Nifedipine

Chemical formula: C₁₇H₁₈N₂O₆  Molecular mass: 346.335 g/mol  PubChem compound: 4485

Interactions

Nifedipine interacts in the following cases:

PDE 5 inhibitors

Nifedipine may increase the blood pressure lowering effect of PDE 5 inhibitors.

A-adrenergic blocking agents

Nifedipine may increase the blood pressure lowering effect of α-adrenergic blocking agents.

Weak to moderate inhibitors of the cytochrome P450 3A4

Upon co-administration of 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.

Diuretics

Nifedipine may increase the blood pressure lowering effect of diuretics.

β-blockers

Nifedipine may increase the blood pressure lowering effect of β-blockers. When nifedipine is administered simultaneously with β-receptor blockers, the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases. 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.

Calcium antagonists

Nifedipine may increase the blood pressure lowering effect of other calcium antagonists.

ACE-inhibitors

Nifedipine may increase the blood pressure lowering effect of ACE-inhibitors.

Angiotensin II receptor-antagonists

Nifedipine may increase the blood pressure lowering effect of angiotensin II receptor-antagonists.

Azole anti-mycotics

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

Macrolide antibiotics

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.

Anti-HIV protease inhibitors

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.

Fertility

In single cases of in vitro fertilization 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 fertilization, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.

Carbamazepine, phenobarbitone

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.

Cimetidine

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

Cisapride

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

Digoxin

The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and hence an increase in plasma concentrations of digoxin. The patient should therefore be checked for symptoms of digoxin overdosage as a precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma concentration of digoxin.

Fentanyl

Concomitant administration of nifedipine with fentanyl causes severe hypotension and the need for fluid administration has been observed in patients treated with nifedipine and fentanyl (for anesthesia).

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.

α-methyldopa

Nifedipine may increase the blood pressure lowering effect of α-methyldopa.

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.

Phenytoin

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.

Quinidine

When nifedipine and quinidine have been administered simultaneously, lowered plasma quinidine levels or, after discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine has been observed in individual cases. 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 are recommended. Some authors reported increased plasma concentrations of nifedipine upon coadministration of both drugs, 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.

Quinupristin, dalfopristin

Simultaneous administration of quinupristin/dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine.

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.

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. Upon co-administration of both drugs the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.

Diabetes

Diabetic patients taking nifedipine may require adjustment of their control.

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.

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

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.

In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity.

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 has been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment or to a specific drug effect.

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

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

Fertility

In single cases of in vitro fertilization 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 fertilization, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.

Effects on ability to drive and use machines

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 treatment, on changing the medication and in combination with alcohol.

Adverse reactions


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 list 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”.

Blood and Lymphatic System Disorders

Not Known: Agranulocytosis, Leucopenia

Immune System Disorders

Uncommon: Allergic reaction, Allergic oedema/angioedema (incl. larynx oedema*)

Rare: Pruritus, Urticaria, Rash

Not Known: Anaphylactic/Anaphlactic/anaphylactoid reaction

Psychiatric Disorders

Uncommon: Anxiety reactions, Sleep disorders

Metabolism and Nutrition Disorders

Not Known: Hyperglycaemia

Nervous System Disorders

Common: Headache

Uncommon: Vertigo, Migraine, Dizziness, Tremor

Rare: Par-/Dysaesthesia

Not Known: Hypoaesthesia, Somnolence

Eye Disorders

Uncommon: Visual disturbances

Not Known: Eye pain

Cardiac Disorders

Uncommon: Tachycardia, Palpitations

Not Known: Chest pain (Angina pectoris)

Vascular Disorders

Common: Oedema (incl. Peripheral oedema), Vasodilatation

Uncommon: Hypotension, Syncope

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon: Nosebleed, Nasal congestion

Not Known: Dyspnoea, Pulmonary oedema**

Gastrointestinal Disorders

Common: Constipation

Uncommon: Gastrointestinal and abdominal pain, Nausea, Dyspepsia, Flatulence, Dry mouth

Rare: Gingival hyperplasia

Not Known: Bezoar, Dysphagia, Intestinal obstruction, Intestinal ulcer, Vomiting, Gastroesophageal sphincter insufficiency

Hepatobiliary Disorders

Uncommon: Transient increase in liver enzymes

Not Known: Jaundice

Skin and Subcutaneous Tissue Disorders

Uncommon: Erythema

Not Known: Toxic Epidermal Necrolysis, Photosensitivity allergic reaction, Palpable purpura

Musculoskeletal and Connective Tissue Disorders

Uncommon: Muscle cramps, Joint swelling

Not Known: Arthralgia, Myalgia

Renal and Urinary Disorders

Uncommon: Polyuria, Dysuria

Reproductive System and Breast Disorders

Uncommon: Erectile dysfunction

General Disorders and Administration Site Conditions

Common: Feeling unwell

Uncommon: Unspecific pain, Chills

* = may result in life-threatening outcome
** = cases have been reported when used as tocolytic during pregnancy

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

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