Ascivasc Tablets

ASCIVASC is indicated for the treatment of:

• Mild to moderate hypertension, alone or in combination with other antihypertensive medicines.
• Angina pectoris.

Posology

Hypertension and angina pectoris

Adults

An initial dose of 5 mg ASCIVASC once daily is recommended which may be increased to 10 mg once as day after 10 u2013 14 days of therapy if there is no improvement. No dose reduction is required when adding ASCIVASC to thiazide diuretics, beta blockers, or angiotensin-converting enzyme inhibitors.

Special populations

Elderly

Lower initial doses of ASCIVASC may be used in elderly patients (see section 4.4).

Patients with renal impairment

Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment, therefore the normal dosage is recommended. ASCIVASC is not dialysable.

Patients with hepatic impairment

The pharmacokinetics of amlodipine have not been studied in hepatic impairment. ASCIVASC should be initiated at the lowest dose and titrated slowly in patients with severe hepatic impairment.

Paediatric population

The safety and efficacy of ASCIVASC in children has not been established (see section 4.3).

Method of administration

For oral administration ASCIVASC can be administered with or without the intake of food.

• Hypersensitivity to amlodipine, dihydropyridines or to any of the excipients (see section 6.1).
• Severe hypotension
• Shock, including cardiogenic shock.
• Haemodynamically unstable heart failure after acute myocardial infarction (during the first 28 days).
• Unstable angina pectoris.
• Should not be used for acute reduction of blood pressure.
• Obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis).
• Pregnancy and lactation (see section 4.6).
• Safety in children has not been established.

The safety and efficacy of amlodipine in hypertensive crisis has not been established. Patients with cardiac failure should be treated with caution. Studies in patients with severe heart failure (New York Heart Association (NYHA) class III and IV) have reported a higher incidence of pulmonary oedema in patients treated with amlodipine in comparison to placebo. Calcium channel blockers, including ASCIVASC, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality. The area under the curve (AUC) of ASCIVASC may increase in patients with heart failure. ASCIVASC may have a negative inotropic effect. In patients with severe aortic stenosis, ASCIVASC may increase the risk of developing heart failure.

Patients with hepatic impairment

The half-life of ASCIVASC is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. ASCIVASC 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

The clearance of ASCIVASC is reduced (40 u2013 60 %) in the elderly, resulting in prolongation of the elimination half-life and higher AUC values. Therefore, elderly patients should start ASCIVASC therapy at a lower dose and increase of the dosage should take place with care (see sections 4.2 and 5.2).

Patients with renal impairment

ASCIVASC may be used in patients with renal impairment at normal doses. Changes in ASCIVASC plasma concentrations are not associated with the degree of renal impairment. ASCIVASC is not dialysable.

Lithium-induced neurotoxicity

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

General

Sudden withdrawal of ASCIVASC might be associated with an exacerbation of angina. A gradual decrease of dosage with medical practitioner supervision is recommended. ASCIVASC should be stopped in patients who have ischaemic pain after use. ASCIVASC should be used with caution in patients with hypotension.

Diabetes Mellitus

ASCIVASCu2019s effect on insulin and glucose responses may require antidiabetic therapy to be adjusted.

Interference with diagnostic tests

Calcium channel blockers such as ASCIVASC interfere with plasma aldosterone and renin ratios in laboratory tests.

Porphyria

Safety has not been established.

Paediatric patients

Safety and efficacy of ASCIVASC have not been established.

Effects of other medicines on ASCIVASC

Cytochrome (CYP) 3A4 inhibitors

Concomitant use of ASCIVASC with strong or moderate CYP3A4 inhibitors may give rise to significant increase in ASCIVASC 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 in the co-administration of ASCIVASC with one of the following:

• protease inhibitors (such as ritonavir),
• azole antifungals,
• macrolide antibacterials, such as erythromycin or clarithromycin,
• verapamil,
• diltiazem.

CYP3A4 inducers

The concomitant use of ASCIVASC with CYP3A4 inducers may result in varying plasma concentration of ASCIVASC. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant use of ASCIVASC and a CYP3A4 inducing medicine, particularly with strong CYP3A4 inducers (e.g. rifampicin and St. Johnu2019s wort). The effects of ASCIVASC may be reduced in combination with enzyme-inducing anti-epileptic medicines, such as carbamazepine, phenobarbitone and phenytoin. In contrast, sodium valproate has been reported to increase plasma concentrations.

