Norvasc Tablets 5 mg.10 mg Tablet.

Hypertension

NORVASC is indicated for the treatment of mild to moderate hypertension. NORVASC may be combined with other antihypertensive medicines.

Coronary artery disease (CAD)

Angina pectoris

NORVASC is indicated for the treatment of angina pectoris.

Chronic stable angina

NORVASC is indicated for the first line treatment of myocardial ischaemia, whether due to fixed obstruction (stable angina) and/or vasospasm/vasoconstriction (Prinzmetal's or variant angina) of coronary vasculature. NORVASC may be used alone, as monotherapy, or in combination with other antianginal medicines.

Coronary artery disease

NORVASC is indicated to reduce the risk of coronary revascularisation and the need for hospitalisation due to angina in patients with coronary artery disease. NORVASC is also indicated to reduce the risk of fatal coronary heart disease and non-fatal myocardial infarction, and to reduce the risk of stroke.

Posology

Hypertension and angina pectoris

The initial dose is 5 mg NORVASC once daily, which may be increased to a maximum dose of 10 mg depending on the individual patient's response after 10 u2013 14 days therapy. No dose adjustment of NORVASC is required during combined administration of thiazide diuretics, beta blockers, or angiotensin converting enzyme inhibitors.

Coronary artery disease

The recommended dosage range is 5 u2013 10 mg once daily. In clinical studies the majority of patients required 10 mg.

Special populations

Use in the elderly

The usual dosage regimens are recommended.

Use in patients with impaired hepatic function

NORVASC should be administered with caution in these patients.

Use in renal failure

NORVASC may be used in such patients at normal doses. Changes in plasma concentrations are not correlated with degree of renal impairment.

Paediatric population

The recommended antihypertensive oral dose in paediatric patients ages 6 u2013 17 years is 2,5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in paediatric patients. The effect of NORVASC on blood pressure in patients less than 6 years of age is not known.

Method of administration

For oral use.

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• NORVASC is contraindicated in patients with a known hypersensitivity to dihydropyridines, amlodipine, or to any of the excipients.
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• Concomitant use with grapefruit juice (see section 4.5).
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Concomitant use with potent cytochrome CYP3A4 medicines

The blood pressure lowering effect may be enhanced when potent CYP3A4 inhibitors such as ketoconazole, itraconazole or ritonavir are co-administered (see section 4.5).

Use in the elderly

The time to reach peak plasma concentrations of NORVASC is variable and not significantly different between elderly and younger subjects. NORVASC clearance is decreased with resulting increases in AUC (40 u2013 60 %) and elimination half-life in elderly patients. AUC and elimination half-life in patients with congestive heart failure (CHF) were increased with age. Elderly patients should start NORVASC therapy at a lower dose.

Use in patients with renal failure

NORVASC may be used at normal doses in patients with renal impairment. Changes in amlodipine plasma concentrations are not correlated with the degree of renal impairment. In patients with severe renal impairment, NORVASC doses may need to be reduced. NORVASC is not dialysable.

Use in patients with impaired hepatic function

The half-life of NORVASC is prolonged in patients with impaired liver function. NORVASC should therefore be administered at lower (5 mg) initial dose in these patients.

Use in patients with heart failure

In a long-term, placebo-controlled study (PRAISE-2) of NORVASC in patients with New York Heart Association (NYHA) class III and IV heart failure of non-ischaemic etiology, NORVASC was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

NORVASC has been administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerine, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral hypoglycaemic medicines.

In vitro data from studies with human plasma indicate that NORVASC has no effect on protein binding of the medicines tested (digoxin, phenytoin, warfarin, or indomethacin).

Simvastatin

Co-administration of multiple doses of 10 mg NORVASC with simvastatin resulted in a 77 % increase in exposure to simvastatin compared to simvastatin alone (see simvastatin professional information).

Grapefruit juice

Co-administration of 240 mL of grapefruit juice with a single oral dose of NORVASC 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of NORVASC. The study did not allow examination of the effect of genetic polymorphism in CYP3A4, the primary enzyme responsible for metabolism of NORVASC; therefore, administration of NORVASC with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients, resulting in increased blood pressure lowering effects (see section 4.3).

CYP3A4 inhibitors

Co-administration of a 180 mg daily dose of diltiazem with 5 mg NORVASC in elderly hypertensive patients (69 to 87 years of age) resulted in a 57 % increase in NORVASC systemic exposure and a significant further decrease in systolic blood pressure than with NORVASC alone. Strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of NORVASC. NORVASC should be used with caution when administered with CYP3A4 inhibitors (see section 4.4).

Clarithromycin

Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with NORVASC. Close observation of patients is recommended when NORVASC is co-administered with clarithromycin. There is no information on the effect of the combination on the QT interval.

CYP3A4 inducers

There is no data available regarding the effect of CYP3A4 inducers on NORVASC. Concomitant use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum) may decrease the plasma concentrations of NORVASC. NORVASC should be used with caution when administered with CYP3A4 inducers.

In the following studies, there were no significant changes in the pharmacokinetics of either NORVASC or another medicine within the study, when co-administered.

Special studies: Effect of other medicines on NORVASC

Cimetidine

Co-administration with cimetidine did not alter the pharmacokinetics of NORVASC.

