PLENDIL Prolonged-release tablet Ref.[6817] Active ingredients: Felodipine

The efficacy and safety of felodipine in the treatment of hypertensive emergencies has not been studied.

Felodipine may cause significant hypotension with subsequent tachycardia. This may lead to myocardial ischaemia in susceptible patients.

Felodipine is cleared by the liver. Consequently higher therapeutic concentrations and response can be expected in patients with clearly reduced liver function (see section 4.2).

Concomitant administration of drugs that strongly induce or inhibit CYP3 A4 enzymes result in extensively decreased or increased plasma levels of felodipine, respectively. Therefore, such combinations should be avoided (see section 4.5).

Plendil contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Plendil contains castor oil, which may cause stomach upset and diarrhoea.

Mild gingival enlargement has been reported in patients with pronounced gingivitis/peridontitis. The enlargement can be avoided or reversed by careful oral hygiene.

Sodium Content: Plendil contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Felodipine is metabolised in the liver by cytochrome P450 3A4 (CYP3A4). Concomitant administration of substances which interfere with CYP3A4 enzyme system may affect plasma concentrations of felodipine.

Enzyme interactions

Enzyme inhibiting and enzyme inducing substances of cytochrome P450 isoenzyme 3A4 may exert an influence on the plasma level of felodipine.

Interactions leading to increased plasma concentration of felodipine

CYP3A4 enzyme inhibitors have been shown to cause an increase in felodipine plasma concentrations. Felodipine C_max and AUC increased 8-fold and 6-fold, respectively, when felodipine was coadministered with the strong CYP3A4 inhibitor itraconazole. When felodipine and erythromycin were coadministered, the C_max and AUC of felodipine were increased by about 2.5-fold. Cimetidine increased the felodipine C_max and AUC by approximately 55%. The combination with strong CYP3A4 inhibitors should be avoided.

In case of clinically significant adverse events due to elevated felodipine exposure when combined with strong CYP3A4 inhibitors, adjustment of felodipine dose and/or discontinuation of the CYP3A4 inhibitor should be considered.

Examples:

• Cimetidine
• Erythromycin
• Itraconazole
• Ketoconazole
• Anti-HIV/protease inhibitors (e.g. ritonavir)
• Certain flavonoids present in grapefruit juice

Felodipine tablets should not be taken together with grapefruit juice.

Interactions leading to decreased plasma concentration of felodipine

Enzyme inducers of the cytochrome P450 3A4 system have been shown to cause a decrease in plasma concentrations of felodipine. When felodipine was coadministered with carbamazepine, phenytoin or phenobarbital, the C_max and AUC of felodipine were decreased by 82% and 96% respectively. The combination with strong CYP3A4 inducers should be avoided.

In case of lack of efficacy due to decreased felodipine exposure when combined with potent inducers of CYP3A4, adjustment of felodipine dose and/or discontinuation of the CYP3A4 inducer should be considered.

Examples:

• Phenytoin
• Carbamazepine
• Rifampicin
• Barbiturates
• Efavirenz
• Nevirapine
• Hypericum perforatum (St. John’s wort)

Additional interactions

Tacrolimus

Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted.

Cyclosporin

Felodipine does not affect plasma concentrations of cyclosporin.

Pregnancy

Felodipine should not be given during pregnancy. In non-clinical reproductive toxicity studies there were foetal developmental effects, which are considered to be due to the pharmacological action of felodipine.

Breast-feeding

Felodipine has been detected in breast milk and due to insufficient data on potential effect on the infant, treatment is not recommended during breast-feeding.

Fertility

There are no data on the effects of felodipine on patient fertility. In a non-clinical reproductive study in the rat (see section 5.3), there were effects on foetal development but no effect on fertility at doses approximating to therapeutic.

Felodipine has minor or moderate influence on the ability to drive and use machines. If patients taking felodipine suffer from headache, nausea, dizziness or fatigue and ability to react may be impaired. Caution is recommended especially at the start of treatment.

Summary of the safety profile

Felodipine can cause flushing, headache, palpitations, dizziness and fatigue. Most of these adverse reactions are dose-dependent and appear at the start of treatment or after a dose increase. Should such adverse reactions occur, they are usually transient and diminish with time.

Dose-dependent ankle swelling can occur in patients treated with felodipine. This results from precapillary vasodilatation and is not related to any generalised fluid retention.

Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful oral hygiene.

Tabulated list of adverse reactions

The adverse reactions listed below have been identified from clinical trials and from post marketing surveillance.

The following definitions of frequencies are used: 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.

Table 1. Undesirable effects:

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, Website: www.hpra.ie.

Not applicable.