Pendine 5 mg, 10 mg Tablets.

Hypertension

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

Coronary artery disease (CAD)

Angina pectoris

PENDINE is indicated for the treatment of angina pectoris.

Chronic stable angina

PENDINE 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. PENDINE may be used alone, as monotherapy, or in combination with other antianginal medicines.

Coronary artery disease

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

Hypertension and angina pectoris

Adults

The initial dose is 5 mg PENDINE once daily, which may be increased to a maximum dose of 10 mg depending on the individual patientu2019s response after 10 u2013 14 days of therapy.

No dose adjustment of PENDINE 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

PENDINE should be administered with caution in these patients.

Use in renal failure

PENDINE 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 PENDINE on blood pressure in patients less than 6 years of age is not known.

Method of administration

For oral use.

• Hypersensitivity to amlodipine, dihydropyridines or to any of the excipients listed in section 6.1.
• 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.
• Concomitant use with grapefruit juice (see section 4.5).

The safety and efficacy of amlodipine in hypertensive crisis have 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 (New York Heart Association [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 PENDINE, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

PENDINE may have a negative inotropic effect. The area under the curve (AUC) of PENDINE may increase in patients with heart failure.

Patients with hepatic impairment

The half-life of PENDINE is prolonged and AUC values are higher in patients with impaired hepatic function. PENDINE should therefore be administered at lower initial doses in these patients.

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

Amlodipine clearance is decreased (40 u2013 60 %) in the elderly, which results in increases of amlodipine concentration in the area under the concentration-time curve (AUC) and elimination half-life. Therefore, increase of the dosage should take place with care (see section 5.2).

Patients with renal impairment

PENDINE may be used at normal doses in patients with renal impairment. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.

Porphyria

Safety has not been established.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Grapefruit juice

Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg, such as PENDINE, in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine. The study did not allow examination of the effect of genetic polymorphism in CYP3A4, the primary enzyme responsible for metabolism of PENDINE; therefore, administration of PENDINE 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).

Effects of other medicines on PENDINE

CYP3A4 inhibitors

Concomitant use of PENDINE 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 PENDINE exposure, resulting in an increased risk of hypotension. The clinical translation of these pharmacokinetic (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 PENDINE may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant use of PENDINE and a CYP3A4 inducer, particularly a strong CYP3A4 inducer (such as rifampicin, hypericum perforatum).

Dantrolene (infusion)

The coadministration of calcium channel blockers, such as PENDINE, and dantrolene infusion may result in hyperkalaemia and should be avoided in patients susceptible to malignant hyperthermia, as well as in the management of malignant hyperthermia.

Effects of PENDINE on other medicines

The blood pressure lowering effects of PENDINE adds to the blood pressure-lowering effects of other medicines with antihypertensive properties.

Tacrolimus

There is a risk of increased tacrolimus blood levels when co-administered with PENDINE, but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of PENDINE 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. PENDINE is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, PENDINE may increase exposure of mTOR inhibitors.

Ciclosporin

No medicine interaction studies have been conducted with ciclosporin and PENDINE in healthy volunteers or other populations, with the exception of renal transplant patients, where variable trough concentration increases (average 0 % u2013 40 %) of ciclosporin were observed. Consideration should be given for monitoring ciclosporin levels in renal transplant patients on PENDINE, and ciclosporin dose reductions should be made as necessary.

Simvastatin

Co-administration of multiple doses of 10 mg PENDINE with 80 mg simvastatin resulted in a 77 % increase in exposure to simvastatin compared to simvastatin alone.

Clinical interaction studies have shown that PENDINE does not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

Concurrent administration of sublingual nitroglycerin, long-acting nitrates, beta-blockers or other antianginal medicines with PENDINE may produce additive antihypertensive and antianginal effects. Sublingual nitroglycerin may be used as needed to abort acute angina attacks during amlodipine therapy. Nitrate medication may be used during PENDINE therapy for angina prophylaxis. PENDINE will not protect against the consequences of abrupt beta-blocker withdrawal; gradual beta-blocker dose reduction is recommended.

