Apo-Amlodipine

Apo-Amlodipine

amlodipine

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Amlodipine.
Description
Each tablet contains amlodipine 5 mg or 10 mg, respectively.
Excipients/Inactive Ingredients: Lactose Monohydrate, Magnesium Stearate, Microcrystalline Cellulose, Starch.
Action
Pharmacotherapeutic Group: Calcium-Channel blocker.
Pharmacology: Pharmacodynamics: Amlodipine is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischemic burden by the following two actions: Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements. The mechanism of action of amlodipine also probably involves dilatation of the main arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina) and blunts smoking inducted coronary vasoconstriction.
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and nitroglycerine tablet consumption.
In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes and gout.
Use in Patients with Heart Failure: Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.
A placebo-controlled study designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and angiotensin-converting enzyme (ACE) inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity in patients with heart failure.
In a follow-up, long-term, placebo controlled study of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischemic disease, on stable doses of ACE inhibitors, digitalis and diuretics, amlodipine had no effect on total or cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Use in Patients with Coronary Artery Disease (CAD): The effects of amlodipine on cardiovascular morbidity and mortality, the progression of coronary atherosclerosis, and carotid atherosclerosis were studied in the Prospective Randomized Evaluation of the Vascular Effects of NORVASC Trial (PREVENT). This multicenter, randomized, double blind, placebo-controlled study followed 825 patients with angiographically defined coronary artery disease for three years. The population included patients with previous myocardial infarction (MI) (45%), percutaneous transluminal coronary angioplasty (PTCA) at baseline (42%), or history of angina (69%). Severity of CAD ranged from 1-vessel disease (45% of patients) to 3+ vessel disease (21%). Patients with uncontrolled hypertension (DBP>95 mm Hg) were excluded from the study. Major cardiovascular events were adjudicated by a blinded endpoint committee. Although there were no demonstrable effects on the rate of progression of coronary artery lesions, amlodipine arrested the progression of carotid intima-media thickening. A significant reduction (-31%) was observed in the amlodipine-treated patients in the combined endpoint of cardiovascular death, MI, stroke, PTCA, coronary artery bypass graft (CABG), hospitalization for unstable angina, and worsening congestive heart failure (CHF). A significant reduction (-42%) in revascularization procedures (PTCA and CABG) was also seen in the amlodipine-treated patients. Fewer hospitalizations (-33%) were seen for unstable angina in amlodipine patients than in the placebo group.
CAMELOT enrolled 1997 patients with CAD recently documented by angiography,without left main coronary disease and without heart failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian, 93% enrolled at US sites, 89% with a history of angina, 52% without PCI, 4% with PCI and no stent, and 44% with a stent) were randomized to double-blind treatment with either amlodipine besylate tablets (5-10 mg once daily) or placebo in addition to standard care that included aspirin (89%), statins (83%), betablockers (74%), nitroglycerin (50%), anti-coagulants (40%), and diuretics (32%), but excluded other calcium channel blockers, for 2 years. The primary endpoint was the time to first occurrence of one of the following events: hospitalization for angina pectoris, coronary revascularization, myocardial infarction, and cardiovascular death, and resuscitated cardiac arrest, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease. The outcome of this study was largely derived from the prevention of hospitalizations for angina and the prevention of revascularization procedures (See table).
The other components of the primary endpoint including cardiovascular death, resuscitated cardiac arrest, and myocardial infarction, hospitalization for heart failure, stroke/TIA, or peripheral vascular disease did not demonstrate a significant difference between amlodipine besylate and placebo. (See table.)

