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AMLODIPINE BESYLATE TABLETS

2.5 mg, 5 mg and 10 mg(Each 2.5 mg, 5 mg and 10 mg tablet contains amlodipine besylate equivalent to 2.5 mg, 5 mg and 10 mg amlodipine, respectively)

Rx only

DESCRIPTION

Amlodipine besylate is the besylate salt of amlodipine, a long-acting calcium channel blocker.

Amlodipine besylate 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 molecular formula is C20H25ClN2O5 • C6H6O3S, and its structural formula is:

Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate tablets are formulated as blue tablets equivalent to 2.5 mg, 5 mg and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: colloidal silicon dioxide; dibasic calcium phosphate, anhydrous; magnesium stearate; microcrystalline cellulose; sodium lauryl sulfate; sodium starch glycolate and FD&C Blue #2 lake HT.

CLINICAL PHARMACOLOGY

Mechanism of Action

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Pharmacokinetics and Metabolism

After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

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

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.

Pharmacodynamics

Clinical Studies

Effects in Hypertension

INDICATIONS AND USAGE

1. Hypertension: Amlodipine besylate tablets are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.

2. 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.

3. 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 drugs.

CONTRAINDICATIONS

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

WARNINGS

Increased Angina and/or Myocardial Infarction

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/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.

PRECAUTIONS

General

Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering amlodipine, particularly in patients with severe aortic stenosis.

Use in Patients with Congestive Heart Failure

In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5 to 10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure (see CLINICAL PHARMACOLOGY) 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 to 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 worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.

Beta-Blocker Withdrawal

Amlodipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Patients with Hepatic Failure

Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised when administering amlodipine to patients with severe hepatic impairment.

Drug Interactions

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

Effect of Amlodipine on Other Agents

Drug/Laboratory Test Interactions

None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose of 10 mg amlodipine/dayBased on patient weight of 50 kg.. For the rat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended human dose.

Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose of 10 mg/day on a mg/m2 basis).

Pregnancy

Nursing Mothers

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine is administered.

Pediatric Use

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

Geriatric Use

Clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other 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 (see DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine was well-tolerated at doses up to 10 mg daily. 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 patients and was not significantly different from placebo (about 1%). The most common side effects are headache and edema. The incidence (%) of side effects which occurred in a dose related manner are as follows:

Adverse Event2.5 mg
N = 275
5 mg
N = 296
10 mg
N = 268
Placebo
N = 520
Edema1.83.010.8  0.6
Dizziness1.13.43.41.5
Flushing0.71.42.60.0
Palpitation0.71.44.50.6

Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1% in placebo-controlled clinical trials include the following:

Placebo-Controlled Studies
AMLODIPINE (%)
(N = 1730)
PLACEBO (%)
(N = 1250)
Headache7.37.8
Fatigue4.52.8
Nausea2.91.9
Abdominal Pain1.60.3
Somnolence1.40.6

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:

AMLODIPINEPLACEBO
Adverse EventMale = %
(N = 1218)
Female = %
(N = 512)
Male =%
(N = 914)
Female = %
(N = 336)
Edema5.614.6  1.45.1
Flushing1.54.50.30.9
Palpitations1.43.30.90.9
Somnolence1.31.60.80.3

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 uled to alert the physician to a possible relationship:

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

Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dyspepsia, 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.dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.

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

Musculoskeletal System: arthralgia, arthrosis, muscle cramps, myalgia.

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

Respiratory System: dyspnea, epistaxis.

Skin and Appendages: angioedema, erythema multiforme, pruritus, rash, rash erythematous, rash maculopapular.

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

Urinary System: micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System: dry mouth, sweating increased.

Metabolic and Nutritional: hyperglycemia, thirst.

Hemopoietic: leukopenia, purpura, thrombocytopenia.

The following events occurred in < 0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.

Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina.

Amlodipine 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.

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.

Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

OVERDOSAGE

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. Reports of intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized; another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third (105 mg) was hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A case of accidental drug overdose has been documented in a 19 month old male who ingested 30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted.

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.

DOSAGE AND ADMINISTRATION

The usual initial antihypertensive oral dose of amlodipine besylate tablets is 5 mg once daily with a maximum dose of 10 mg once daily. Small, fragile, or elderly individuals, 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.

Dosage should be adjusted according to each patient's need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient's response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.

The recommended dose for chronic stable or vasospastic angina is 5 to 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. See ADVERSE REACTIONS section for information related to dosage and side effects.

Pediatric Patients

Information related to the dosing of amlodipine in the treatment of hypertension in pediatric patients age 6 to 17 is approved for Pfizer Inc's amlodipine. However, due to Pfizer's marketing exclusivity rights, this drug product is not labeled for pediatric use.

Coadministration with Other Antihypertensive and/or Antianginal Drugs

Amlodipine besylate tablets have been safely administered with thiazides, ACE inhibitors, beta-blockers, long-acting nitrates, and/or sublingual nitroglycerin.

