Full Prescribing Info
Amlodipine besylate.
Each uncoated tablet contains: S (-) Amlodipine Besylate equivalent to S (-) Amlodipine 2.5 mg/5 mg.
Excipients/Inactive Ingredients: Microcrystalline cellulose, dibasic calcium phosphate dihydrate, yellow iron oxide, colloidal silicon dioxide, sodium starch glycolate and magnesium stearate.
Pharmacotherapeutic group: Selective calcium channel blockers with mainly vascular effects - Dihydropyridine derivatives. ATC Code: C08CA.
Pharmacology: Pharmacodynamics: S(-) Amlodipine is a pharmacologically active enantiomer of amlodipine. S(-) Amlodipine is an allosteric modulator and acts on the L-type of calcium channels. Receptor binding studies have shown that out of the two forms only the (S)-enantiomer of amlodipine binds to and blocks L-type calcium channels whereas the (R)-enantiomer has no activity on these channels.
The mechanism of the antihypertensive action of S(-) Amlodipine is due to a direct relaxant effect on vascular smooth muscle.
The precise mechanism by which S(-) Amlodipine relieves angina has not been fully determined but the following two actions play a role: 1. Decreases peripheral resistance by arteriolar vasodilatation leading to the reduction in oxygen requirement and energy consumption of cardiac smooth muscles.
2. Decreases coronary vascular resistance and can lead to an increase in coronary blood flow.
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure (in both supine and standing positions) throughout the 24 hour interval.
In patients with angina, once daily administration of amlodipine increases total exercise time, the delay of occurrence of anginal attack and the delay of the occurrence of a 1-mm ST interval. Amlodipine decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
Pharmacokinetics: Absorption/Distribution: Administration of S(-) Amlodipine (2.5 mg) as a single dose gives maximum plasma concentration (Cmax) of 8.3 to 9.3 ng/mL in 2 to 3 hrs (Tmax). S(-) Amlodipine shows approximately 93% plasma protein binding in hypertensive patients. The mean AUC0-t value (t = 48 hrs) of S(-) Amlodipine tablets (2.5 mg) is 95±14 ng·hr/mL.
Metabolism/Elimination: S(-) 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. The plasma elimination half-life of S(-) Amlodipine has been found to be 31±13 hrs.
Sampine tablet is indicated for hypertension and chronic stable angina pectoris.
Dosage/Direction for Use
Adults: For both hypertension and angina, the usual initial dose is 2.5 mg S(-) Amlodipine once daily which may be increased to a maximum dose of 5 mg depending on the individual patient's response.
Elderly patients: S(-) 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.
Patients with renal impairment: Changes in S(-) Amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. S(-) Amlodipine is not dialyzable.
Patients with 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 S(-) Amlodipine have not been studied in severe hepatic impairment. S(-) Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.
Method of administration: Oral administration.
In humans, experience with intentional overdose is limited.
Symptoms: 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 in amlodipine which can be applicable to S(-) Amlodipine as well.
Treatment: Clinically significant hypotension due to S(-) 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. Since S(-) Amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
S (-) Amlodipine is contraindicated in patients with: Hypersensitivity to dihydropyridine derivatives, amlodipine 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 Precautions
The safety and efficacy of S(-) Amlodipine in hypertensive crisis has not been established.
Patients with cardiac failure: Patients with heart failure should be treated with caution. Calcium channel blockers, including S(-) 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 S(-) Amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. S(-) 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 renal failure: S(-) Amlodipine may be used in such patients at normal doses. Changes in S(-) Amlodipine plasma concentrations are not correlated with degree of renal impairment. S(-) Amlodipine is not dialyzable.
Effects on Ability to Drive and Use Machines: S(-) Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking S(-) Amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.
Use in the Elderly: In the elderly increase of the dosage should take place with care.
Use In Pregnancy & Lactation
Pregnancy: The safety of S(-) Amlodipine in human pregnancy has not been established.
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.
Lactation: It is not known whether S(-) Amlodipine is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with S(-) Amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of S(-) Amlodipine therapy to the mother.
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 S(-) Amlodipine on fertility.
Adverse Reactions
On the basis of clinical data, only minor side effects have been reported with the use of S(-) Amlodipine. Adverse events were of mild in nature and no serious adverse events were reported. In a postmarketing surveillance study of S (-)Amlodipine, it was found to be well tolerated (n = 353) in patients with hypertension. Only 78 patients (out of 353) reported side effects.
Classification of expected frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Gastrointestinal disorders: Common: Constipation.
Uncommon: Nausea, dyspepsia.
Hepatobiliary disorders: Uncommon: Increased liver enzymes.
Nervous system disorders: Common: Dizziness, headache.
Vascular disorders: Common: Orthostatic hypotension, Pedal edema, flushing.
Ear and labyrinth disorders: Uncommon: Tinnitus, Vertigo.
Psychiatric disorders: Uncommon: Sleeping disorder, Irritability, anxiety, Emotional lability, Memory deterioration.
Cardiac disorders: Uncommon: Palpitation.
General disorders and administration site conditions: Common: Fatigability.
Uncommon: Weakness.
Adverse Drug Reaction: Inform doctors about unexpected reactions after using drugs.
Drug Interactions
CYP3A4 inhibitors: Concomitant use of S(-) 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 S(-) Amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, Hypericum perforatum) may give a lower plasma concentration of S(-) Amlodipine. S(-) Amlodipine should be used with caution together with CYP3A4 inducers.
Administration of S(-) 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 hyperkalemia after administration of verapamil and dantrolene I.V. Due to risk of hyperkalemia, it is recommended that the co administration of calcium channel blockers such as S(-) Amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Effects of S(-) Amlodipine on other medicinal products: The blood pressure lowering effects of S(-) Amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.
Simvastatin: Limit the dose of simvastatin in patients on S(-) Amlodipine to 20 mg daily.
Store below 30°C.
Shelf-Life: 36 months.
MIMS Class
Calcium Antagonists
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.
Tab (light yellow, round shaped, flat face, beveled edged, uncoated with 'K' embossed on one side and plain on other side) 2.5 mg x 2 x 14's. 5 mg x 2 x 14's.
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