Nifedipine

(BAN, USAN, rINN)
Nifedipine Chemical formula
Synonyms: Bay-a-1040; Nifedipiini; Nifedipin; Nifedipina; Nifedipinas; Nifédipine; Nifedipino; Nifedipinum. Dimethyl 1,4-dihydro-2,6dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylate.
Cyrillic synonym: Нифедипин.

💊 Chemical information

Chemical formula: C17H18N2O6 = 346.3.
CAS — 21829-25-4.
ATC — C08CA05.
ATC Vet — QC08CA05.

Pharmacopoeias.

In Chin., Eur., Int., Jpn, and US.

Ph. Eur. 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.

USP 31

(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 1 to slow photodegradation of nifedipine solutions. An extemporaneously prepared solution of nifedipine in a peppermintflavoured vehicle was reported 2 to be stable for at least 35 days when stored in amber glass bottles. 1. Thoma K, Klimek R. Photostabilization of drugs in dosage forms without protection from packaging materials. Int J Pharmaceutics 1991; 67: 169–75. 2. Dentinger PJ, et al. Stability of nifedipine in an extemporaneously compounded oral solution. Am J Health-Syst Pharm 2003; 60: 1019–22.

💊 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 hypersensitivity 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 cardiovascular1 and overall mortality.2 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,3 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.4-6 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.7 In addition, many of the studies that led to the negative reports used the older shortacting calcium-channel blockers. The calcium-channel blockers used now are largely modified-release formulations of short halflife blockers or are calcium-channel blockers with long halflives. 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) reported8 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 study9 in post-myocardial infarction patients failed to show any increase in mortality after one year in those receiving calciumchannel blockers. Another cohort study10 in patients with hypertension also found no overall increase in mortality with calciumchannel blockers, although there was a trend towards a higher rate with short-acting formulations. A meta-analysis11 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,12 while a lower incidence of cardiovascular events was reported for amlodipine compared with atenolol.13 A long-term study14 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.
1. Psaty BM, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995; 274: 620–5
2. Furberg CD, et al. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92: 1326–31
3. McCarthy M. US NIH issues warning on nifedipine. Lancet 1995; 346: 689–90
4. Opie LH, Messerli FH. Nifedipine and mortality: grave defects in the dossier. Circulation 1995; 92: 1068–72
5. Grossman E, Messerli FH. Calcium antagonists in cardiovascular disease: a necessary controversy but an unnecessary panic. Am J Med 1997; 102: 147–9
6. Stanton AV. Calcium channel blockers. BMJ 1998; 316: 1471–3
7. Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension. Effects of calcium antagonists on the risks of coronary heart disease, cancer and bleeding. J Hypertens 1997; 15: 105–15
8. Staessen JA, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757–64. Correction. ibid.; 1636
9. Jollis JG, et al. Calcium channel blockers and mortality in elderly patients with myocardial infarction. Arch Intern Med 1999; 159: 2341–8
10. Abascal VM, et al. Calcium antagonists and mortality risk in men and women with hypertension in the Framingham Heart Study. Arch Intern Med 1998; 158: 1882–6
11. Pahor M, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Lancet 2000; 356: 1949–54
12. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–97. Correction. ibid.; 289: 178
13. Dahlöf B, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906
14. Poole-Wilson PA, et al on behalf of the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) investigators. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364: 849–57.

Carcinogenicity.

An observational study carried out between 1988 and 1992 suggested that calcium-channel blockers were associated with an increased risk of cancer.1 Subsequent studies have failed to support this finding.2-7 A review by the WHO/ISH concluded that there is no good evidence that calcium-channel blockers increase cancer risk,8 and the biological basis for an effect of calcium-channel blockers on cancer risk has also been questioned.9 The large, long-term, randomised Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT)10 found no increase in the incidence of cancer in patients receiving a calcium-channel blocker (amlodipine) compared with those receiving a diuretic (chlortalidone).
1. Pahor M, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–7
2. Jick H, et al. Calcium-channel blockers and risk of cancer. Lancet 1997; 349: 525–8
3. Rosenberg L, et al. Calcium channel blockers and the risk of cancer. JAMA 1998; 279: 1000–4
4. Braun S, et al. Calcium channel blocking agents and risk of cancer in patients with coronary heart disease. J Am Coll Cardiol 1998; 31: 804–8
5. Sajadieh A, et al. Verapamil and risk of cancer in patients with coronary artery disease. Am J Cardiol 1999; 83: 1419–22
6. Meier CR, et al. Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer. Arch Intern Med 2000; 160: 349–53
7. Cohen HJ, et al. Calcium channel blockers and cancer. Am J Med 2000; 108: 210–15
8. Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension. Effects of calcium antagonists on the risks of coronary heart disease, cancer and bleeding. J Hypertens 1997; 15: 105–15
9. Mason RP. Calcium channel blockers, apoptosis and cancer: is there a biologic relationship? J Am Coll Cardiol 1999; 34: 1857–66
10. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–97. Correction. ibid.; 289: 178.