Although no u201crebound effectu201d has been reported upon discontinuation of amlodipine, a gradual decrease of dosage with medical practitioner supervision is recommended.

Women of childbearing potential / Contraception in males and females

Women of childbearing potential and their partners should be advised to ensure adequate contraceptive cover.

Pregnancy

The safety of PENDINE in pregnancy has not been established. In animal studies, reproductive toxicity was observed at high doses.

Breastfeeding

PENDINE is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 u2013 7 %, with a maximum of 15 %. The effect of PENDINE on infants is unknown.

Fertility

There have been reports of reversible biochemical changes in the head of spermatozoa in patients receiving calcium channel blockers, such as PENDINE. Clinical data regarding the potential effect of PENDINE on human fertility are insufficient.

PENDINE can have minor or moderate influence on the ability to drive and use machines. If patients taking PENDINE suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is advised before driving a vehicle or operating machinery until the effects of PENDINE are known, especially at the start of treatment.

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

The following adverse reactions have been reported during treatment with PENDINE:

Blood and the lymphatic system disorders

Less frequent: Thrombocytopenia, leukopenia.

Immune system disorders

Less frequent: Allergic reactions with pruritus, rash, angioedema and erythema multiforme.

Metabolism and nutrition disorders

Less frequent: Hyperglycaemia.

Psychiatric disorders

Less frequent: Depression, mood changes (including anxiety, insomnia, confusion).

Nervous system disorders

Frequent: Dizziness, headache (especially at the beginning of treatment), somnolence.

Less frequent: Hypertonia, hypoesthesia, paraesthesia, peripheral neuropathy, tremor, dysgeusia, extrapyramidal disorder.

Eye disorders

Frequent: Visual disturbances (including diplopia).

Ear and labyrinth disorders

Less frequent: Tinnitus.

Cardiac disorders

Frequent: Palpitations.

Less frequent: Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation).

Vascular disorders

Frequent: Flushing.

Less frequent: Hypotension (including orthostatic hypotension), syncope, vasculitis.

Respiratory, thoracic and mediastinal disorders

Frequent: Dyspnoea.

Less frequent: Coughing, rhinitis.

Gastrointestinal disorders

Frequent: Nausea, abdominal pain, dyspepsia, altered bowel habits (including diarrhoea and constipation).

Less frequent: Vomiting, gingival hyperplasia, pancreatitis, dry mouth, gastritis.

Hepatobiliary disorders

Less frequent: Hepatitis, jaundice, hepatic enzyme increased (mostly consistent with cholestasis).

Skin and subcutaneous tissue disorders

Less frequent: Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria, angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity, toxic epidermal necrolysis.

Frequency unknown: Toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Frequent: Ankle swelling, muscle cramps.

Less frequent: Arthralgia, back pain, myalgia.

Renal and urinary disorders

Less frequent: Micturition disorder, nocturia, increased urinary frequency.

Reproductive system and breast disorders

Less frequent: Impotence, gynaecomastia.

General disorders and administration site conditions

Frequent: Fatigue, peripheral oedema, asthenia.

Less frequent: Pain, chest pain, malaise.

Investigations

Less frequent: Weight increased, weight decreased.

Paediatric population

Paediatric patients (ages 6 u2013 17 years) Adverse events were similar to those seen in adults. In studies, the most frequently reported adverse events were: Nervous system disorders: Headache, dizziness. Vascular disorders: Vasodilation. Respiratory, thoracic and mediastinal disorders: Epistaxis. Gastrointestinal disorders: Abdominal pain. General disorders and administration site conditions: Asthenia.

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 PENDINE. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications https://www.sahpra.org.za/Publications/Index/8

In humans experience with intentional overdose is limited.

Symptoms

Available data for amlodipine 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.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24 u2013 48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Treatment

Clinically significant hypotension due to PENDINE overdosage requires 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 of benefit in reversing the effects of calcium channel blockade.

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. Treatment is symptomatic and supportive.