Keep out of reach of children.
Read the directions carefully before use.
For prescription only.
QUALITATIVE AND QUANTITATIVE COMPOSITION:
Active ingredient
Amlodipine (as amlodipine besilate) ..... 10 mg
Excipients q.s ………………..…… 1 capsule
Hard capsule.
Product description: An orange/white to off-white hard capsule containing homogeneous drug powder.
Box of 3 blisters x 10 hard capsules.
ATC code: C08CA01.
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 ischaemic burden by the following two actions:
1. 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.
2. The mechanism of action also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina) and blunts smoking-induced 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 1mm ST segment depression, and decreases both angina attack frequency and nitroglycerine 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 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 amlodipine 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.
The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-centre, randomized, double- blind, placebo-controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 5-10 mg, 655 patients were treated with placebo, in addition to standard care of statins, beta-blockers, diuretics and aspirin, for 2 years. The key efficacy results are presented in the table below. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.
Incidence of significant clinical outcomes for CAMELOT
* 1). Defined in CAMELOT as cardiovascular death, nonfatal MI, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure (CHF), fatal or nonfatal stroke or transient ischemic attack (TIA), any diagnosis of peripheral vascular disease (PVD) in a subject not previously diagnosed as having PVD or any admission for a procedure for the treatment of PVD.
2). The composite cardiovascular (CV) endpoint was the primary efficacy endpoint in CAMELOT.
Treatment to prevent heart attack trial (ALLHAT)
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. 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.
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 edema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Use in pediatric patients (ages 6 to 17 years)
The efficacy of amlodipine in hypertensive pediatric patients 6 to 17 years of age was demonstrated in one 8-week double-blind, placebo-controlled randomized withdrawal trial in 268 patients with hypertension. All patients were randomized to the 2.5 mg or 5 mg treatment arms and followed for 4 weeks after which they were randomized to continue 2.5 mg or 5 mg amlodipine or placebo for an additional 4 weeks. Compared with baseline, once daily treatment with amlodipine 5 mg resulted in statistically significant reductions in systolic and diastolic blood pressures. Placebo-adjusted, mean reduction in seated systolic blood pressure was estimated to be 5.0 mmHg for the 5 mg dose of amlodipine and 3.3 mmHg for the 2.5 mg dose of amlodipine. Subgroup analyses indicated that younger pediatric patients aged 6 to 13 years had efficacy results comparable to those of the older pediatric patients aged 14 to 17 years
Absorption
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. Absorption of amlodipine is unaffected by consumption of food.
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. Steady state plasma levels are reached after 7-8 days of consecutive dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in 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 “area under the curve” (AUC) and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure (CHF) were as expected for the patient age group studied.
Use in pediatrics
In one clinical chronic exposure study, 73 hypertensive pediatric patients, ages 12 months to less than or equal to 17 years, amlodipine was dosed at an average daily dose of 0.17 mg/kg. Clearance for subjects with the median weight of 45 kg were 23.7 L/hr and 17.6 L/hr for males and females, respectively. This is in a similar range to the published estimates of 24.8 L/hr in a 70 kg adult. The average estimate for volume of distribution for a 45 kg patient was 1130 L (25.11 L/kg). Maintenance of the blood pressure effect over the 24-hour dosing interval was observed with little difference in peak and trough variation effect. When compared with historical adult pharmacokinetics the parameters observed in this study indicate that once daily dosing is appropriate.
Use in hepatic impairment:
Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.
In patients with renal failure
Amlodipine is extensively metabolised to inactive metabolites. 10% of the parent compound is excreted unchanged in urine. Changes in amlodipine plasma concentration are not correlated with degree of renal impairment. Therefore the normal dosage is recommended. Amlodipine is not dialysable.
Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.
Fertility
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility.
Pregnancy
The safety of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses.
Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
Breast-feeding
It is not known whether amlodipine is excreted in breast milk.
A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the woman.
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Effects of amlodipine on other medicinal products
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporin.
Simvastatin: Co-administration of multiple doses of 10 mg of 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.
The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.
The following adverse reactions (ADR) have been observed and reported during treatment with amlodipine with the following frequencies: Very common (ADR ≥ 1/10); common (1/100 ≤ ADR < 1/10); uncommon (1/1000 ≤ ADR < 1/100); rare (1/10000 ≤ ADR < 1/1000); very rare (ADR < 1/10000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Blood and lymphatic system disorders: Very rare: Leukocytopenia, thrombocytopenia.
