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  • Norvasc®
    / Pfizer


    Active Ingredient
    Amlodipine Besylate 5 mg, 10 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Tablets

    20 X 5 mg

    partial basket chart 9109 14042

    Tablets

    30 X 5 mg

    partial basket chart 27186

    Tablets

    20 X 10 mg

    partial basket chart 9110 14043

    Tablets

    30 X 10 mg

    partial basket chart 27185

    Dosage

    Adults: For both hypertension and angina, the usual initial dose is 5 mg once daily which may be increased to a maximum dose of 10 mg depending on the individual patient’s response.
    In hypertensive patients, Norvasc® has been used as monotherapy or in combination with a thiazide diuretic, alpha blocker, beta blocker, or an angiotensin converting enzyme inhibitor. For angina, Norvasc® may be used as monotherapy or in combination with other antianginal medicinal products.
    No dose adjustment of Norvasc® is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors.
    Dosage should be adjusted according to each patient’s need. In general, titration should proceed over 7 to 14 days so that the physician can fully assess the patient’s response to each dose level. Titration may proceed more rapidly, however, if clinically warranted, provided the patient is assessed frequently.
    Small, fragile or elderly individuals, or patients with hepatic insufficiency may be started on 2.5 mg once daily, and this dose may be used when adding Norvasc® to other antihypertensive or antianginal drugs.
    Increases in AUC and elimination half life in patients with congestive heart failure were as expected for the patient age group studied.
    Elderly patients: Norvasc® 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 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.
    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.
    Children under 6 years old: No data are available.
    Method of administration: Tablet for oral administration.


    Indications

    Treatment of mild to moderate Hypertension. It may be used alone or in combination with other antihypertensive agents.
    Treatment of chronic stable Angina. Norvasc® may be used alone or in combination with other antianginal agents.
    Treatment of confirmed or suspected vasospastic Angina (Prinzmetal’s or variant Angina). Norvasc® may be used as monotherapy or in combination with other antianginal drugs.


    Contra-Indications

    Hypersensitivity to dihydropyridine derivatives, amlodipine or to 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 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. 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.
    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.


    Side Effects

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


    Drug interactions

    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: 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).
    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.
    Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. 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.
    Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
    Cyclosporine: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% -40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.
    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.
    In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.


    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.
    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.


    Overdose

    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.


    Important notes

    Storage: Store below25°C. protect from light


    Manufacturer
    R-PHARM Germany GmbH, Illertissen, Germany
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