Aprate 5mg or 10mg Tablet

APRATE is indicated for the:

• Treatment of angina pectoris.
• Treatment of mild-to moderate hypertension, alone or in combination with other antihypertensives.

Hypertension and Angina Pectoris:

Adults: An initial dose of 5 mg APRATE once daily is recommended which may be increased to 10 mg once a day after 10 - 14 days of therapy if there is no improvement. No dose reduction is required when adding APRATE to thiazide diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors.

Special populations

In the elderly: Lower initial doses of APRATE may be used in elderly patients, but increase of the dosage should take place with care (see section 4.4)

In patients with renal impairment: Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, APRATE is not dialysable.

In 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. APRATE should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Paediatric population: Safety and efficacy have been established.

Method of administration: Tablet for oral administration. APRATE can be administered with or without the intake of food. Grapefruit and grapefruit juice should be avoided (see section 4.5).

Missed dose: If a dose is missed, the tablet should be taken as soon as the missed dose is remembered. Two tablets should not be taken to make up for the missed dose.

• hypersensitivity to amlodipine, dihydropyridines or to any of the ingredients of APRATE.
• severe hypotension
• shock, including cardiogenic shock
• haemodynamically unstable heart failure after acute myocardial infarction (during the first 28 days)
• obstruction of the outflow tract of the left ventricle (e.g. high-grade aortic stenosis)
• unstable angina pectoris
• safety in children has not been established
• pregnancy and lactation.

The substitutability or interchangeability with other amlodipine containing products has not been established. The safety and efficacy of APRATE in hypertensive crisis has not been established.

APRATE should not be used to treat angina attack in chronic stable angina, nor should it be used for the acute reduction of blood pressure in adults.

In patients with severe aortic stenosis, APRATE may increase the risk of developing heart failure. Sudden withdrawal of APRATE might be associated with an exacerbation of angina. A gradual decrease of dosage with medical practitioner supervision is recommended. APRATE should be stopped in patients who have ischaemic pain after use.

Diabetes mellitus: APRATEu2019s effect on insulin and glucose responses may require antidiabetic therapy to be adjusted.

Interference with diagnostic tests: Calcium channel blockers, such as APRATE, reduce the plasma aldosterone: renin ratio by increasing renin production and reducing plasma aldosterone concentrations, consequently, primary hyperaldosteronism has been misdiagnosed as essential hypertension.

Use in the Elderly: Amlodipine clearance is decreased (40 u2014 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, elderly patients should start APRATE therapy at a lower dose (see section 4.4).

Use in Renal Failure: Although APRATE is excreted primarily via the kidney, mild renal impairment does not appear to have an effect on the plasma concentrations. Severe renal impairment may however require a dosage reduction. Amlodipine is not dialysable.

Use in Impaired Hepatic Function: The half-life of APRATE is significantly prolonged in patients with impaired hepatic function. APRATE should therefore be administered at lower doses in these patients.

Paediatric population: Safety and efficacy has not been established.

Use in Cardiac Failure: An increased incidence of pulmonary oedema has been reported. APRATE may have a negative inotropic effect. AUC of APRATE may increase in patients with heart failure.

Porphyria: Safety has not been established. Patients who are taking APRATE should inform the anaesthetist accordingly, before receiving anaesthesia.

Concurrent administration of sublingual nitroglycerin, long-acting nitrates, beta-blockers or other antianginal agents with amlodipine 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 amlodipine therapy for angina prophylaxis.

Amlodipine 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.

Enhanced antihypertensive effects may be seen in concomitant use with medicines such as aldesleukin and antipsychotics that cause hypotension. Administration of APRATE with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

APRATE may modify insulin and glucose responses and therefore diabetic patients may need to adjust their antidiabetic treatment when receiving APRATE (see section 4.4).

APRATE is extensively metabolised in the liver by the cytochrome P450 isoenzyme CYP3A4 and interactions may occur with other medicines, such as quinidine or procainamide, sharing the same metabolic pathway, since both groups possess negative inotropic properties.

The effects of APRATE may be reduced in combination with enzyme-inducing antiepileptics such as carbamazepine, phenobarbitone and phenytoin. In contrast, sodium valproate has been reported to increase plasma concentrations.

