ADALAT Tablet Ref.[51097] Active ingredients: Nifedipine

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

There are no safety and efficacy data from well-controlled studies in pregnant women (see Fertility, pregnancy and lactation).

Animal studies have shown a variety of embryotoxic, placentotoxic and fetotoxic effects when administered during and after the period of organogenesis (see Section 5.3 PRECLINICAL SAFETY DATA).

From the clinical evidence available, a specific prenatal risk has not been identified. Although an increase in perinatal asphyxia, caesarean deliveries 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 after week 20 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.

Careful monitoring of blood pressure must be exercised, also when administered with intravenous magnesium sulfate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and fetus.

In patients with mild, moderate or severe impaired liver function, careful monitoring and a dose reduction may be necessary. The pharmacokinetics of nifedipine have not been investigated in patients with severe hepatic impairment (see Dose and method of administration and Pharmacokinetic properties). Therefore, nifedipine should be used with caution in patients with severe hepatic impairment.

ADALAT OROS modified release tablets are not bioequivalent to immediate release nifedipine capsules and tablets and patients should be carefully monitored if it is decided to switch between immediate release and modified release nifedipine or vice versa.

Nifedipine is metabolised via the cytochrome P450 3A4 system. Medicines that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (see Interaction with other medicines and other forms of interaction).

Medicines, which are weak to moderate inhibitors of the cytochrome P450 3A4 system and therefore may lead 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.

Upon co-administration with these medicines, the blood pressure should be monitored and if necessary, a reduction of the nifedipine dose should be considered.

Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. For use in special populations, see Dose and method of administration.

Medicines that affect nifedipine

The blood pressure lowering effect of nifedipine may be potentiated by co-administration of other antihypertensive medicines.

When ADALAT is administered simultaneously with ß-receptor blockers, the patient should be carefully monitored, since fairly severe hypotension can occur. Deterioration of heart failure is also known to develop in isolated cases.

Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Medicines 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 Special warnings and precautions for use).

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

Rifampicin:

Rifampicin strongly induces the cytochrome P450 3A4 system. With co-administration of 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 Contraindications).

Upon co-administration of the following weak to moderate inhibitors of the cytochrome P450 3A4 system, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Dose and method of administration).

Macrolide Antibiotics (e.g. erythromycin):

No interaction studies have been carried out between ADALAT and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other medicines. Therefore, the potential for an increase in nifedipine plasma concentrations with coadministration of both medicines cannot be excluded (see Special warnings and precautions for use).

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

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

A clinical study investigating the potential of a drug interaction between ADALAT and certain anti-HIV protease inhibitors has not yet been performed. Medicines of this class are known to inhibit the cytochrome P450 3A4 system. In addition, medicines of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with ADALAT, a substantial increase in plasma concentrations of nifedipine due to an increased absorption and decreased elimination cannot be excluded (see Special warnings and precautions for use).

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

A formal interaction study investigating the potential of a drug interaction between ADALAT and certain azole anti-mycotics has not yet been performed. Medicines of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with ADALAT, a substantial increase in systemic bioavailability of nifedipine due to an increased absorption cannot be excluded (see Section Special warnings and precautions for use).

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 Special warnings and precautions for use).

Nefazodone:

A clinical study investigating the potential of a drug interaction between ADALAT and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other medicines. Therefore, an increase of nifedipine plasma concentrations upon coadministration of both drugs cannot be excluded (see Special warnings and precautions for use).

Quinupristin/Dalfopristin:

Simultaneous administration of quinupristin/dalfopristin and ADALAT may lead to increased plasma concentrations of nifedipine (see Special warnings and precautions for use).

Valproic Acid:

No formal studies have been performed to investigate the potential interaction between ADALAT 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 Special warnings and precautions for use).

Cimetidine:

Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect (see Special warnings and precautions for use).

Further studies

Cisapride:

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

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

Phenytoin induces the cytochrome P450 3A4 system. With co-administration of phenytoin, the bioavailability of nifedipine is reduced and its efficacy weakened. When both drugs are concomitantly administered, the clinical response to ADALAT 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 medicines, 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 ADALAT and carbamazepine or phenobarbitone. As both medicines 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.

Effects of nifedipine on other medicines

Blood pressure lowering medicines

ADALAT may increase the blood pressure lowering effect of concomitant applied antihypertensives, such as:

• diuretics
• -blockers
• ACE-inhibitors
• angiotensin II receptor-antagonists
• other calcium antagonists
• -adrenergic blocking agents
• PDE5 inhibitors
• -methyldopa

When ADALAT is administered simultaneously with ß-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 ADALAT and digoxin may lead to reduced digoxin clearance and hence an increase in plasma concentrations of digoxin. As a precaution therefore, the patient should be checked for symptoms of digoxin overdosage and, if necessary, the glycoside dose should be reduced, taking account of the plasma concentration of digoxin.

