Nifedipine. Adverse Effects
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In China, Europe, International, Japan, and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Nifedipine). A yellow crystalline powder. Practically insoluble in water; sparingly soluble in dehydrated alcohol; freely soluble in acetone. When exposed to daylight or to certain wavelengths of artificial light it is converted to a nitrosophenylpyridine derivative, while exposure to ultraviolet light leads to formation of a nitrophenylpyridine derivative. Solutions should be prepared in the dark or under light of wavelength greater than 420 nm, immediately before use. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Nifedipine). A yellow powder. Practically insoluble in water; soluble 1 in 10 of acetone. When exposed to daylight or to certain wavelengths of artificial light it is converted to a nitrosophenylpyridine derivative, while exposure to ultraviolet light leads to formation of a nitrophenylpyridine derivative. Store in airtight containers. Protect from light.
Stability. Yellow food colourings such as curcumin have been used to slow photodegradation of nifedipine solutions. An extemporaneously prepared solution of nifedipine in a peppermint-flavoured vehicle was reported to be stable for at least 35 days when stored in amber glass bottles.
Adverse Effects
The most common adverse effects of nifedipine are associated with its vasodilator action and often diminish on continued therapy. They include dizziness, flushing, headache, hypotension, peripheral oedema, tachycardia, and palpitations. Nausea and other gastrointestinal disturbances, increased micturition frequency, lethargy, eye pain, visual disturbances, and mental depression have also occurred. A paradoxical increase in ischaemic chest pain may occur at the start of treatment and in a few patients excessive fall in blood pressure has led to cerebral or myocardial ischaemia or transient blindness.
There have been reports of rashes (including erythema multiforme), fever, and abnormalities in liver function, including cholestasis, due to hyper sensitivity reactions. Gingival hyperplasia, myalgia, tremor, and impotence have been reported.
Some tablets formulated for once-daily use are covered in a membrane which is not digested and may cause gastrointestinal obstruction; bezoars may rarely occur. Overdosage may be associated with bradycardia and hypotension; hyperglycaemia, metabolic acidosis, and coma may also occur.
Nifedipine has been reported to be teratogenic in animals.
Effects on mortality. Since 1995 there have been reports and reviews that have implicated calcium-channel blockers (particularly short-acting nifedipine and high doses) in increasing cardiovascular and overall mortality. Possible links with cancer, haemorrhage, and depression and suicide are discussed separately (see Cancer Occurrence, Effects on the Blood, and Effects on Mental Function, below, respectively). In response, the US National Heart, Lung, and Blood Institute issued a statement warning that short-acting nifedipine should be used with great caution (if at all), especially at higher doses, in the treatment of hypertension, angina, and myocardial infarction, and in some countries short-acting nifedipine preparations have been withdrawn. However, there has been much debate and controversy over the reports that questioned the safety of calcium-channel blockers.
A review by the WHO/ISH pointed out that much of the evidence for adverse effects comes from observational studies or small randomised studies and concluded that, as there was insufficient evidence to confirm either benefit or harm, recommendations on the management of angina, hypertension, and myocardial infarction should remain unchanged. In addition, many of the studies that led to the negative reports used the older short-acting calcium-channel blockers. The calcium-channel blockers used now are largely modified-release formulations of short half-life blockers or are calcium-channel blockers with long half-lives.
Studies completed after the WHO/ISH review have generally failed to show any increase in mortality with calcium-channel blockers, although their effects on cardiovascular outcomes remain less clear. A placebo-controlled study (SYST-EUR) reported a reduction in incidence of stroke and cardiovascular events in 4695 elderly patients treated with nitrendipine (and enalapril and hydrochlorothiazide in addition if necessary) for isolated systolic hypertension, while a retrospective cohort study in post-myocardial infarction patients failed to show any increase in mortality after one year in those receiving calcium-channel blockers. Another cohort study in patients with hypertension also found no overall increase in mortality with calcium-channel blockers, although there was a trend towards a higher rate with short-acting formulations. A meta-analysis of randomised studies comparing calcium-channel blockers with other antihypertensives in patients with hypertension suggested that calcium-channel blockers were associated with an increased risk of major cardiovascular events (except stroke) although all-cause mortality was not increased. However, large, long-term studies have found no difference in cardiovascular outcomes or overall mortality in patients randomised to amlodipine or chlortalidone, while a lower incidence of cardiovascular events was reported for amlodipine compared with atenolol. A long-term study of nifedipine added to standard therapy in patients with stable angina also found no increased mortality, and there was a reduced need for coronary interventions.
