lower dose suggested in the elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect.

Coronary artery disease: The recommended dose range for patients with coronary artery disease is 5–10 mg once daily. In clinical studies, the majority of patients required 10 mg [see Clinical Studies (14.4)].

2.2 Children

The effective antihypertensive oral dose in pediatric patient’s ages 6–17 years is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology (12.4), Clinical Studies (14.1)].

3 DOSAGE FO RMS AND STRENGTHS

Amlodipine Besylate Tablets USP, equivalent to 2.5 mg of amlodipine are white to off-white, round, flat-faced, beveled-edge tablets, de-bossed “Є” on one side and “55” on the other side.

Amlodipine Besylate Tablets USP, equivalent to 5 mg of amlodipine are white to off-white, round, flat- faced beveled-edge tablets, de-bossed “Є56” on one side and plain on the other side.

Amlodipine Besylate Tablets USP, equivalent to 10 mg of amlodipine are white to off-white, round, flat-faced beveled-edge tablets, debossed “Є57” on one side and plain on the other side.

4 CONTRAINDICATIONS

Amlodipine besylate tablets are contraindicated in patients with known sensitivity to amlodipine.

5 WARNINGS AND PRECAUTIONS

5.1 Hypotension

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

5.2 Increased Angina or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine besylate tablets, particularly in patients with severe obstructive coronary artery disease.

5.3 Patients with Hepatic Failure

Because amlodipine besylate tablets are extensively metabolized by the liver and the plasma elimination half-life (t 1/2 ) is 56 hours in patients with impaired hepatic function, titrate slowly when administering amlodipine besylate tablets to patients with severe hepatic impairment.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Amlodipine besylate tablets have been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine besylate tablets was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine besylate tablets were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate tablets (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine besylate tablets because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows:

Amlodipine Placebo
2.5 mg 5 mg 10 mg
N=275 N=296 N=268 N=520
Edema 1.8 3.0 10.8 0.6
Dizziness 1.1 3.4 3.4 1.5
Flushing 0.7 1.4 2.6 0.0
Palpitation 0.7 1.4 4.5 0.6

Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:

Amlodipine Besylate (%) Placebo (%)
(N=1730) (N=1250)
Fatigue 4.5 2.8
Nausea 2.9 1.9
Abdominal Pain 1.6 0.3
Somnolence 1.4 0.6

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:

Amlodipine Besylate Placebo
Male=% Female=% Male=% Female=%
(N=1218) (N=512) (N=914) (N=336)
Edema 5.6 14.6 1.4 5.1
Flushing 1.5 4.5 0.3 0.9
Palpitations 1.4 3.3 0.9 0.9
Somnolence 1.3 1.6 0.8 0.3

The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Cen tral and Peripheral Nervous Sys tem: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gas trointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal Sys tem: arthralgia, arthrosis, muscle cramps1 myalgia.

Psychiatric: sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Resp iratory Sys tem: dyspnea1 epistaxis.

Skin and Appendages : angioedema, erythemamultiforme, pruritus, 1rash, 1 rash erythematous, rash maculopapular.

Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.

Urinary Sys tem: micturition frequency, micturition disorder, nocturia.

Autonomic Nervous Sys tem: dry mouth, sweating increased.

Metabolic and Nutritional: hyperglycemia, thirst.

Hemopoietic: leukopenia, purpura, thrombocytopenia.

1 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

Amlodipine besylate therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine.

In the CAMELOT and PREVENT studies [see Clinical Studies (14.4)] , the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

6.2 Pos t 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.

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.

Post marketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Amlodipine besylate tablets have been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular

Disease, diabetes mellitus, and abnormal lipid profiles.

7 DRUG INTERACTIONS

7.1 Impact of Other Drugs on Amlodipine

CYP3A Inhibitors

Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology (12.3)].

CYP3A Inducers

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

Sildenafil

Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology (12.2)].

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