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    Amlodipine, 5 mg tablets

    Drug formTablets

    ATC categoryCardiology, angiology

    ATC subcategoryCalcium channels blockers

    Brand nameAmlodipine

    Generic nameAmlodipine

    Composition

    Each tablet contains:

    active ingredient: amlodipine (as besylate)–5 mg;
    excipients: calcium phosphate dibasic, microcrystalline cellulose (avicel), sodium starch glycolate, magnesium stearate.

    Pharmaceutical form

    Tablets
    White or off white biconvex scored tablets.

    Chemical name and CAS number

    3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.
    111470-99-6.

    Pharmacological group and ATC code

    Calcium channel blockers, selective calcium channel blockers with mainly vascular effects. C08CA01

    Clinical particulars

    Therapeutic indications

    Hypertension
    Chronic stable angina pectoris
    Vasospastic (Prinzmetal’s) angina.

    Posology and method of administration

    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 patients

    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 (see sections 4.4 and 5.2).

    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 (see sections 4.4 and 5.2). 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.

    Patients with 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.

    Paediatric population

    Children and adolescents with hypertension from 6 years to 17 years of age.
    The recommended antihypertensive oral dose in paediatric patients ages 6-17 years is 2.5 mg once daily as a starting dose, 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 (see sections 5.1 and 5.2).

    Children under 6 years old

    No data are available.
    Method of administration
    Tablet for oral administration.

    Contraindications
    Amlodipine is contraindicated in patients with:

  • hypersensitivity to dihydropyridine derivatives, amlodipine or to any of the excipients listed in section 6.1;
  • severe hypotension.
    • Special warnings and precautions for use

    The safety and efficacy of amlodipine in hypertensive crisis has not been established.

    Patients with cardiac failure

  • Patients with heart failure should be treated with caution. In a long-term, placebo controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group (see section 5.1). 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.


    • Patients with hepatic impairment

  • 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 (see sections 4.2 and 5.2).


    • Patients with renal impairment

  • 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.dialysable.
    • Interaction with other medicinal products and other forms of interaction

    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 resulting in an increased risk of hypotension. 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 hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, 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 cyclosporine.


    • 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.
    • 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 (see section 5.3).
  • 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 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 amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).
    • Effects on 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.
    Undesirable effects

    Summary of the safety profile:

    The most commonly reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

    Tabulated list of adverse reactions

    The following adverse reactions have been observed and reported during treatment with amlodipine with the following 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

    System organ class
    Frequency
    Adverse reactions
    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
  • Rare
  • Common
    		•
  • Depression, mood changes (including anxiety), insomnia.
  • Confusion.
  • Somnolence, dizziness, headache (especially at the beginning of the treatment).
    		•
    Nervous system disorders
  • Common
  • Uncommon
  • Very rare
    		•
  • Somnolence, dizziness, headache (especially at the beginning of the treatment).
  • Tremor, dysgeusia, syncope, hypoaesthesia, paraesthesia.
  • Hypertonia, peripheral neuropathy.
    		•
    Eye disorders Uncommon Visual disturbance (including diplopia)
    Ear and labyrinth disorders
  • Uncommon
  • Common
    		•
  • Tinnitus
  • Palpitations
    		•
    Cardiac disorders Uncommon Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)
    Vascular disorders
  • Common
  • Uncommon
  • Very rare
    		•
  • Hyperemia
  • Hypotension
  • Vasculitis
    		•
    Respiratory, thoracic and mediastinal disorders
  • Common
  • Uncommon
    		•
  • Dyspnoea, rhinitis
  • Cough
    		•
    Gastrointestinal disorders
  • Common
  • Uncommon
  • Very rare
    		•
  • Abdominal pain, nausea.
  • Vomiting, dry mouth, dyspepsia, altered bowel habits (including diarrhoea and constipation).
  • Pancreatitis, gastritis, gingival hyperplasia
    		•
    Hepatobiliary disorders Very rare Hepatitis, jaundice, hepatic enzyme increased*
    Skin and subcutaneous tissue disorders
  • Uncommon


  • Very rare
    		•
  • Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema.
  • Angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity, urticaria.
    		•
    Musculoskeletal and connective tissue disorders
  • Common
  • Uncommon
    		•
  • Ankle swelling
  • Arthralgia, myalgia, back pain, muscle cramps
    		•
    Renal and urinary disorders Uncommon Micturition disorder, nocturia, increased urinary frequency.
    Reproductive system and breast disorders Uncommon Impotence, gynaecomastia
    General disorders and administration site conditions
  • Common
  • Uncommon
    		•
  • Fatigue, Oedema
  • Chest pain, asthenia, pain, malaise
    		•
    Investigations Uncommon Weight increased, weight decreased



    *mostly consistent with cholestasis

    Exceptional cases of extrapyramidal syndrome have been reported.

     

    Overdoseage

    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.

    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 10 mg has been shown to reduce the absorption rate of amlodipine.

    Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

    Pharmacokinetic properties
    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.

    The bioavailability of amlodipine is not affected by food intake.

    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.

    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%.

    Elderly population

    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.

    Paediatric population

    A population PK study has been conducted in 74 hypertensive children aged from 1 to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited.

    Preclinical safety data

    Reproductive toxicology

    Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

    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/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m2 basis). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

    Carcinogenesis, mutagenesis

    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 rats 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.

    Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

    *Based on patient weight of 50 kg.

    Incompatibilities

    Not applicable.

    Presentation

    3 blister packets with 10 tablets in each with insert leaflet in the cardboard box.

    Expiry date

    3 years.

    Storage conditions

    Store at temperature not higher than 250C, out of the reach of children, in original pack.

    Special precautions for disposal and other handling

    Any unused products and waste materials should be disposed of in accordance with local regulations.