HOW SUPPLIED

Amlodipine Besylate Tablets are available containing 2.5 mg, 5 mg or 10 mg of amlodipine base.

The 2.5 mg tablets are blue, round, biconvex, unscored tablets debossed with M on one side of the tablet and A8 on the other side. They are available as follows:

NDC 0378-5208-77
bottles of 90 tablets

NDC 0378-5208-05
bottles of 500 tablets

The 5 mg tablets are blue, round, biconvex, unscored tablets debossed with M on one side of the tablet and A9 on the other side. They are available as follows:

NDC 0378-5209-77
bottles of 90 tablets

NDC 0378-5209-05
bottles of 500 tablets

The 10 mg tablets are blue, round, biconvex, unscored tablets debossed with M on one side of the tablet and A10 on the other side. They are available as follows:

NDC 0378-5210-77
bottles of 90 tablets

NDC 0378-5210-05
bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Detach Patient Information Leaflet at each perforation and give leaflet to patient.

Viagra® is a registered trademark of Pfizer Inc.

Mylan Pharmaceuticals Inc.
Morgantown, W.V. 26505

REVISED JULY 2006
AMDP:R6P

SUMMARY OF INFORMATION ABOUT AMLODIPINE BESYLATE TABLETS

Read this information carefully before you start amlodipine and each time you refill your prescription. There may be new information. This information does not replace talking with your doctor. If you have any questions about amlodipine, ask your doctor. Your doctor will know if amlodipine is right for you.

What is amlodipine?

Amlodipine is a type of medicine known as a calcium channel blocker (CCB). It is used to treat high blood pressure (hypertension) and a type of chest pain called angina. It can be used by itself or with other medicines to treat these conditions.

High Blood Pressure (hypertension): High blood pressure comes from blood pushing too hard against your blood vessels. Amlodipine relaxes your blood vessels which lets your blood flow more easily and helps lower your blood pressure. Drugs that lower blood pressure lower your risk of having a stroke or heart attack.

Angina: Angina is a pain or discomfort that keeps coming back when part of your heart does not get enough blood. Angina feels like a pressing or squeezing pain, usually in your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaws, or back. Amlodipine can relieve this pain.

Who should not use amlodipine?

Do not use amlodipine besylate tablets if you are allergic to amlodipine (the active ingredient in amlodipine besylate tablets), or to the inactive ingredients. Your doctor or pharmacist can give you a ul of these ingredients.

What should I tell my doctor before taking amlodipine?

Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies. Tell your doctor if you:

  • ever had heart disease
  • ever had liver problems
  • are pregnant, or plan to become pregnant. Your doctor will decide if amlodipine is the best treatment for you.
  • are breastfeeding. Do not breastfeed while taking amlodipine. You can stop breastfeeding or take a different medicine.

How should I take amlodipine?

  • Take amlodipine once a day, with or without food. You can take amlodipine with most drinks, including grapefruit juice.
  • It may be easier to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime. Do not take more than one dose of amlodipine at a time.
  • If you miss a dose, take it as soon as you remember. Do not take amlodipine if it has been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular time.
  • Other medicines: You can use nitroglycerin and amlodipine together. If you take nitroglycerin for angina, don't stop taking it while you are taking amlodipine.
  • While you are taking amlodipine, do not stop taking your other prescription medicines, including any other blood pressure medicines, without talking to your doctor.
  • If you took too much amlodipine, call your doctor or Poison Control Center, or go to the nearest hospital emergency room right away.

What should I avoid while taking amlodipine?

  • Do not breastfeed. It is not known if amlodipine will pass through your milk.
  • Do not start any new prescription or non-prescription medicines or supplements, unless you check with your doctor first.

What are the possible side effects of amlodipine?

Amlodipine may cause the following side effects. Most side effects are mild or moderate:

  • headache
  • swelling of your legs or ankles
  • tiredness, extreme sleepiness
  • stomach pain, nausea
  • dizziness
  • flushing (hot or warm feeling in your face)
  • arrhythmia (irregular heartbeat)
  • heart palpitations (very fast heartbeat)

It is rare, but when you first start amlodipine or increase your dose, you may have a heart attack or your angina may get worse. If that happens, call your doctor right away or go directly to a hospital emergency room.

Tell your doctor if you are concerned about any side effects you experience. These are not all the possible side effects of amlodipine. For a complete ul, ask your doctor or pharmacist.

How do I store amlodipine?

Keep amlodipine away from children. Store amlodipine besylate tablets at controlled room temperature (between 68 and 77 degrees Fahrenheit).

Keep amlodipine out of the light. Do not store in the bathroom.

Keep amlodipine in a dry place.

General advice about amlodipine

Sometimes, doctors will prescribe a medicine for a condition that is not written in the patient information leaflets. Only use amlodipine the way your doctor told you to. Do not give amlodipine to other people, even if they have the same symptoms you have. It may harm them.

You can ask your pharmacist or doctor for information about amlodipine or call 1-877-446-3679 (1-877-4-INFO-RX).

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

JANUARY 2005
PL:AMDP:R1

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