Immune system disorders: Very rare: Allergic reactions.
Metabolism and nutrition disorders: Very rare: Hyperglycaemia.
Psychiatric disorders: Uncommon: Insomnia, mood changes (including anxiety), depression. Rare: Confusion.
Nervous system disorders: Common: Somnolence, dizziness, headache (especially at the beginning of the treatment). Uncommon: Tremor, dysgeusia, syncope, hypoesthesia, paresthesia. Very rare: Hypertonia, peripheral neuropathy.
Eye disorders: Uncommon: Visual disturbance (including diplopia).
Ear and labyrinth disorders: Uncommon: Tinnitus.
Cardiac disorders: Common: Palpitations. Very rare: Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation).
Vascular disorders: Common: Flushing. Uncommon: Hypotension. Very rare: Vasculitis.
Respiratory, thoracic and mediastinal disorders: Uncommon: Dyspnoea, rhinitis. Very rare: Cough.
Gastrointestinal disorders: Common: Abdominal pain, nausea. Uncommon: Vomiting, dyspepsia, altered bowel habits (including diarrhoea and constipation), dry mouth. Very rare: Pancreatitis, gastritis, gingival hyperplasia.
Hepatobiliary disorders: Very rare: Hepatitis, jaundice, hepatic enzymes increased (usually accompanied by cholestasis).
Skin and subcutaneous tissue disorders: Uncommon: Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema. Very rare: Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity.
Musculoskeletal and connective tissue disorders: Common: Ankle swelling. Uncommon: Arthralgia, myalgia, muscle cramps, back pain.
Renal and urinary disorders: Uncommon: Micturition disorder, nocturia, increased urinary frequency.
Reproductive system and breast disorders: Uncommon: Impotence, gynecomastia.
General disorders and administration site conditions: Common: Oedema, fatigue. Uncommon: Chest pain, asthenia, pain, malaise.
Investigations: Uncommon: Weight increase, weight decrease.
Please inform your doctor of all undesirable effects upon drug administration.
In humans, experience with intentional overdose is limited.
Symptoms
Overdoses could result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Treatment
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.
Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10mg has been shown to reduce the absorption rate of amlodipine.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
Store in dry places, not exceeding 300C, protect from light.
The safety and efficacy of amlodipine in hypertensive crisis has not been established (including hypertensive urgencies, hypertensive emergencies).
Patients with cardiac failure
Patients with cardiac failure should be treated with caution. In a long-term, in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Use in patients with impaired hepatic function
The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.
Use in elderly patients
In the elderly, increase of the dosage should take place with care.
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 dialysable.
- Hypertension.
- Chronic stable angina pectoris.
- Vasospastic (Prinzmetal's) angina.
- Severe hypotension.
- Shock (including cardiogenic shock).
- Hypersensitivity to dihydropyridine derivatives, amlodipine or any of the excipients.
- Haemodynamically unstable heart failure after acute myocardial infarction.
- Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis).
Method of administration: Capsule for oral administration.
Posology
Adults
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.
In hypertensive patients, amlodipine has been used in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, amlodipine may be used as monotherapy or in combination with other antianginal medicinal products in patients with angina that is refractory to nitrates and/or to adequate doses of beta blockers.
No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.
Special populations
Elderly
Amlodipine used at similar doses in elderly or younger patients is equally well tolerated. Normal dosage regimens are recommended in the elderly, but increase of the dosage should take place with care.
Renal impairment
Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. Amlodipine is not dialysable.
Hepatic impairment
Dosage recommendations have not been established in patients with mild to moderate hepatic impairment; therefore dose selection should be cautious and should start at the lower end of the dosing range. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.
Paediatric population
Children and adolescents from 6 years to 17 years of age.
The recommended oral dose in paediatric patients aged 6-17 years is 2.5 mg once daily, up-titrated to 5 mg once daily if blood pressure goal is not achieved after 4 weeks. Doses in excess of 5 mg daily have not been studied in paediatric patients.
Children under 6 years old
No data are available.
Note: Dosage of amlodipine 10 mg: Use with Apitim 10.
Dosage of amlodipine 5 mg: Use with Apitim 5.
Doses of amlodipine 2.5 m: Use another suitable product.
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