Grapefruit juice

Administration of ASCIVASC 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)

The co-administration of calcium channel blockers (such as ASCIVASC) 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 ASCIVASC on other medicines

The blood pressure lowering effects of ASCIVASC adds to the blood pressure-lowering effects of other medicines with antihypertensive properties. ASCIVASC will not protect against the consequences of abrupt beta-blocker withdrawal. Gradual beta-blocker dose reduction is recommended.

Tacrolimus

Although the pharmacokinetic mechanism remains uncertain, there is a risk of increased tacrolimus blood levels when tacrolimus is used concomitantly with ASCIVASC. In order to avoid toxicity of tacrolimus, administration of ASCIVASC in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus.

Mechanistic Target of Rapamycin (mTOR) Inhibitors

Caution is advised with the concomitant use of ASCIVASC and mTOR inhibitors (such as temsirolimus, everolimus and sirolimus). ASCIVASC is a weak CYP3A inhibitor and as mTOR inhibitors are CYP3A substrates, the concomitant use with ASCIVASC may increase exposure of mTOR inhibitors.

Ciclosporin

In renal transplant patients, the co-administration of ciclosporin and amlodipine resulted on variable trough concentrations increases of ciclosporin (0 % u2013 40 %). Monitoring and appropriate dose adjustments of ciclosporin is advised in renal transplant patients with concomitant administration of ASCIVASC. No drug interaction studies have been conducted with ciclosporin and ASCIVASC in healthy volunteers or any other populations.

Simvastatin

When compared to the administration of simvastatin alone, studies have shown concomitant use of 80 mg simvastatin and 10 mg ASCIVASC in multiple doses resulted in a 77 % increase of simvastatin exposure. It is advised to limit the dose of simvastatin in patients on ASCIVASC to 20 mg daily. Clinical interaction studies have shown that ASCIVASC does not affect the pharmacokinetics of atorvastatin, digoxin and warfarin.

CYP3A4 substrates

ASCIVASC 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.

Antianginal medicines

Concurrent administration of sublingual nitro-glycerine, long acting nitrates, or other antianginal medicines with ASCIVASC may produce additive antihypertensive and antianginal effects. Sublingual nitro-glycerine may be used as needed to abort acute angina attacks during ASCIVASC therapy. Nitrate medicine may be used during ASCIVASC therapy for angina prophylaxis.

Pregnancy

The safety of ASCIVASC in pregnancy has not been established. ASCIVASC is contraindicated during pregnancy (see section 4.3). Animal studies have reported reproductive toxicity at high doses of ASCIVASC.

Breastfeeding

ASCIVASC is excreted in human milk. The use of ASCIVASC during breastfeeding is contraindicated. (See section 4.3). 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 amlodipine on infants is unknown.

Fertility

Reversible biochemical changes in the head of spermatozoa have been reported in patients treated with calcium channel blockers, such as ASCIVASC. Clinical data regarding the potential effect of ASCIVASC on human fertility are insufficient.

ASCIVASC can have minor or moderate influence on the ability to drive and use machines. Side effects such as dizziness, headache, fatigue or nausea may impair the ability to react. Caution is advised before driving a vehicle or operating machinery until the effects of ASCIVASC are known, especially at the start of treatment.

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 summary of adverse reactions

The following adverse reactions have been reported during treatment with ASCIVASC: with the following frequencies: frequent, less frequent and frequency unknown (cannot be estimated from the available data).

Exceptional cases of extrapyramidal syndrome have been reported.

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 ASCIVASC. 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:

Symptoms of overdose

In overdose side effects may be exaggerated and exarcebated. 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.

Management of overdose

Clinically significant hypotension due to ASCIVASC 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 beneficial in reversing the effects of calcium channel blockade. In healthy volunteers the use of charcoal up to 2 hours after administration of ASCIVASC 10 mg has been shown to reduce the absorption rate of amlodipine. Since ASCIVASC is highly protein-bound, dialysis is not likely to be of benefit.