Calcium-channel blockers (class II calcium antagonists).

Nifedipine - hypertension

One capsule contains 5 mg nifedipine

Capsule, soft. Orange, gelatine ovoid capsules containing a yellow viscous fluid.

For the prophylaxis of chronic stable angina pectoris, the treatment of Raynaud's phenomenon and essential hypertension. For patients suffering from essential hypertension or chronic stable angina pectoris, and treated with fast release forms of nifedipine (Adalat 5 [5 mg] and Adalat [10 mg] capsules), a dose dependent increase in the risk of cardiovascular complications (e.g., myocardial infarction) and mortality may occur. Due to this, Adalat 5 and Adalat capsules should only be used for treatment of patients with essential hypertension or chronic stable angina pectoris if no other treatment is appropriate.

Adalat capsules should be swallowed whole with a little liquid, either with or without food. The maximum total daily dose is 60 mg. The recommended starting dose is 5 mg every eight hours with subsequent titration of dose according to response permitting an increase to a maximum of 20 mg every eight hours.

Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all.

The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.

Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored, and in severe cases, a dose reduction may be necessary.

Patients with renal impairment should not require adjustment of dosage.

Treatment may be continued indefinitely.

Nifedipine is not recommended for use in children.

Adalat 5 should not be taken with grapefruit juice.

Not recommended.

Adalat 5 must not be administered to patients with known hypersensitivity to nifedipine, or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients.

Adalat 5 is contraindicated in pregnancy before week 20 and during breastfeeding.

Adalat 5 must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within 4 weeks of an acute myocardial infarction.

Adalat 5 should not be used for the treatment of acute attacks of angina.

The safety of Adalat 5 in malignant hypertension has not been established.

Adalat 5 should not be used for secondary prevention of myocardial infarction.

Adalat 5 should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction.

Adalat 5 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.

Adalat 5 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. Adalat 5 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).

Treatment with short-acting nifedipine may induce an exaggerated fall in blood pressure and reflex tachycardia, which can cause cardiovascular complications such as myocardial and cerebrovascular ischaemia.

As with other vasoactive substances, angina pectoris may very rarely occur (data from spontaneous reports) with immediate release nifedipine, especially at the start of the treatment. Data from clinical studies confirm that the occurrence of angina pectoris attacks is uncommon.

In patients suffering from angina pectoris an increase in frequency, duration and severity of angina pectoris attacks may occur, especially at the start of the treatment.

The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.

Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulphate, 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.

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

Adalat 5 should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

At doses higher than those recommended, there is some concern about increased mortality and morbidity in the treatment of ischaemic heart disease, in particular after myocardial infarction.

The use of Adalat 5 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.

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.

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.

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.

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. In the majority of these cases, no formal studies to assess the potential for a drug interaction between nifedipine and the drug(s) listed have been undertaken, thus far.

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

Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to nifedipine should be monitored and, if necessary, an increase in 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 is discontinued.

Drugs decreasing nifedipine exposure:

• rifampicin (see above)

• phenytoin

• carbamazepine

• phenobarbital

Effects of nifedipine on other drugs

Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives.

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 overdosage and, if necessary, the glycoside dose should be reduced.

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. 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 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.

Other forms of interaction

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

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%). ADRs derived from post marketing reports (status: 31 Mar 2006) are printed in bold italic.

* = may result in life-threatening outcome

Bayer

(POM)

04 June 2009