NIFELAT Film-coated tablet Ref.[28292] Active ingredients: Nifedipine

Caution is advised in patients with very low blood pressure (severe hypotension with systolic pressure <90 mm Hg), in case of manifest heart failure and severe aortic stenosis. Like other vascular active substances, nifedipine may cause angina pectoris attacks at the beginning of treatment. This is very rare. Isolated cases of myocardial infarction have been reported in association with nifedipine. It has not been possible to ascertain whether the treatment or the natural course of underlying disease caused the infarction.

Nifelat should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifelat should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.6). Careful monitoring of blood pressure is necessary, even when co-administering nifedipine with intravenous magnesium sulfate, due to the risk of severe hypotension, which may harm both mother and fetus.

Nifelat is not recommended for use during breast-feeding because nifedipine excretion in human breast milk has been reported and the effect of oral absorption of small amounts of nifedipine are not known (see section 4.6).

In patients with hepatic impairment, blood pressure should be closely monitored and dose reduction may be necessary. There are no pharmacokinetic data in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Nifedipine is metabolised by the cytochrome P450 3A4 system. Drugs that inhibit or induce this enzyme system may therefore alter first-pass metabolism and/or systemic clearance of nifedipine (see section 4.5).

Drugs that are inhibitors of the cytochrome P450 3A4 system, and therefore may give rise to increased plasma concentrations of nifedipine, are e.g:

• macrolide antibiotics (e.g., erythromycin).
• anti-HIV protease inhibitors (e.g., ritonavir).
• azole antimycotics (e.g., ketoconazole).
• the antidepressants nefazodone and fluoxetine.
• quinupristin/dalfopristin.
• valproic acid.
• cimetidine.

In concomitant use of these medications, blood pressure should be monitored. If necessary, a reduction of the nifedipine dose may be considered.

Concomitant use of nifedipine and cytochrome P450 3A4 inducers may lead to a sharp decrease in nifedipine plasma concentrations and a high risk of a lack of effect.

For use in specific patient groups, see section 4.2.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Drugs that affect nifedipine

Nifedipine is metabolised by the enzyme system cytochrome P450 3A4 (CYP3A4), which is located in both intestinal mucosa and in the liver. Medicinal products which inhibit or induce this enzyme may therefore alter the first-pass metabolism (after oral administration) or clearance of nifedipine (see section 4.4).

Both the extent and duration of interactions should be considered when administering nifedipine together with the following medicinal products:

Cytochrome P450 inducers

Rifampicin

Rifampicin strongly induces CYP3A4. When co-administration with rifampicin, the bioavailability of nifedipine is significantly reduced and thus the effect is weakened. In co-administration with rifampicin, the nifedipine exposure was reduced by an average of 97%. The use of nifedipine in combination with rifampicin is therefore contraindicated (see section 4.3).

When nifedipine is co-administered with the following weak to moderate inhibitors of CYP3A4, blood pressure must be monitored and a reduction in the nifedipine dose must be considered, if necessary,

CYP3A4-inducing antiepileptic drugs, such as phenytoin, carbamazepine and phenobarbital

Phenytoin induces the cytochrome CYP3A4 system. When co-administered with phenytoin, the bioavailability of nifedipine is reduced by 73% and thus the effect is weakened. When both medicinal products are given at the same time, the clinical response of nifedipine should be monitored and, if necessary, an increase in nifedipine dose should be considered. If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when treatment with phenytoin is discontinued.

No studies have been performed to investigate the possibility of interaction between nifedipine and carbamazepine or phenobarbital. As both drugs have been shown to decrease the plasma concentration of the structurally similar calcium antagonist nimodipine due to enzyme induction, a decrease in the plasma concentration of nifedipine and thus reduced effect may not be ruled out.

St. John’s wort

When co-administered with St. John’s wort, a CYP3A4 inducer, the clinical response to nifedipine should be monitored and an increase of the dose of nifedipine considered, if necessary. Should the treatment with St. John’s wort be discontinued, the clinical response of nifedipine should be monitored and the dose of nifedipine reduced, if necessary.

Cytochrome P450 inhibitors

Concomitant use of nifedipine with cytochrome P450 3A4 inhibitors may lead to a sharp increase in the plasma concentration and effect of nifedipine. If concomitant treatment with such medicinal products is necessary, blood pressure should be monitored and the dose reduced, if necessary. Combination with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir, indinavir, saquinavir, atazanavir, nelfinavir, clarithromycin, telithromycin, nefazodone) should be avoided. Any combination with moderate CYP3A4 inhibitors (eg fluconazole, erythromycin, diltiazem, verapamil, aprepitant) should be used with caution.