Carcinogenicity. An observational study carried out between 1988 and 1992 suggested that calcium-channel blockers were associated with an increased risk of cancer. Subsequent studies have failed to support this finding. A review by the WHO/ISH concluded that there is no good evidence that calcium-channel blockers increase cancer risk, and the biological basis for an effect of calcium-channel blockers on cancer risk has also been questioned. The large, long-term, randomised Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) found no increase in the incidence of cancer in patients receiving a calcium-channel blocker (amlodipine) compared with those receiving a diuretic (chlortalidone).
Effects on the blood. Treatment with nifedipine significantly reduces platelet aggregation in vitro and results indicating inhibition of platelet function in healthy subjects receiving oral (but not intravenous) nifedipine have been reported. Thus, concern has been expressed that calcium-channel blockers may have the potential to produce haemorrhagic complications in surgical patients (specifically, those undergoing coronary bypass surgery). Major surgical bleeding was associated with nimodipine in patients undergoing cardiac valve replacement, although it has been used in other situations apparently without an increased risk of bleeding.
Conflicting results have been reported with regard to the risk of gastrointestinal bleeding. A prospective cohort study in 1636 elderly hypertensive patients, and a subsequent case-control study, reported that calcium-channel blockers were associated with an increased risk of gastrointestinal haemorrhage compared with beta blockers. However, it was suggested that this may have been due to a protective effect of beta blockers rather than an adverse effect of calcium-channel blockers, and another study also suggested that the risk of gastrointestinal bleeding was not materially increased by calcium-channel blockers. Calcium-channel blockers have also been associated with a number of blood dyscrasias; there have been case reports of aplastic anaemia with nifedipine, and of thrombocytopenia with amlodipine and with diltiazem.
Effects on the brain. Cerebral ischaemia has been reported in small numbers of patients given nifedipine.
Effects on carbohydrate metabolism. There are reports of deterioration of diabetes, reduction in glucose tolerance, and development of diabetes in patients given nifedipine. Nifedipine has also been reported to increase plasma-glucose concentrations. However, other reports and studies have found no change in glucose tolerance in either diabetic or non-diabetic patients taking nifedipine. See also Diabetes Mellitus under Precautions, below.
Effects on the ears. There have been isolated reports of tinnitus associated with several calcium-channel blockers including nifedipine, nicardipine, nitrendipine, diltiazem, verapamil, and cinnarizine.
Effects on the eyes. Individual reports have implicated nifedipine in the development of transient retinal ischaemia and blindness, and of periorbital oedema. In a postmarketing survey painful or stinging eyes were more common in patients receiving nifedipine (178 of 757 evaluable) than in those given captopril (45 of 289), although the cause was uncertain. Nifedipine has also been suggested as a risk factor in the development of cataract, but the numbers involved in this analysis are small and it is possible that the risk, if it exists, relates to hypertension rather than nifedipine treatment.
Effects on the heart. The use of nifedipine has been associated with the development of various heart disorders in some patients. Complete heart block has been reported in an elderly patient who had previously developed heart block with verapamil, and sudden circulatory collapse has been reported in 4 patients receiving nifedipine who underwent routine coronary bypass surgery. One patient died despite all attempts at resuscitation. However, probably the majority of reports have concerned the development or aggravation of cardiac ischaemia, up to and including frank myocardial infarction after use of short-acting nifedipine. Such cases appear to be chiefly associated with a too-rapid fall in blood pressure after the use of sub lingual nifedipine for hypertensive urgencies or emergencies, or occur in patients with a history of ischaemic heart disease. For discussion of the effects of calcium-channel blockers on cardiovascular mortality, see above.
WITHDRAWAL. Exacerbation of coronary ischaemia and thrombosis of arteriovenous graft could have resulted from withdrawal of nifedipine in a patient. Abrupt withdrawal of nisoldipine from 15 patients with stable angina pectoris after 6 weeks of therapy resulted in severe unstable angina in 2 patients and acute myocardial infarction in another. It was postulated that the withdrawal effect could be due to an increase in sensitivity of vascular α2 adrenoceptors to circulating adrenaline.
Effects on the kidneys. Calcium-channel blockers may be of benefit in various forms of kidney disorder (see under Uses and Administration, below). However, reversible deterioration in renal function without any appreciable accompanying decline in systemic arterial blood pressure has been reported in 4 patients with underlying renal insufficiency receiving nifedipine, and in another report nifedipine increased urinary protein excretion and exacerbated renal impairment in 14 type 2 diabetic patients. Excessive diuresis occurred in a patient given nifedipine for angina pectoris, and nocturia in 9 patients referred for prostatic surgery was also attributed to nifedipine
Effects on the liver. A number of cases of hepatitis, apparently due to a hypersensitivity reaction, and frequently accompanied by fever, sweating, chills, rigor, and arthritic symptoms, have been reported in patients receiving nifedipine.
