NORVASC^® reduces systolic blood pressure (mm Hg ) across a wide range of patients with hypertension¹

NORVASC^® significantly reduced the risk of CV events¹

ACCOMPLISH: Results from a multicentre, randomised, double-blind trial of amlodipine 5 to 10 mg once daily + benazepril 20 to 40 mg once daily or hydrochlorothiazide 12.5 to 25 mg once daily + benazepril 20 to 40 mg once daily in 11,506 patients with hypertension and at high risk for CV events. The primary endpoint was the composite of death from CV causes and CV events, defined as nonfatal myocardial infarction, stroke, hospitalisation for unstable angina, resuscitation after sudden cardiac arrest and coronary revascularization.¹

ACCOMPLISH: Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension; CV: cardiovascular,

RRR: relative risk reduction.

NORVASC^® significantly reduced cardiovascular mortality in patients with hypertension and ≥3 risk factors¹

ASCOT-BPLA: A multicentre, prospective, randomised, controlled trial, which included 19,257 patients with hypertension and 3 or more cardiovascular risk factors, who were randomly assigned to receive either an amlodipine-based regimen (amlodipine 5 to 10 mg with the addition of perindopril 4 to 8 mg, if needed) or an atenolol-based regimen (atenolol 50 to 100 mg with the addition of bendroflumethiazide 1.25 to 2.5 mg, if needed). The use of amlodipine-based therapy was associated with a nonsignificant 10% reduction in the incidence of the primary endpoint (HR 0.90, 95% CI 0.79-1.02, P =0.1052).¹

NORVASC^® demonstrated improved efficacy in stroke prevention compared with diuretics/beta-blockers, ARBs and ACEIs^1,2

Adapted from Staessen JA, et al. Hypertens Res. 2005; Messerli FH, et al. Hypertension. 2006.

Pooled odds ratio with 95% CIs were computed from the number of events and the number of patients per group randomly assigned in each trial by use of stratified 2 x 2 contingency tables.²

CCBs reduced stroke risk by 18% vs. other classes of antihypertensive agents³

Rothwell PM, et al: The Review discusses shortcomings of the usual blood-pressure hypothesis, provides background to accompanying reports on the importance of blood-pressure variability in prediction of risk of vascular events and in accounting for benefits of antihypertensive drugs, and draws attention to clinical implications.³

ACEI: angiotensin-converting enzyme inhibitor; ALLHAT: Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial; ARB: angiotensin II receptor blocker; ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial; BB: beta-blocker; BB/D: beta-blocker/diuretic; BPV: blood pressure variability; CAMELOT: Comparison of Amlodipine vs Enalapril to limit Occurrences of Thrombosis Trial; CCB: calcium-channel blocker; Cl: confidence interval; IDNT: Irbesartan Type II Diabetic Neuropathy Trial; INVEST: lnternationalVerapamil Trandolapril Study; NORDIL: Nordic Diltiazem study; PREVENT: Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial. SBP: systolic blood pressure; SD: standard deviation; VALUE: Valsartan Antihypertensive Long-term Use Evaluation trial.

NORVASC^® provides 24-hour continuous reductions in systolic blood pressure¹

Results from a double-blind, randomised, parallel, placebo-controlled study to evaluate the effect of amlodipine on ambulatory blood pressure in patients (N= 16) with hypertension. Ambulatory blood pressure was measured for 24 hours at 30-minute intervals at the end of the placebo run-in phase and again after 4 weeks of double-blind therapy. Hourly blood pressures were calculated as the average of the measurements taken at 2 consecutive points.¹

NORVASC^® significantly reduced blood pressure variability in patients with hypertension vs. atenolol (all P<0.0001)¹

ASCOT-BPLA: A multicentre, prospective, randomized, controlled trial, which included 19,257 patients with hypertension and 3 or more cardiovascular risk factors but no coronary heart disease, who were randomly assigned to receive either an amlodipine-based regimen (amlodipine 5 to 10 mg with the addition of perindopril 4 to 8 mg, if needed) or an atenolol-based regimen (atenolol 5O to 100 mg with the addition of bendroflumethiazide 1.25 to 2.5 mg, if needed).¹