Macrolide antibiotics (e.g. erythromycin)

No interaction studies with nifedipine and macrolide antibiotics have been performed. Some macrolide antibiotics inhibit CYP3A4-mediated metabolism of other medicinal products. The possibility of an increase in plasma concentration of nifedipine in co-administration of both drugs can therefore not be ruled out (see section 4.4).

Azithromycin, which is structurally similar to macrolide antibiotics, has no inhibitory effect on CYP 3A4.

Anti-HIV protease inhibitors (e.g. ritonavir)

No clinical study has yet been conducted to investigate the potential interaction between nifedipine and certain anti-HIV protease inhibitors. Drugs in this group are known to inhibit the CYP3A4 system. Additionally, drugs in this group have been shown to inhibit the CYP3A4-mediated metabolism of nifedipine in vitro. In co-administration with nifedipine, a significant increase in the plasma concentration of nifedipine due to decreased first-pass metabolism and decreased elimination cannot be ruled out (see section 4.4).

Azol antifungals (e.g. ketoconazole)

No interaction study has yet been conducted to investigate the potential interaction interaction between nifedipine and certain azole antifungals. Drugs in this group are known to inhibit the CYP3A4 system. In concomitant oral administration with nifedipine, a significant increase in the systemic bioavailability of nifedipine, due to decreased first-pass metabolism cannot be ruled out (see section 4.4).

Fluoxetine

No clinical study has yet been conducted to investigate the potential interaction between nifedipine and fluoxetine. Fluoxetine has been shown to inhibit CYP3A4-mediated metabolism of nifedipine in vitro. An increase in plasma concentration of nifedipine in co-administration of both drugs can therefore not be ruled out (see section 4.4).

Nefazodone

No clinical study has yet been conducted to investigate the potential interaction between nifedipine and nefazodone. Nefazodone is known to inhibit CYP3A4-mediated metabolism of other drugs. An increase in the plasma concentration of nifedipine in co-administration of both drugs can therefore not be ruled out (see section 4.4).

Quinupristin / dalfopristin

Co-administration of quinopristin/dalfopristin and nifedipine resulted in a 44% increase in the plasma concentration of nifedipine (see section 4.4).

Valproic acid

No interaction studies have been performed regarding the potential interaction between nifedipine and valproic acid. As valproic acid has been shown to increase the plasma concentration of the structurally similar calcium antagonist nimodipine due to enzyme inhibition, an increase in plasma concentrations of nifedipine and thus increased efficacy cannot be ruled out (see section 4.4).

Cimetidine

Due to its inhibition of cytochrome P450 3A4, cimetidine increases the plasma concentrations of nifedipine and may increase the antihypertensive effect (see section 4.4).

Co-administration of the H2-antagonist cimetidine increased the plasma concentrations of nifedipine by 100%. The combination should be used with caution and the dose of nifedipine may need to be reduced.

Additional studies

Cisapride

Co-administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.

Diltiazem

Diltiazem increases the plasma concentration of nifedipine by approximately 50%.

Effect of nifedipine on other drugs:

Antihypertensive drugs

Nifedipine may potentiate the antihypertensive effect of other co-administered
antihypertensive agents such as:

• Diuretics
• Beta blockers
• ACE inhibitors
• Angiotensin II (AT-II) receptor antagonists
• Other calcium channel blockers
• Alpha-adrenergic blockers
• PDE5 inhibitors
• Alphamethyldopa

When nifedipine is given concomitantly with beta-blockers, the patient should be closely monitored as the combination in isolated cases can lead to a worsening of the patient’s of heart failure.

Digoxin

Co-administration of nifedipine and digoxin may lead to decreased clearance of digoxin and thus an increase in the plasma concentrations of digoxin. The patient should therefore as a precautionary measure be monitored for symptoms of digoxin overdose and if necessary, the glycoside dose should be reduced taking into account the plasma concentration of digoxin.

Quinidine

When nifedipine and quinidine are co-administered, isolated cases of reduced plasma concentrations of quinidine or, after discontinuation of nifedipine, sharply increased plasma quinidine concentrations have been observed. Therefore, monitoring of plasma concentrations of quinidine and, if necessary, an adjustment of the quinidine dose is recommended when nifedipine is co-administered or discontinued. Published results on increased plasma concentrations of nifedipine in co-administration of both drugs exist, but also of results where no change in pharmacokinetics of nifedipine was observed.