Effects on the menstrual cycle. Menorrhagia in 2 women and menstrual irregularity with heavy bleeding in another have been reported in association with nifedipine treatment.
Effects on mental function. Insomnia, hyperexcitability, pacing, agitation, and depression were reported in a patient in association with nifedipine therapy. The symptoms disappeared within 2 days of withdrawal of nifedipine. Four further cases of major depression, which developed within a week of starting nifedipine and resolved within a week of stopping the drug, have been reported.
Although 2 epidemiological studies suggested that calcium-channel blockers may promote suicide, a subsequent study found no evidence of an association between depression and the use of calcium-channel blockers, and the number of suicides was low. Further studies have also failed to find an increased risk of suicide with calcium-channel blockers compared with other an-tihypertensive drugs.
Effects on the mouth. GINGIVAL HYPERPLASIA. A number of reports have implicated nifedipine in the development of gingival hyperplasia. In most cases it has occurred about 1 to 6 months after starting therapy and has resolved after stopping nifedipine. A patient who had taken nifedipine for 12 years developed gingival hyperplasia shortly after the dosage of nifedipine was increased. Amlodipine has also induced gingival overgrowth. A study involving 115 patients given nifedipine, diltiazem, or verapamil for at least 3 months indicated that gingival hyperplasia is an important adverse effect that may occur with calcium-channel blockers in general. Dihydropyridine calcium-channel blockers were among the most common drugs associated with reports of gingival hyperplasia in the Australian Adverse Drug Reactions Advisory Committee database.
PAROTITIS. Acute swelling of the parotid glands occurred in a patient after sublingual administration of nifedipine.
Effects on the neuromuscular system. Severe muscle cramps have been reported in a few patients taking nifedipine; in one patient the cramps were associated with widespread paraesthesia. Reversible myoclonic dystonia associated with nifedipine has been reported in a patient. Severe rhabdomyolysis developed in a patient with a transplanted kidney who was receiving an intravenous infusion of nifedipine. The patient recovered rapidly once the infusion was stopped. There has also been a report of myopathy, myalgia, and arthralgia associated with amlodipine, and of arthralgia in a patient receiving diltiazem.
Parkinsonism is a recognised adverse effect of flunarizine and cinnarizine, which have calcium-channel blocking properties (see Extrapyramidal Disorders under Flunarizine). It has also been reported with diltiazem and with amlodipine.
Effects on the oesophagus. Calcium-channel blockers decrease lower oesophageal sphincter pressure and have been used in oesophageal motility disorders (see below), but a retrospective cohort study found that calcium-channel blockers may also precipitate or exacerbate gastro-oesophageal reflux disease.
Effects on the peripheral circulation. An erythromelalgia-like eruption occurred in a patient 8 weeks after starting therapy with nifedipine. Symptoms included severe burning pain and swelling in the feet and lower legs, which were fiery red, tender, and warm to the touch. Symptoms resolved in 2 days when nifedipine was stopped. Similar effects have been reported in other patients on nifedipine. Erythromelalgia has also been reported with nicardipine. This type of erythromelalgia may be termed secondary erythermalgia.
Effects on the respiratory system. There have been some reports of pulmonary oedema being precipitated by nifedipine therapy in patients with aortic stenosis. Nifedipine has also been reported to exacerbate impaired tissue oxygenation in patients with cor pulmonale secondary to obstructive airways disease.
For a report of exacerbation of laryngeal oedema, see under Hypersensitivity, below.
Effects on the skin and nails. The commonest skin reactions to nifedipine have been rash, pruritus, urticaria, alopecia, and exfoliative dermatitis; there have been a few reports of erythema multiforme and the Stevens-Johnson syndrome. Erythema mul-tiforme occurred in a patient after substitution of amlodipine for nifedipine and cross-sensitivity, manifest as a pruritic maculopapular rash, has been reported between amlodipine and diltiazem. Generalised pruritus has been reported with amlodipine. Other skin reactions that have been reported with nifedipine include severe photosensitivity reactions, nonthrombocytopenic purpuric rashes, and telangiectasias, including photodistributed telangiectasias, and pemphigoid nodularis. Photo distributed telangiectasias have also been reported with amlodipine, and in one case recurred 3 years later. Am-lodipine has also been associated with a case of lichen planus. For reference to erythromelalgia, see under Effects on the Peripheral Circulation, above.