Quinidine

When nifedipine and quinidine have been administered simultaneously, occasionally lowered quinidine plasma concentrations have been observed in individual cases. Some authors reported increased plasma concentrations of nifedipine upon co-administration of both medicines, while others did not observe an alteration in the pharmacokinetics of nifedipine. Therefore, the blood pressure should be carefully monitored if quinidine is added to an existing therapy with nifedipine. If necessary, the dose of nifedipine should be decreased. Also, in some cases after the discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine have been noted. For this reason, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration and, if necessary, adjustment of the quinidine dose is recommended.

Tacrolimus

Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Data recently published indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. With co-administration, 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 may be increased. After regular intake of grapefruit juice, this effect may last for at least 3 days after the last ingestion of grapefruit juice.

Ingestion of grapefruit / grapefruit juice is therefore to be avoided while taking nifedipine (see Dose and method of administration).

Interactions shown not to exist

Ajmaline

Concomitant administration of nifedipine and ajmaline has no effect on the metabolism of ajmaline.

Aspirin

Concomitant administration of nifedipine and aspirin 100 mg has no effect on the pharmacokinetics of nifedipine. Co-administration of nifedipine does not alter the effect of aspirin 100 mg on the platelet aggregation and bleeding time.

Benazepril

Concomitant administration of nifedipine and benazepril has no effect on the pharmacokinetics of nifedipine.

Candesartan/Cilexetil

Concomitant administration of nifedipine and candesartan/cilexetil has no effect on the pharmacokinetics of either medicine.

Debrisoquine

Concomitant administration of nifedipine and debrisoquine has no effect on the metabolic ratio of debrisoquine.

Doxazosin

Concomitant administration of nifedipine and doxazosin has no effect on the pharmacokinetics of nifedipine.

Irbesartan

Concomitant administration of nifedipine and irbesartan has no effect on the pharmacokinetics of irbesartan.

Omeprazole

Concomitant administration of nifedipine and omeprazole has no clinically relevant effect on the pharmacokinetics of nifedipine.

Orlistat

Concomitant administration of nifedipine and orlistat has no effect on the pharmacokinetics of nifedipine.

Pantoprazole

Concomitant administration of nifedipine and pantoprazole has no effect on the pharmacokinetics of nifedipine.

Ranitidine

Concomitant administration of nifedipine and ranitidine has no effect on the pharmacokinetics of nifedipine.

Rosiglitazone

Concomitant administration of nifedipine and rosiglitazone has no clinically relevant effect on the pharmacokinetics of nifedipine.

Talinolol

Concomitant administration of nifedipine and talinolol has no effect on the pharmacokinetics of nifedipine.

Triamterene hydrochlorothiazide

Concomitant administration of nifedipine and triamterene hydrochlorothiazide has no effect on the pharmacokinetics of nifedipine.

Other forms of interaction

Nifedipine may cause falsely increased spectrophotometric values of urinary vanillyl-mandelic acid. However, measurement with HPLC is unaffected.

Pregnancy

ADALAT is contraindicated in pregnancy before week 20 (see Contraindications).

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

Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum and malformation of the ribs. Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.

Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic at several times the recommended maximum dose for humans.

Breastfeeding

Nifedipine passes into the breast milk. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.

Fertility

In vitro fertilisation

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, can impair the ability to drive or to operate machinery. This applies particularly at the start of the treatment, on changing the medication and in combination with alcohol.

Adverse drug reactions (ADRs) based on placebo-controlled studies with ADALAT sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n=2661; placebo n=1486; status: 22 Feb 2006 and the ACTION study: nifedipine n=3825; placebo n=3840) 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 Table 1 below. With each frequency grouping, ADRs are presented in order of decreasing seriousness.

The frequencies are defined as: Common ≥1/100 to <1/10 (≥1% to <10%), Uncommon ≥1/1000 to <1/100 (≥0.1% to <1%), Rare ≥1/10000 to <1/1000 (≥0.01% to <0.1%).

Table 1. Adverse Drug Reactions reported based on clinical trial data:

^* = may result in life-threatening outcome

In dialysis patients with malignant hypertension and hypovolaemia, a distinct fall in blood pressure can occur as a result of vasodilation.

Post marketing adverse effects

The ADRs identified during the ongoing market surveillance and for which a frequency could not be estimated are: agranulocytosis, leukopaenia, anaphylactic/anaphylactoid reaction, hyperglycaemia, hypoaesthesia, somnolence, eye pain, chest pain (angina pectoris), dyspnoea, vomiting, gastrooesophageal sphincter insufficiency, jaundice, toxic epidermal necrolysis, photosensitivity allergic reaction, palpable purpura, arthralgia and myalgia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions. https://nzphvc.otago.ac.nz/reporting/

Not applicable.