Therefore, blood pressure should be closely monitored if quinidine is given during ongoing treatment with nifedipine. If necessary, the dose of nifedipine should be reduced.

Tacrolimus

Tacrolimus is metabolised by CYP3A4 system. Recently published data suggest that the dose of tacrolimus co-administered with nifedipine may need to be reduced in individual cases. When co-administrating both drugs, plasma concentrations of tacrolimus should be monitored and a reduction in the tacrolimus dose be considered, if necessary.

Vinblastine, vincristine, vindesine and vinorelbine appear to be metabolised by CYP3A4. Concomitant treatment of vincristine and nifedipine quadrupled the half-life of vincristine.

Interactions with food

Grapefruit juice

Grapefruit juice inhibits the CYP3A4 system. Administration of nifedipine in combination with grapefruit juice may lead to elevated plasma levels and prolonged effect of nifedipine due to decreased first-pass metabolism or reduced clearance. As a result, the blood pressure lowering effect may increase. After regular consumption of grapefruit juice, this effect may persist for at least three days.

Intake of grapefruit or grapefruit juice should therefore be avoided during treatment with nifedipine (see section 4.2).

Other interactions

Nifedipine may cause falsely increased spectrophotometric values of vanillylmandelic acid. However, measurement by HPLC is unaffected.

Pregnancy

Nifedipine is contraindicated during pregnancy prior to week 20. Nifelat should not be used during pregnancy unless treatment with nifedipine is warranted by clinical condition of the woman. Nifedipine should be reserved for women with severe hypertension who do not respond to standard treatment (see section 4.4).

There are no adequate well-controlled studies in pregnant women. Available information is insufficient to rule out side effects affecting unborn babies and neonates.

In animal studies, nifedipine has shown embryotoxic, fetotoxic and teratogenic effects (see section 5.3).

Clinical experience has not identified any specific prenatal risk. Although an increase of perinatal asphyxia, caesarean delivery, prematurity and intrauterine growth inhibition have been reported. It is unclear whether these reports are due to the underlying hypertension, treatment of it or any specific drug effect. After week 20 of pregnancy, Nifelat should therefore be given only on strict indications and after the mother’s needs have been carefully weighed against the risks to the fetus.

Acute pulmonary oedema has been observed when calcium channel blockers, including nifedipine, have been used as tocolytics during pregnancy (see section 4.8), especially in cases of multiple pregnancies (twins or more), together with intravenous dosing and/or concomitant use of beta2 agonists.

Breast-feeding

Nifedipine is excreted in human breast milk. The nifedipine concentrations in the milk are closely comparable to maternal serum concentration. After administration of immediate-release dosage forms, the mother should wait 3-4 hours before breast-feeding or pumping to reduce the infant’s exposure to nifedipine (see section 4.4).

Fertility

In isolated cases of in vitro fertilisation, calcium antagonists such as nifedipine have been associated with reversible biochemical changes in the anterior part of spermatozoa, which may lead to impaired sperm function. In men who repeatedly fail to become fathers using in vitro fertilisation, and where no other explanation is available, calcium channel blockers such as nifedipine should be considered as a possible cause.

Reactions to the drug, which may vary in intensity from person to person, may affect the ability to drive or perform precision work (see section 4.8). This applies above all when treatment is started, when changing drugs and in combination with alcohol.

Listed below are undesirable effects based on placebo-controlled studies with nifedipine according to CIOMS III frequency categories (clinical trial database: nifedipine n=2,661; placebo n=1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n=3,825; placebo n=3,840): Undesirable effects listed under “Common” were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).

The frequency of undesirable effects reported with nifedipine-containing products is summarised in the table below. The frequency of undesirable effects reported with products containing nifedipine is summarised in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000, <1/1,000). Undesirable effects only observed during ongoing safety follow-up after marketing, and for which a frequency cannot be calculated, is indicated under “Not known”.

^* Cases have been reported during use as tocolytics during pregnancy (see section 4.6)

In dialysis patients with severe hypertension and hypovolaemia significant hypotension may occur as a result of vasodilation.

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 the national reporting system.

Cyprus: Pharmaceutical Services, Ministry of Health, CY-1475 Nicosia, Fax: +357 22608649, Website: www.moh.gov.cy/phs

Not applicable.