Nail and periungual pigmentation developed in a 75-year-old man 18 months after starting amlodipine; it was much improved 2 years after the drug was stopped.
Effects on taste. Distortion of taste and smell has been reported in 2 patients taking nifedipine, but a large survey involving 922 patients receiving nifedipine and 343 taking captopril did not show any association of taste disturbances with nifedipine. Sudden loss of taste has also been reported in a patient who had been taking amlodipine for several years; the sense of taste returned when amlodipine was stopped, but taste loss recurred on rechallenge.
Gynaecomastia. Unilateral gynaecomastia developed in 3 men 4, 6, and 26 weeks after starting nifedipine therapy.
Haemorrhage. See Effects on the Blood, above.
Hypersensitivity. Nifedipine is associated with various hyper-sensitivity reactions including skin rashes and effects on the liver(see above).
Nifedipine, given sublingually, exacerbated laryngeal swelling that developed in a woman after the use of isosorbide dinitrate spray.
Oedema. Oedema of the feet and ankles is a common adverse effect of nifedipine and other dihydropyridine calcium-channel blockers. It occurs typically 2 or more weeks after starting treatment and is caused by pre-capillary arteriolar dilatation rather than fluid retention. Evidence from a study in 10 diabetic subjects beginning nifedipine therapy, 5 of whom developed ankle oedema, suggested that nifedipine abolished the reflex vasoconstriction produced when the feet are below the level of the heart which is believed to prevent excessive fluid filtration into the tissues.
The oedema may respond to simple measures such as elevation of the feet or to a reduction in dosage but if it persists the calcium-channel blocker should be withdrawn.
Generalised oedema and facial and upper extremity oedema have been reported in patients taking amlodipine, but in both cases symptoms resolved on withdrawal of the drug.
Treatment of Adverse Effects
Activated charcoal may be given orally to adults or children who present within 1 hour of ingesting a potentially toxic overdose of nifedipine. Alternatively, gastric lavage may be considered in adults. Supportive and symptomatic care should be given. Hypotension may respond to placing the patient in the supine position with the feet raised; plasma expanders may be given, although cardiac overload should be avoided. If hypotension is not corrected, calcium should be given intravenously. The usual initial dose is 10 to 20 mL of 10% calcium gluconate given by slow intravenous injection or infusion; alternatively, up to 10 mL of 10% calcium chloride may be given. Glucagon may also be used. If hypotension persists, an intravenous sympathomimetic such as isoprenaline, dopamine, or noradrenaline may also be necessary. Bradycardia may be treated with atropine, isoprenaline, or cardiac pacing. Dialysis is not useful as nifedipine is highly protein bound. Plasmapheresis may be beneficial.
Overdosage. The management of calcium-channel blocker overdosage is mainly supportive (see Treatment of Adverse Effects, above). Cardiovascular effects usually predominate and, although severe toxicity is more likely in overdosage with non-dihydropyridines such as verapamil or diltiazem, treatment of overdosage is similar for all calcium-channel blockers. Prompt gastrointestinal decontamination, atropine to reverse bradycardia, and cardiovascular support with intravenous fluids, sympathomimetics, and possibly inotropes, are the mainstays of treatment. Intravenous calcium is also widely used, and high doses may be required; intravenous glucagon may also be given. Fampridine has been suggested as a specific antagonist, and successful use of vasopressin or terlipressin has been reported in patients with resistant hypotension. There is also some evidence that high-dose insulin, with glucose if required to maintain normal blood-glucose concentrations, may be of benefit. Most reports of overdosage have been with verapamil. The following are some individual reports with nifedipine:
• Hypotension, tachycardia, and flushing, followed by hypokalaemia, were seen in a patient who took nifedipine 600 mg as modified-release tablets together with an overdose of paracetamol, but there was no evidence of heart block. The patient was given calcium gluconate intravenously and subsequently activated charcoal and lactulose. Absorption of nifedipine was essentially complete 10 hours after ingestion. Potassium chloride was given orally to treat hypokalaemia and acetylcysteine was used to manage the paracetamol poisoning.
• Third-degree AV block, progressing to asystole, developed in a 14-month-old child who ingested about 800 mg of nifedipine. During cardiopulmonary resuscitation a total of 700 mg of calcium chloride was given, together with atropine, adrenaline, and sodium bicarbonate. The stomach was subsequently emptied by gastric lavage and activated charcoal given. The patient remained tachycardic and hypotensive, with evidence of pulmonary oedema and hyperglycaemia, and was given intravenous electrolytes and dopamine infusions and assisted ventilation, together with treatment to control subsequent tonic-clonic seizures. She eventually made an apparently complete recovery apart from a moderate speech delay.
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