In the X-CELLENT trial,
NORVASC^® significantly reduced 24-hour systolic BPV vs. candesartan²

The X-CELLENT study was a multicentre, randomised, double-blind, placebo-controlled study conducted in 2370 outpatients with essential hypertension. The inclusion criteria included SBP ≥150 mm Hg and <180 mm Hg and DBP ≥95 mm Hg and <110 mm Hg or SBP ≥160 mm Hg and <80 mm Hg and DBP <90 mm Hg. After a 4-week selection and run-in placebo period, 1762 subjects were randomised to receive placebo, indapamide SR (1.5 mg), candesartan (8.0 mg) or amlodipine (5.0 mg), all given once daily in the morning for a treatment period of 12 weeks. ABPM data were analysed in 577 patients before and after 3 months of anti hypertensive treatment to investigate the effect of different anti hypertensive agents on BP and BPV.²

CCBs show 24% reduction of systolic BPV than other classes of antihypertensive agents³

From an analysis of 6 large, randomised trials of CCBs versus beta-blockers, ARBs or ACEls in which the mean SBP and systolic BPV (estimated by SD) during follow-up were reported by the treatment group. The variance ratio is an estimate of the difference in variation in SBP between the groups (SD2 /SD2). Group SD SBP was lower on CCBs despite no overall difference in mean SBP.³

ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm; BP: blood pressure; BPV: blood pressure variability;  DBP: diastolic blood pressure; SR: sustained release; SBP: systolic blood pressure; X-CELLENT: Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients.

NORVASC^® provides significantly greater reductions of morning systolic BP surge vs. nifedipine²

An open crossover study of patients (N=40) with mild to moderate essential hypertension (DBP between 95 and 115 mm Hg). Patients were randomly divided into 2 groups: Group A received amlodipine and then nifedipine GITS; Group B received these treatments in the reverse order. Initial doses were amlodipine 5 mg or nifedipine GITS 30 mg. If BP control (defined as DBP <90 mm Hg or 10% reduction from baseline) was not achieved after 2 weeks, the dose of either medication could be doubled (to amlodipine 10 mg or nifedipine GITS 60 mg). Each treatment phase lasted 12 weeks. Before and after each treatment phase, 24-hour ABPM was performed, with measurements obtained every 15 minutes between 7 AM and 11 PM, and every 30 minutes between 11 PM and 7 AM. Both drugs significantly reduced BP.²

The study evaluated  the effects of monotherapy with the long-acting angiotensin II receptor blocker valsartan compared with the long-acting calcium antagonist amlodipine on ambulatory and morning BP. Ambulatory BP was monitored before and after once-daily dose of valsartan (valsartan group, n = 38) and amlodipine (amlodipine group, n = 38) therapy in 76 hypertensive patients. To achieve the target BP of ≤140/90 mm Hg, valsartan was titrated from 40 mg/day to 160 mg/day (mean dose 124 mg/day) and amlodipine was titrated from 2.5 mg/day to 10 mg/day (mean dose 6.4 mg/day).¹
BP: blood pressure

Dosing Recommendations of NORVASC^®1

Important Safety Information:¹

Therapeutic indications - Hypertension and Chronic stable angina and Vasospastic angina (Prinzmetal’s angina).¹

Contraindications - Amlodipine is contraindicated in patients with: Hypersensitivity to dihydropyridine derivatives, amlodipine or to any of the excipients listed here NORVASC 5mg Hard Capsule: Microcrystalline cellulose, Dried maize starch, Magnesium stearate. Composition of the hard-capsule coat: gelatine, yellow of quinoline, black iron oxide, titanium dioxide, Printing ink: lacquer gum, black iron oxide. NORVASC 10 mg Hard Capsule: Microcrystalline cellulose, Dried maize starch, Magnesium stearate. Composition of the hard gelatine coat: gelatine, yellow of quinoline, black iron oxide, yellow iron oxide titanium dioxide, Printing ink: lacquer gum, black iron oxide.; Severe hypotension; shock (including cardiogenic shock); Obstruction of ejection route of left ventricle (e.g. high degree of aortic stenosis); cardiac failure hemodynamically unstable following acute myocardial infarction.¹

