Amlovie® 5 (Amlodipine 5mg)
Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers with mainly vascular effects. ATC code: C08CA01.
Each tablet contains 5 mg amlodipine (as amlodipine besilate).
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 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 dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal’s or variant angina).
- Chronic stable angina pectoris.
- Vasospastic (Prinzmetal’s) angina pectoris.
Posology and mode of administration
Adults: For treatment of both hypertension and angina pectoris the usual initial dose is 5 mg once daily. If the desired therapeutic effect cannot be achieved within 2-4 weeks this dose may be increased to a maximum dose of 10 mg daily (as single dose) 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.
- 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.
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.
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.
Pediatric population: Children with hypertension from 6 years to 17 years of age: the recommendedantihypertensive oral dose in paediatric patient’s ages 6-17 years is 2.5 mg oncedaily as a starting dose, up-titrated to 5 mg once daily if blood pressure goal isnot achieved after 4 weeks. Doses in excess of 5 mg daily have not beenstudied in paediatric patients.
Children under 6 years old: the effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
Method of administration
Tablet for oral administration.
Amlodipine is contra-indicated in patients with:
- hypersensitivity to amlodipine, dihydropyridine derivatives or any of the Excipients.
- severe hypotension,
- shock, including cardiogenic shock,
- obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis),
- haemodynamically unstable heart failure after acute myocardial infarction.
Special warning and precautions for use
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
Cardiac failure: Patients with heart failure should be treated with caution. In a long-term, placebocontrolled study in patients with severe heart failure (NYHA class III and IV) thereported incidence of pulmonary oedema was higher in the amlodipine treatedgroup than in the placebo group, but this was not indicating an aggravation of theheart failure. Calcium channel blockers, including Amlodipine, should be usedwith caution in patients with congestive heart failure, as they may increase therisk of future cardiovascular events and mortality.
Myocardial infarction: There are no data to support the use of amlodipine alone, during or within one month of a myocardial infarction.
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.
Elderly patients: In the elderly, increase of the dosage should take place with care.
Renal failure: Amlodipine may be used in such patients at normal doses. Change in Amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialyzable.
Interactions with other medicinal products and other forms of interactions
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: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).
Consumption of grapefruit/grapefruit juice should be avoided while taking amlodipine. The intake of grapefruit juice may result in increased plasma amlodipine concentrations, which may enhance the blood pressure lowering effects of amlodipine. This interaction has been observed with other dihydropyridine calcium antagonists and represents a class effect.
Fertility, pregnancy and lactation
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.
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.
Lactation: Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. 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 mother.
Effects on the ability to drive and use machines
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.
The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.
In humans, experience with intentional overdose is limited.
Symptoms: Available data suggest that large 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.
Management: 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.