Click on icon to see table/diagram/image

Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension. A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional CHD risk factor, including myocardial infarction or stroke >6 months or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI [0.90-1.07] p=0.65. Among Secondary Endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs 7.7%, RR 1.38, 95% Cl [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.96 95% CI [0.89-1.02] p=0.20.
Pharmacokinetics: Absorption: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours postdose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 L/kg. Absorption of amlodipine is unaffected by consumption of food.
Biotransformation/Elimination: The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Steady state plasma levels are reached after 7-8 days of consecutive dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Use in the Elderly: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.
Toxicology: Preclinical Safety Data: Carcinogenesis: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to and for rates twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.
Mutagenesis: Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
Impairment of Fertility: There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/ka/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis).
*Based on patient weight of 50 kg.
Indications/Uses
Essential Hypertension: Amlodipine is indicated for the first line treatment of hypertension and can be used as the sole agent to control blood pressure in the majority of patients. Patients not adequately controlled on a single antihypertensive agent may benefit from the addition of amlodipine, which has been used in combination with a thiazide diuretic, alpha blockers, beta adrenoceptor blocking agent, or an angiotensin-converting enzyme inhibitor.
Coronary Artery Disease (CAD): Chronic Stable Angina: Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal drugs.
Vasospastic Angina (Prinzmetal's or variant angina): Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy, or in combination with other antianginal drugs.
Dosage/Direction for Use
For both hypertension and angina the usual initial dose is 5 mg amlodipine once daily which may be increased to a maximum dose of 10 mg depending on the individual patient's response.
For patients with coronary artery disease the recommended dosage range is 5-10 mg once daily. In clinical studies the majority of patients required 10 mg once daily (see Pharmacology: Pharmacodynamics under Actions).
No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta-blockers and angiotensin-coverting enzyme inhibitors.
Use in the Elderly: Normal dosage regimens are recommended. Amlodipine, used at similar doses in elderly or younger patients, is equally well tolerated.
Use in Children: Safety and effectiveness of amlodipine in children have not been established.
Use in Patients with Impaired Hepatic Function: See PREACUTIONS.
Use in Renal Failure: Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialyzable.
Overdosage
Available data suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption. Gastric lavage may be worthwhile in some cases. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
Contraindications
APO-AMLODIPINE is contraindicated in patients with a known sensitivity to dihydropyrimidines, amlodipine, or any of the inert ingredients.
Special Precautions
Use in Patients with Heart Failure: In a long-term, placebo controlled study of amlodipine in patients with NYHA III and IV heart failure of non-ischemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo (see PHARMACOLOGY: PHARMACODYNAMICS under ACTIONS).
Use in Patients with Impaired Hepatic Function: As with all calcium antagonists, amlodipine half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. The drug should therefore be administered with caution in these patients.
Effects on Ability to Drive and Use Machines: Clinical experience with amlodipine indicates that it is unlikely to impair a patient's ability to drive or use machinery.
Use In Pregnancy & Lactation
Safety of amlodipine in human pregnancy or lactation has not been established. Amlodipine does not demonstrate toxicity in animal reproductive studies other than to delay parturition and prolong labor in rats at a dose level fifty times the maximum recommended dose in humans. Accordingly, use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and fetus.
Adverse Reactions
Amlodipine is well tolerated. In placebo controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effects were:
Autonomic Nervous System: flushing.
Body As A Whole: fatigue.
Cardiovascular, General: edema.
Central & Peripheral Nervous System: dizziness, headache.
Gastrointestinal: abdominal pain, nausea.
Heart Rate/Rhythm: palpitations.
Psychiatric: somnolence.
In these clinical trials no pattern of clinically significant laboratory test abnormalities related to amlodipine has been observed.
Less commonly observed side effects in marketing experience include: Autonomic Nervous System: dry mouth, increased sweating.
Body As A Whole: asthenia, back pain, malaise, pain, weight increase/decrease.
Cardiovascular, General: hypotension, syncope.
Central & Peripheral Nervous System: hypertonia, hypoesthesia/paresthesia, peripheral neuropathy, tremor.
Endocrine: gynecomastia.
Gastrointestinal: altered bowel habits, dyspepsia (including gastritis), gingival hyperplasia, pancreatitis, vomiting.
Metabolic/Nutritional: hyperglycemia.
Mucoskeletal: arthralgia, muscle cramps, myalgia.
Platelet/Bleeding/Clotting: purpura, thrombocytopenia.
Psychiatric: impotence, insomnia, mood changes.
Respiratory: coughing, dyspnea, rhinitis.
Skin/Appendages: alopecia, skin discolouration, urticaria.
Special Senses: taste perversion, tinnitus.
Urinary: increased urinary frequency, micturition disorder, nocturia.
Vascular (extracardiac): vasculitis.
Vision: visual disturbances.
White Blood Cell/R.E.S: leucopenia.
Rarely, allergic reactions including pruritus, rash, angioedema and erythema multiforme. Hepatitis, jaundice and hepatic enzyme elevations have also been reported very infrequently (mostly consistent with cholestasis). Some cases severe enough to require hospitalization have been reported in association with the use of amlodipine. In many instances, causal association is uncertain.
As with other calcium channel blockers the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.
Drug Interactions
Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerine, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin).
Special studies: 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 dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
ALUMINIUM/MAGNESIUM (antacid): Co-administration of an aluminium/magnesium antacid 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.
Special studies: 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.
CYCLOSPORIN: Pharmacokinetic studies with cyclosporine have demonstrated that amlodipine does not significantly alter the pharmacokinetics of cyclosporin.
Drug/Laboratory Test Interactions: None known.
Storage
Store below 25°C.
ATC Classification
C08CA01 - amlodipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Tab 5 mg (white to off-white, round unscored, imprinted "APO" on one side and "AML" over "5" on the other side) x 30's. 10 mg (white to off-white, round unscored, imprinted "APO" on one side and "AML" over "10" on the other side) x 30's.
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