Concomitant use with strong or moderate CYP3A4 inhibitors, protease inhibitors, azole antifungals, macrolide antibacterials (such as clarithromycin, erythromycin, verapamil or diltiazem, ketoconazole, itraconazole and ritonavir) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (i.e. rifampicin, hypericum perforatum, St. Johnu2019s Wort) may give a lower plasma concentration of amlodipine. APRATE should be used with caution together with CYP3A4 inducers.

Dantrolene may cause hyperkalaemia when used concomitantly with calcium channel blockers such as APRATE. Due to risk of hyperkalaemia, it is recommended that the co-administration of APRATE be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

The use of lithium with APRATE may cause lithium induced neurotoxicity in the form of nausea, vomiting, diarrhoea, ataxia, tremors and/or tinnitus, caution is therefore recommended.

Tacrolimus: There is a risk of increased tacrolimus blood levels when coadministered with APRATE. In order to avoid toxicity of tacrolimus, administration of APRATE in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

Co-administration of multiple doses of 10 mg of APRATE 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 APRATE to 20 mg daily.

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 APRATE on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).

Pregnancy: Safety in pregnancy and lactation has not been established (see section 4.3).

Breast-feeding: APRATE is excreted in human milk and therefore should not be administered in lactating women.

APRATE can cause side effects such as dizziness. During APRATE administration, patients should be cautioned about re-engaging in activities requiring rapid and precise responses such as driving a vehicle or operating machinery.

a. Summary of the safety profile: The most frequently reported adverse reactions during treatment are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

b. Tabulated list of adverse reactions: System Organ Class Frequency Side effects Blood and lymphatic system disorders Less frequent Purpura, leukopenia, thrombocytopenia, haemorrhagic complications in surgical patients, blood dyscrasias Immune system disorders Less frequent Hypersensitivity reactions: pruritus, rash, angioedema and erythema multiforme Metabolism and nutrition disorders Less frequent Hyperglycaemia Psychiatric disorders Less frequent Insomnia, mood changes (including anxiety), depression Nervous system disorders Frequent Dizziness, headache, somnolence Less frequent Mood changes, peripheral neuropathy increased sweating, hypertonia, hypoaesthesia/paraesthesia, tremor, taste perversion (dysgeusia) Eye disorders Less frequent Visual disturbances Ear and labyrinth disorders Less frequent Tinnitus Cardiac disorders Frequent Palpitations Less frequent Myocardial infarction, dysrhythmia (including ventricular tachycardia and atrial fibrillation), chest pain, bradycardia Vascular disorders Frequent Flushing, peripheral oedema Less frequent Hypotension (including orthostatic hypotension), syncope, vasculitis Respiratory, thoracic and mediastinal disorders Less frequent Dyspnoea, coughing, rhinitis Gastrointestinal disorders Frequent Nausea, abdominal pain, altered bowel habits Less frequent Vomiting, dyspepsia, gingival hyperplasia, pancreatitis, dry mouth, constipation, diarrhoea Hepato-biliary disorders Less frequent Hepatitis, jaundice, raised liver enzymes (mostly consistent with cholestasis) Skin and subcutaneous tissue disorders Less frequent Alopecia exanthema, pruritus, purpura, skin discolouration, hyperhidrosis, rash, erythema multiforme, exfoliative dermatitis, Stevens Johnson syndrome, photosensitivity Musculoskeletal, connective tissue and bone disorders Frequent Ankle swelling Less frequent Arthralgia, asthenia, back pain, muscle cramps, myalgia Renal and urinary disorders Less frequent Increased urinary frequency, micturition disorder, nocturia Reproductive system and breast disorders Less frequent Impotence, gynaecomastia General disorders and administrative site conditions Less frequent Fatigue, Facial oedema, upper extremity oedema Investigations Less frequent Weight increase/decrease

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 Reaction Reporting Formu201d, found online under SAHPRAu2019s publications https://www.sahpra.org.za/Publications/Index/8.

Signs and symptoms: Overdosage could result in excessive peripheral vasodilatation, resulting in marked and probably prolonged systemic hypotension. 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 - 48 hours post ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Management of overdose: Clinically significant hypotension due to APRATE overdosage requires active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevating of extremities and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided there in no contraindication to its use. Intravenous calcium gluconate may be of benefit in reversing the effects of calcium channel blockade. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. There is no documented experience with APRATE overdosage. Gross over-dosage could result in excessive peripheral vasodilation, resulting in marked and probably prolonged systemic hypotension. TREATMENT IS SYMPTOMATIC AND SUPPORTIVE.