FENAMON SR Modified release tablet Ref.[28313] Active ingredients: Nifedipine

Nifedipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blocker preferably over 8-10 days.

Nifedipine may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Nifedipine will not prevent possible rebound effects after cessation of other antihypertensive therapy.

Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm Hg), in cases of manifest heart failure and in the case of severe aortic stenosis.

Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.6).

Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and foetus. For further information regarding use in pregnancy, refer to section 4.6.

Nifedipine is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human milk and the effects of oral absorption of small amounts of nifedipine exposure to the infant are not known (see section 4.6).

In patients with impaired liver function, careful monitoring, and in severe cases, a dose reduction may be necessary.

Nifedipine should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

The use of nifedipine in diabetic patients may require adjustment of their control.

In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.

Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (see section 4.5).

Drugs that are known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:

• 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.

Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered (see section 4.5).

For use in special populations see section 4.2.

Fenamon SR contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Fenamon SR also contains sunset yellow, which may cause allergic reactions.

Drugs that affect nifedipine

Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine (see section 4.4).

The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs:

Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated (see section 4.3).

Upon co-administration of known inhibitors of the cytochrome P450 3A4 system, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see section 4.2). If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when the treatment is discontinued.

Drugs increasing nifedipine exposure:

• macrolide antibiotics (e.g., erythromycin),
• anti-HIV protease inhibitors (e.g., ritonavir),
• azole anti-mycotics (e.g., ketoconazole),
• fluoxetine,
• nefazodone,
• quinupristin/dalfopristin,
• cisapride,
• valproic acid,
• cimetidine,
• diltiazem.

Macrolide antibiotics (e.g., erythromycin)

No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore the potential for an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see section 4.4).

Azithromycin, although structurally related to the class of macrolide antibiotics is void of CYP3A4 inhibition.

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

A clinical study investigating the potential of a drug interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with nifedipine, a substantial increase in plasma concentrations of nifedipine due to a decreased first pass metabolism and a decreased elimination cannot be excluded (see section 4.4).

Azole anti-mycotics (e.g., ketoconazole)

A formal interaction study investigating the potential of a drug interaction between nifedipine and certain azole anti-mycotics has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded (see section 4.4).

Fluoxetine

A clinical study investigating the potential of a drug interaction between nifedipine and fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see section 4.4).

Nefazodone

A clinical study investigating the potential of a drug interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs. Therefore an increase of nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (see section 4.4).

Quinupristin / Dalfopristin

Simultaneous administration of quinupristin/dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine (see section 4.4).

Valproic acid

No formal studies have been performed to investigate the potential interaction between nifedipine and valproic acid. As valproic acid has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, an increase in nifedipine plasma concentrations and hence an increase in efficacy cannot be excluded (see section 4.4).

Cimetidine

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

Further studies

Cisapride

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

Cytochrome P450 3A4 system inducing anti-epileptic drugs, such as phenytoin, carbamazepine and phenobarbitone

Phenytoin induces the cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of nifedipine is reduced and thus its efficacy weakened. When both drugs are concomitantly administered, the clinical response to nifedipine should be monitored and, if necessary, an increase of the nifedipine dose considered. If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when the treatment with phenytoin is discontinued.

No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine or phenobarbitone. As both drugs have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction, a decrease in nifedipine plasma concentrations and hence a decrease in efficacy cannot be excluded.

Drugs decreasing nifedipine exposure:

• rifampicin (see above)
• phenytoin
• carbamazepine
• phenobarbital

Effects of nifedipine on other drugs

Blood pressure lowering drugs

Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensive, such as:

• diuretics,
• β-blockers,
• ACE-inhibitors,
• Angiotensin 1(AT1) receptor- antagonists,
• other calcium antagonists,
• α-adrenergic blocking agents,
• PDE5 inhibitors,
• α-methyldopa.

When nifedipine is administered simultaneously with beta-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.

Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. The patient should therefore be subjected to precautionary checks for symptoms of digoxin over dosage and, if necessary, the glycoside dose should be reduced, taking account of the plasma concentration of digoxin.

Quinidine: Co-administration of nifedipine with quinidine may lower plasma quinidine levels, and after discontinuation of nifedipine, a distinct increase in plasma quinidine levels may be observed in individual cases. Consequently, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Some authors reported increased plasma concentrations of nifedipine upon co-administration of both drugs, while others did not observe an alteration in the pharmacokinetics of nifedipine. Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased.

Tacrolimus: Tacrolimus is metabolised via the cytochrome P450 3A4 system. Published data indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.

Drug-food interactions

Grapefruit juice

Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect of nifedipine may be increased. After regular intake of grapefruit juice, this effect may last for at least three days after the last ingestion of grapefruit juice. Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine (see section 4.2).

Other forms of interaction

Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.

Pregnancy

Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.4).

In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).

There are no adequate and well-controlled studies in pregnant women.

From the clinical evidence available a specific prenatal risk has not been identified, although an increase in perinatal asphyxia, caesarean delivery, as well as prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment, or to a specific drug effect.

The available information is inadequate to rule out adverse drug effects on the unborn and newborn child. Therefore any use in pregnancy requires a very careful individual risk benefit assessment and should only be considered if all other treatment options are either not indicated or have failed to be efficacious.

Acute pulmonary oedema has been observed when calcium channel blockers, among others nifedipine, have been used as a tocolytic agent during pregnancy (see section 4.8), especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists.

Breast-feeding

Nifedipine is excreted in the breast milk. The nifedipine concentration in the milk is almost comparable with mother serum concentration. For immediate release formulations, it is proposed to delay breastfeeding or milk expression for 3 to 4 hours after drug administration to decrease the nifedipine exposure to the infant (see section 4.4).

Fertility

In single cases of in vitro fertilisation calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa’s head section that may result in impaired sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.

Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or to operate machinery (see section 4.8). This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.

Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n=2,661; placebo n=1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n=3,825; placebo n=3,840) are listed below: ADRs listed under “common” were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).

The frequencies of ADRs reported with nifedipine-containing products are 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 to <1/1,000). The ADRs identified only during the ongoing postmarketing surveillance, and for which a frequency could not be estimated, are listed under “Not known”.

^* = may result in life-threatening outcome.
^** = cases have been reported when used as tocolytic during pregnancy (see section 4.6)

In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can 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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

Not applicable.