Pregnancy and lactation - Fertility, pregnancy and lactation. Pregnancy category: There are no adequate and well controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the risk to the fetus. There are insufficient clinical data regarding the potential effect of amlodipine on fertility. Lactation: There is no data regarding the excretion of amlodipine in the breast milk. Interactions with other medicinal products and other forms of interaction.¹

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.¹

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). ¹

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. ¹

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.¹

Over dosage in humans - experiencing intentional overdose is limited. Symptoms the available data suggest that significant overdose may cause excessive peripheral vasodilation, and possibly, reflex tachycardia. Pronounced and possibly prolonged systemic hypotension has been reported to lead to shock with a fatal outcome. Treatment Clinically significant hypotension due to amlodipine overdose requires active cardiovascular support including frequent monitoring of the respiratory and cardiac functions, keeping the extremities elevated and treating the volemic and urinary volume.¹

Safety profile summary - Very common (≥1/10); common (≥1/100 to <1/10); the most commonly reported adverse reactions during treatment are drowsiness, dizziness, headaches, palpitations, vasomotor flushes, abdominal pain, nausea, ankle swellings, fatigue, asthenia, muscle cramps, dypesia, altered bowel habits, dyspnoea, visual disturbances, somnolence, (very common) oedemas.¹

Norvasc ^® (Amlodipine) Abbreviated Prescribing Information

Presentation: Norvasc is supplied as 5 mg yellow and white hard capsule with AML5 printed in black on one side and the Pfizer logo on the other, containing Amlodipine Besylate. Indications: Hypertension, Chronic stable angina pectoris and Vasospastic (Prinzmetal's) angina. Dosage and Administration: 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. No dose adjustment of Norvasc is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors. Elderly patients: 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. Children and adolescents with hypertension (6 - 17 years): Recommended oral dose 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 of amlodipine 2.5 mg are not possible with this medicinal product. Children under 6 years old: No data are available. Method of administration: Hard capsule for oral administration. Contraindications: 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 warnings and precautions: The safety and efficacy of amlodipine in hypertensive crisis has not been established. Patients with cardiac failure: 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 Amlodipine should 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: Increase of the dosage should take place with care. Patients with renal impairment: Amlodipine may be used at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable. Sodium: The medication contains less than 1mmol sodium (23mg) per capsule, this is to say essentially ‘sodium -free’. Interactions: CYP3A4 inhibitors Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (e.g., 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, which may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required. CYP3A4 inducers: 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): 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. Other drugs with antihypertensive properties: 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. Monitoring of tacrolimus blood levels is required and dose adjustment of tacrolimus when appropriate. Use of 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: 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. Atorvastatin, digoxin & warfarin: In clinical interaction studies, amlodipine did not affect the pharmacokinetics of these drugs. Fertility, Pregnancy and lactation: Pregnancy: The safety of amlodipine in human pregnancy has not been established. Breast-feeding: Amlodipine is excreted in human milk. 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. Fertility: Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility. 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: Commonly reported adverse reactions during treatment are somnolence, dizziness, headache (especially at the beginning of the treatment), visual disturbance (including diplopia), palpitations, flushing, dyspnoea, abdominal pain, nausea, dyspepsia, altered bowel habits, (including diarrhoea and constipation), ankle swelling, muscle cramps, oedema, fatigue and asthenia. Overdose: Symptoms: 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: 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. Dialysis is not likely to be of benefit. Pharmaceutical precautions: Store below 30 °C. Do not use Norvasc after the expiry date which is stated on the carton/blister label after EXP: The expiry date refers to the last day of that month. Keep out of the sight and reach of children.
Reference: Norvasc SmPC Gulf States, Jordan and Iraq: Revision dated November 2020 for UAE (Registered 5mg capsule), Qatar (Registered 5mg capsule), Bahrain (Registered 5mg capsule), Jordan (Registered 5mg and 10mg capsule) & Iraq (Registered 5mg capsule); September 2020 for Oman (Registered 5mg capsule) & Kuwait (Registered 5mg capsule).

Date of Document: 16^th of January 2023

Full prescribing information is available upon request.