Innovasc 5 mg, 10 mg Tablets

INNOVASC is indicated for the:

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

Hypertension and angina pectoris

Adults

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

Special populations

Elderly

Lower initial doses of INNOVASC 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. INNOVASC is not dialysable.

Patients with hepatic impairment

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

Paediatric population

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

Method of administration

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

• Hypersensitivity to amlodipine, dihydropyridines or to any of the ingredients of INNOVASC.
• 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 (during the first 28 days)
• Unstable angina pectoris.
• Should not be used for acute reduction of blood pressure.
• 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

Patients with heart 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 INNOVASC, 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 INNOVASC may increase in patients with heart failure. INNOVASC may have a negative inotropic effect.

In patients with severe aortic stenosis, INNOVASC may increase the risk of developing heart failure.

Patients with hepatic impairment

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

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

Lithium-induced neurotoxicity

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

General

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

Diabetes Mellitus

INNOVASCu2019s effect on insulin and glucose responses may require antidiabetic therapy to be adjusted.

Interference with diagnostic tests

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

Porphyria

Safety has not been established

Paediatric population

Safety and efficacy have not been established.

Effects of other medicines on INNOVASC

Cytochrome (CYP) 3A4 inhibitors

The concomitant use of INNOVASC with strong or moderate CYP3A4 inhibitors may result in an significant increase in INNOVASC exposure, increasing the risk of hypotension. The clinical translation of these pharmacokinetic (PK) variations may be more pronounced in the elderly. Clinical monitoring and dose adjustments may be required in the co-administration of INNOVASC 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 INNOVASC with CYP3A4 inducers may result in varying plasma concentration of INNOVASC. The monitoring of blood pressure and dose regulation is advised during and after the concomitant use of INNOVASC and a CYP3A4 inducing medicine, particularly a strong CYP3A4 inducing medicine (such as rifampicin and St. Johnu2019s wort). The effects of INNOVASC 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 INNOVASC 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 blocking medicine (such as INNOVASC) 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 INNOVASC on other medicines

Antihypertensive medicine

The blood pressure lowering effects of INNOVASC adds to the blood pressure-lowering effects of other medicines with antihypertensive properties. INNOVASC 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 INNOVASC. In order to avoid toxicity of tacrolimus, monitoring of blood levels and appropriate dose adjustments of tacrolimus is advised when co-administered with INNOVASC.

Mechanistic target of Rapamycin (mTOR) inhibitors

Caution is advised with the concomitant use of INNOVASC and mTOR inhibitors (such as temsirolimus, everolimus and sirolimus). INNOVASC is a weak CYP3A inhibitor and as mTOR inhibitors are CYP3A substrates, the concomitant use with INNOVASC may increase the 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 are advised in renal transplant patients with concomitant administration of INNOVASC. No drug interaction studies have been conducted with ciclosporin and INNOVASC in healthy volunteers or any other populations.

Simvastatin

When compared to the administration of simvastatin alone, studies have shown that the concomitant use of 80 mg simvastatin and 10 mg INNOVASC in multiple doses resulted in a 77 % increase of simvastatin exposure. It is advised to limit the dose of simvastatin to 20 mg per day when co-administered with INNOVASC.

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

CYP3A4 substrates

INNOVASC 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 INNOVASC may produce additive antihypertensive and antianginal effects. Sublingual nitro-glycerine may be used as needed to abort acute angina attacks during INNOVASC therapy. Nitrate medicine may be used during INNOVASC therapy for angina prophylaxis.

Pregnancy

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

Breastfeeding

INNOVASC is excreted in human milk. The use of INNOVASC 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

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

INNOVASC can have a minor or moderate influence on the ability to drive and use machines. Side effects, such as dizziness, headaches, fatigue or nausea may impair the ability to react. Caution is advised before driving a vehicle or operating machinery until the effects of INNOVASC 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 INNOVASC:

Blood and lymphatic system disorders

Less frequent: leukocytopenia, thrombocytopenia, purpura, haemorrhage, blood dyscrasias

Immune system disorders

Less frequent: hypersensitivity reactions (pruritus, rash, angioedema, erythema multiforme)

Metabolism and nutrition disorders

Less frequent: hyperglycaemia

Psychiatric disorders

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

Nervous system disorders

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

Less frequent: tremor, dysgeusia, syncope, hypoaesthesia, paraesthesia, hypertonia, peripheral neuropathy

Eye disorders

Frequent: visual disturbance (including diplopia)

Ear and labyrinth disorders

Less frequent: tinnitus

Cardiac disorders

Frequent: palpitations

Less frequent: dysrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction

Vascular disorders

Frequent: flushing

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

Respiratory, thoracic and mediastinal disorders

Frequent: dyspnoea

Less frequent: cough, rhinitis

Gastrointestinal disorders

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

Less frequent: vomiting, dry mouth, pancreatitis, gastritis, gingival hyperplasia

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Less frequent: alopecia, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria, angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity

Frequency unknown: toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Frequent: ankle swelling, muscle cramps

Less frequent: arthralgia, myalgia, back pain

Renal and urinary disorders

Less frequent: micturition disorder, nocturia, increased urinary frequency

Reproductive system and breast disorders

Less frequent: impotence, gynaecomastia

General disorders and administrative site conditions

Frequent: oedema, fatigue, asthenia, peripheral oedema

Less frequent: chest pain, pain, malaise, taste perversion

Investigations

Less frequent: increased weight, decreased weight

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 INNOVASC. Healthcare 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: www.sahpra.org.za

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 (24-48 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 INNOVASC 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 INNOVASC 10 mg has been shown to reduce the absorption rate of amlodipine. Since INNOVASC is highly protein-bound, dialysis is not likely to be of benefit.