NIVADIL Prolonged release capsule, hard Ref.[9636] Active ingredients: Nilvadipine

Cimetidine and, to a lesser extent, other histamine H₂-antagonists may lead to an increase in the Nilvadipine plasma concentration. Therefore, the daily dose of 1 × 8 mg Nilvadipine (equivalent to 1 Nivadil 8 mg prolonged release capsule) should not be exceeded.

Nilvadipine should be administrated with care in patients with severe hepatic impairment (liver cirrhosis) the dose should not be increased because Nivadil has a higher bio-availability in such patients. In patients with severe renal insufficiency (creatinine clearance <30 ml/min, dialysis patients) this product should be administered only under very close supervision and with extreme caution since as yet only insufficient therapeutic experience has been gained in this regard.

Care should also be taken in cases of decompensated cardiac insufficiency. Patients with mild bradycardia, first degree AV block or prolonged PR interval should be observed closely.

The concurrent administration of Nilvadipine and other anti-hypertensive drugs or tricyclic anti-depressive agents may result in an additional anti-hypertensive effect. Clinical studies have not yielded any indication of a negative inotropic effect; nevertheless, patients concomitantly treated with Nivadil and a beta-receptor blocker should be particularly carefully monitored, since drugs from this class of substances may result in heart failure when administered in combination with beta-receptor blockers.

Certain structurally related drugs may amplify the negative inotropic action of anti-arrhythmic agents like amiodarone and quinidine. In isolated cases simultaneous treatment with other drugs of the same pharmacological class has led to the observation of a decrease in the plasma quinidine level; monitoring of the plasma quinidine level is therefore recommended in patients on combination therapy. Similar observations have not been made with Nivadipine. Since in rare cases Nilvadipine may cause an increase in plasma digoxin level, monitoring of this parameter is recommended

Other dihydropyridine calcium entry blockers have been reported to increase the plasma concentration of concomitantly administered cyclosporin. Until further clinical data concerning the concomitant administration of Nilvadipine and cyclosporin are available, it is recommended that cyclosporin plasma levels are monitored during a comedication of Nivadil and cyclosporin.

Since Nivadil is metabolised by cytochrome P-450, drugs or food constituents that induce or inhibit this system may affect plasma concentrations of Nivadil.

In vitro studies show that Nilvadipine is metabolised by cytochrome P450 3A4 (CYP3A4). Nilvadipine should be administered with care when coadministered with CYP3A4 inhibitors, like: antiproteases, ketoconazole, itraconazole, erythromycin, and clarithromycin.

Anticonvulsants which induce cytochrome P-450 have been reported to decrease the bio-availability of dihydropyridines. Although there is no experience in this regard with Nivadil, it is recommended not to use Nivadil in patients concomitantly treated with enzyme- inducing anticonvulsants such as phenytoin, carbamazepine or phenobarbital.

Concurrent dosing of Cimetidine, and, to a lesser extent, other structurally related substances, Nilvadipine in a specific interaction study led on average to a doubling of Nilvadipine plasma levels. A daily dose of 1 × 8 mg Nilvadipine should not be exceeded when Nilvadipine and cimetidine are used concomitantly.

Taking Nivadil after a high fat breakfast increase bio-availability by 42%. The patient should be informed that taking Nivadil in the fasted state may decrease its bio-availability.

As with other calcium channel blockers of the dihydropyridine group, a stronger increase in Nilvadipine concentrations in the blood has been reported when Nilvadipine was taken together with grapefruit juice than when it was taken with water.

Nilvadipine should not be taken with grapefruit juice because its metabolism may be inhibited.

In an animal study, concomitant use of verapamil and intravenous dantrolene resulted in hyperkalemia accompanied by ventricular fibration and circulatory collapse. The relevance of these results for Nilvadipine is not known, but a risk that these events occur clinically cannot be excluded when Nilvadipine is used concomitantly with dantrolene.

Pregnancy

No clinical experience with Nilvadipine in pregnancy or lactation is present. Preclinical investigations have not yielded any indication of a damaging potential of the substance on the foetus. The class of dihydropyridines has shown the potential to prolong delivery and parturition, which was not observed with Nilvadipine. As a consequence, Nilvadipine could be used in pregnancy only if the benefit justifies the potential risk to the foetus.

Lactation

The results of animal tests have shown that Nilvadipine (or its metabolites) is excreted in human milk. Therefore, breast feeding is not advised during use of Nilvadipine. Since there has yet been no experience gained regarding the possible effects of the substance on the suckling infant, the child should be weaned from the breast in cases in which treatment of the nursing mother with Nivadil is regarded as necessary.

No studies on the effects on the ability to drive and use machines have been performed with Nilvadipine. However, caution should be exercised because dizziness may occur during antihypertensive treatment.

The management of hypertension with this drug requires regular checks by the physician. The occurrence of reactions, which may differ in severity from one person to another, may impair the patient’s ability to drive vehicles and to operate machinery. This precaution applies particularly at the beginning of therapy, or when dosage is changed, or with concurrent consumption of alcohol.

The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Blood and the lymphatic system disorders

Rare: Anaemia

Very rare: Leukopenia, Thrombocytopenia

Metabolism and nutrition disorders

Rare: Appetite disorder

Nervous system disorders

Common: Headache, Dizziness

Rare: Tinnitus, Nervousness, Insomnia

Eye disorders

Rare: Increased intraocular pressure, Blurred vision

Ear and labyrinth disorders

Rare: Epistaxis, Dry mouth

Cardiac disorders

Uncommon: Tachycardia, Palpitations, Angina Pectoris

Very rare: Myocardial infarction

Vascular disorders

Common: Flushing

Uncommon: Hypotension, Hypertensive crisis

Respiratory, thoracic and mediastinal disorders

Rare: Dyspnoea

Gastrointestinal disorders

Uncommon: Nausea, Abdominal discomfort, Abdominal distension, Constipation, Diarrhoea

Rare: Vomiting, Increased weight, Decreased weight

Very rare: Gingival hyperplasia

Hepato-biliary disorders

Uncommon: Transaminases increased, Blood alkaline phosphatase increased

Skin and subcutaneous tissue disorders

Uncommon: Hypersensitivity reactions, Rash, Pruritus, Erythema

Rare: Paraesthesia

Very rare: Peripheral coldness, Alopecia

Musculoskeletal, connective tissue and bone disorders

Uncommon: Tremor, Myalgia, Arthralgia, Sensation of heaviness

Rare: Neck pain, Chest discomfort

Renal and urinary disorders

Rare: Pollakiuria

Reproductive system and breast disorders

Rare: Erectile dysfunction

Very rare: Gynaecomastia

General disorders and administration site conditions

Common: Peripheral oedema

Uncommon: Fatigue

Rare: Hyperhidrosis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Not applicable.