Amlosin 5 mg: Each uncoated tablet contains Amlodipine 5 mg (equivalent to 6.934 mg of Amlodipine Besilate).
Amlosin 10 mg: Each uncotaed tablet contains Amlodipine 10 mg (equivalent to 13.868 mg of Amlodipine Besilate).
Amlodipine 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 empirical formula is C20H25ClN2O5·C6H6O3S.
Amlodipine besylate is a white crystalline powder. It is slightly soluble in water and sparingly soluble in ethanol. Amlodipine besylate Tablets are formulated as white tablets equivalent to 5 and 10 mg of amlodipine for oral administration.
Excipients/Inactive Ingredients: In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: Microcrystalline cellulose, Silica, Colloidal Anhydrous and Magnesium Stearate.
Pharmacology: Pharmacodynamics: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (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 ischaemic 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 coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
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 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
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 (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that Amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.
In a follow-up, long term, placebo controlled study (PRAISE-2) of Amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, Amlodipine had no effect on total cardiovascular mortality. In this same population Amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
A randomized double-blind morbidity-mortality study called the Antihypertensive and 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: previous myocardial infarction or stroke (> 6 months prior to enrollment) 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% CI [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.
In a study involving 268 children aged 6-17 years with predominantly secondary hypertension, comparison of a 2.5mg dose, and 5.0mg dose of amlodipine with placebo, showed that both doses reduced Systolic Blood Pressure significantly more than placebo. The difference between the two doses was not statistically significant.
The long-term effects of amlodipine on growth, puberty and general development have not been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood have also not been established.
Pharmacokinetics: Absorption, distribution, plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Biotransformation/elimination: The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is extensively metabolised 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.
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 (ACE) inhibitor.
Coronary Artery Disease: 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.
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 mg to 10 mg once daily. In clinical studies, the majority of patients required 10 mg once daily (see Pharmacology: Pharmacodynamics: Use in Patients with Coronary Artery Disease under Actions).
No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta-blockers, and ACE inhibitors.
Use in the Elderly: Normal dosage regimens are recommended. Amlodipine, used at similar doses in the 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 Precautions.
Use in Patients with Renal Failure: Amlodipine may be used at normal doses in patients with renal failure. Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment. Amlodipine is not dialyzable.
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 10mg 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.
Amlodipine is contra-indicated in patients with a known sensitivity to dihydropyridines, amlodipine or any of the excipients.
Amlodipine should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina).
Pregnancy and lactation.
Use in patients with Heart Failure: In a long-term, placebo controlled study (PRAISE-2) of Amlodipine in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema 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's 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.
There are no data to support the use of Amlodipine alone, during or within one month of a myocardial infarction.
The safety and efficacy of Amlodipine in hypertensive crisis has not been established.
Effects on Ability to Drive and Use Machines: Clinical experience with Amlodipine indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.
The safety of amlodipine in human pregnancy or lactation has not been established. Amlodipine does not demonstrate toxicity in animal reproductive studies other than delay in parturition and prolongation of labor in rats at a dose level 50 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. There was no effect on the fertility of rats treated with amlodipine (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Amlodipine is well tolerated. In placebo controlled clinical trials involving patients with hypertension or angina, the most commonly observed side effects were: Vascular Disorders: Flushing.
Nervous System Disorders: Dizziness, headaches, somnolence.
Gastrointestinal Disorders: Abdominal pain, nausea.
Cardiac Disorders: Palpitations.
General Disorders and Administration Site Conditions: Fatigue, oedema.
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: General Disorders and Administrative Site Conditions: Asthenia, malaise, pain.
Investigations: Weight increased/decreased.
Nervous System Disorders: Hypertonia, hypoaesthesia/paraesthesia, peripheral neuropathy, syncope, dysgeusia, tremor, extrapyramidal disorder.
Reproductive System and Breast Disorders: Gynaecomastia, erectile dysfunction.
Gastrointestinal Disorders: Change in bowel habits, dry mouth, dyspepsia (including gastritis), gingival hyperplasia, pancreatitis, vomiting.
Metabolism and Nutrition Disorders: Hyperglycemia.
Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, muscle spasms, myalgia.
Blood and Lymphatic System Disorders: Leukopenia, thrombocytopenia.
Psychiatric Disorders: Insomnia, mood altered.
Respiratory, Thoracic and Mediastinal Disorders: Coughing, dyspnoea, rhinitis.
Skin and Subcutaneous Tissue Disorders: Alopecia, hyperhidrosis, purpura, skin discoloration, urticaria.
Ear and Labyrinth Disorders: Tinnitus.
Renal and Urinary Disorders: Pollakiuria, micturition disorder, nocturia.
Vascular Disorders: Hypotension, vasculitis.
Eye Disorders: Visual impairment.
Rarely reported events were allergic reaction 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 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 (MI), arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.
Cyclosporin: No drug interaction studies have been conducted with cyclosporin and amlodipine in healthy volunteers or other populations, with the exception of renal transplant patients. Various studies in renal transplant patients report that co-administration of amlodipine with cyclosporin affects the trough concentrations of cyclosporin, from no change up to an average increase of 40%. Consideration should be given for monitoring cyclosporin levels in renal transplant patients on amlodipine.
Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Ethanol (Alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Aluminum/Magnesium (Antacid): Co-administration of aluminum/magnesium (antacid) with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Simvastatin: Co-administration of multiple doses of 10 mg 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.
CYP3A4 Inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients (69 to 87 years of age) resulted in a 57% increase in amlodipine systemic exposure. Co-administration of erythromycin in healthy volunteers (18 to 43 years of age) did not significantly change amlodipine systemic exposure (22% increase in area under the concentration versus time curve [AUC]). Although the clinical relevance of these findings is uncertain, pharmacokinetic variations may be more pronounced in the elderly.
Strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution when administered with CYP3A4 inhibitors.
Clarithromycin: Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.
CYP3A4 Inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum (St. John's Wort) may decrease the plasma concentrations of amlodipine. Amlodipine should be used with caution when administered with CYP3A4 inducers.
Store below 30°C and protect from moisture.
C08CA01 - amlodipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
Sign Out