Aluminium/magnesium (antacid)

Co-administration of an aluminium/magnesium antacid with a single dose of NORVASC had no significant effect on the pharmacokinetics of NORVASC.

Sildenafil

A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of NORVASC. When NORVASC and sildenafil were used in combination, each medicine independently exerted its own blood pressure lowering effect.

Special studies: Effect of NORVASC on other medicines

Digoxin

Co-administration of NORVASC with digoxin did not change serum digoxin levels or digoxin renal clearance in healthy volunteers.

Ethanol (alcohol)

Single and multiple 10 mg doses of NORVASC had no significant effect on the pharmacokinetics of ethanol.

Warfarin

Co-administration of NORVASC with warfarin did not change the warfarin prothrombin response time.

Ciclosporin

No medicine interaction studies have been conducted with ciclosporin and NORVASC in healthy volunteers or other populations, with the exception of renal transplant patients. Various studies in renal transplant patients report that co-administration of NORVASC with ciclosporin increased the trough concentrations of ciclosporin and increased ciclosporin toxicity, from no change up to an average increase of 40 %. Consideration should be given for monitoring ciclosporin levels in renal transplant patients on NORVASC.

Tacrolimus

There is a risk of increased tacrolimus blood levels and toxicity when co-administered with NORVASC. In order to avoid toxicity of tacrolimus, administration of NORVASC in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Medicine/laboratory test interactions

None known.

Safety of NORVASC in pregnancy or lactation has not been established.

NORVASC can cause dizziness. The patientu2019s ability to drive or use machinery should be individually assessed.

Tabulated summary of adverse reactions

The following adverse events, listed according to the system organ class have been categorised as follows: Very common ( u2265 1/10); common ( u2265 1/100 to < 1/10); uncommon ( u2265 1/1 000 to < 1/100); rare ( u2265 1/10 000 to < 1/1 000); very rare ( < 1/10 000).

MedDRA System Organ Class Frequency Undesirable effects

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• Blood and lymphatic system disorders Uncommon Leukopenia, thrombocytopenia
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• Immune system disorders Rare Allergic reaction including pruritus, rash, angioedema and erythema multiforme
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• Metabolism and nutrition disorders Uncommon Hyperglycaemia
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• Psychiatric disorders Uncommon Insomnia, mood changes
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• Nervous system disorders Common Somnolence, dizziness, headache
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• Uncommon Tremor, dysgeusia, syncope, hypoaesthesia, paraesthesia, hypertonia, peripheral neuropathy, extrapyramidal disorder
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• Eye disorders Uncommon Visual impairment
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• Ear and labyrinth disorders Uncommon Tinnitus
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• Cardiac disorders Common Palpitations
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• Very rare Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), chest pain
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• Vascular disorders Common Flushing
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• Uncommon Hypotension, vasculitis
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• Respiratory, thoracic and mediastinal disorders Uncommon Dyspnoea, rhinitis, cough
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• Gastrointestinal disorders Common Abdominal pain, nausea
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• Uncommon Vomiting, dyspepsia (including gastritis), altered bowel habits, dry mouth, pancreatitis, gingival hyperplasia
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• Hepatobiliary disorders Very rare Hepatitis, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis)
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• Skin and subcutaneous tissue disorders Uncommon Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash
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• Very rare Angioedema, erythema multiforme, urticaria
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• Musculoskeletal and connective tissue disorders Uncommon Arthralgia, myalgia, muscle spasms, back pain
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• Renal and urinary disorders Uncommon Micturition disorder, nocturia, pollakiuria
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• Reproductive system and breast disorders Uncommon Erectile dysfunction, gynaecomastia
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• General disorders and administration site conditions Common Oedema, fatigue
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• Uncommon Asthenia, pain, malaise
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• Investigations Uncommon Weight increase, weight decrease
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Paediatric population

Paediatric patients (ages 6 u2013 17 years) Adverse events were similar to those seen in adults. In a study of 268 children, the most frequently reported adverse events were:

MedDRA System Organ Class Undesirable effects

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• Nervous system disorders Headaches, dizziness
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• Vascular disorders Vasodilation
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• Respiratory, thoracic, and mediastinal disorders Epistaxis
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• Gastrointestinal disorders Abdominal pain
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• General disorders and administration site conditions Asthenia
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Severe adverse events (predominantly headache) were experienced by 7,2 % with NORVASC 2,5 mg, 4,5 % with NORVASC 5 mg, and 4,6 % with placebo. The most common cause of discontinuation from the study was uncontrolled hypertension. There were no discontinuations due to laboratory abnormalities. There was no significant change in heart rate.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Available data suggest that overdosage could result in excessive peripheral vasodilation and possibly reflex tachycardia, with subsequent marked and prolonged systemic hypotension. Shock with fatal outcome has been reported. Administration of activated charcoal to healthy volunteers immediately after or up to 2 hours after NORVASC 10 mg ingestion has been shown to significantly decrease NORVASC absorption. Activated charcoal given 6 hours after NORVASC had no effect. Clinically significant hypotension due to NORVASC overdosage may need active cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. Treatment is symptomatic and supportive. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Since NORVASC is highly protein-bound, dialysis is not likely to be of benefit.