Effects on the blood.

Treatment with nifedipine significantly reduces platelet aggregation in vitro1 and results indicating inhibition of platelet function in healthy subjects receiving oral (but not intravenous) nifedipine have been reported.2,3 Thus, concern has been expressed4 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,5 although it has been used in other situations apparently without an increased risk of bleeding.6 Conflicting results have been reported with regard to the risk of gastrointestinal bleeding. A prospective cohort study in 1636 elderly hypertensive patients,7 and a subsequent case-control study,8 reported that calcium-channel blockers were associated with an increased risk of gastrointestinal haemorrhage compared with beta blockers. However, it was suggested9 that this may have been due to a protective effect of beta blockers rather than an adverse effect of calcium-channel blockers, and another study10 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,11 and of thrombocytopenia with amlodipine12 and with diltiazem.13,14
1. Ośmiałwska Z, et al. Effect of nifedipine monotherapy on platelet aggregation in patients with untreated essential hypertension. Eur J Clin Pharmacol 1990; 39: 403–4
2. Winther K, et al. Dose-dependent effects of verapamil and nifedipine on in vivo platelet function in normal volunteers. Eur J Clin Pharmacol 1990; 39: 291–3
3. Walley TJ, et al. The effects of intravenous and oral nifedipine on ex vivo platelet function. Eur J Clin Pharmacol 1989; 37: 449–52
4. Becker RC, Alpert JS. The impact of medical therapy on hemorrhagic complications following coronary artery bypass grafting. Arch Intern Med 1990; 150: 2016–21
5. Wagenknecht LE, et al. Surgical bleeding: unexpected effect of a calcium antagonist. BMJ 1995; 310: 776–7
6. Öhman J and others. Surgical bleeding and calcium antagonists. BMJ 1995; 311: 388–9. [Several letters.
7. Pahor M, et al. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996; 347: 1061–5
8. Kaplan RC, et al. Use of calcium channel blockers and risk of hospitalized gastrointestinal tract bleeding. Arch Intern Med 2000; 160: 1849–55
9. Suissa S, et al. Antihypertensive drugs and the risk of gastrointestinal bleeding. Am J Med 1998; 105: 230–5
10. Kelly JP, et al. Major upper gastrointestinal bleeding and the use of calcium channel blockers. Lancet 1999; 353: 559
11. Laporte J-R, et al. Fatal aplastic anaemia associated with nifedipine. Lancet 1998; 352: 619–20
12. Usalan C, et al. Severe thrombocytopenia associated with amlodipine treatment. Ann Pharmacother 1999; 33: 1126–7
13. Lahav M, Arav R. Diltiazem and thrombocytopenia. Ann Intern Med 1989; 110: 327
14. Michalets EL, Jackson DV. Diltiazem-associated thrombocytopenia. Pharmacotherapy 1997; 17: 1345–8.

Effects on the brain.

Cerebral ischaemia1,2 has been reported in small numbers of patients given nifedipine.
1. Nobile-Orazio E, Sterzi R. Cerebral ischaemia after nifedipine treatment. BMJ 1981; 283: 948
2. Schwartz M, et al. Oral nifedipine in the treatment of hypertensive urgency: cerebrovascular accident following a single dose. Arch Intern Med 1990; 150: 686–7.

Effects on carbohydrate metabolism.

There are reports of deterioration of diabetes,1 reduction in glucose tolerance,2 and development of diabetes1,3 in patients given nifedipine. Nifedipine has also been reported to increase plasma-glucose concentrations.3,4 However, other reports and studies have found no change in glucose tolerance in either diabetic or non-diabetic patients taking nifedipine.5-10 See also Diabetes Mellitus under Precautions, below.
1. Bhatnagar SK, et al. Diabetogenic effects of nifedipine. BMJ 1984; 289: 19
2. Giugliano D, et al. Impairment of insulin secretion in man by nifedipine. Eur J Clin Pharmacol 1980; 18: 395–8
3. Zezulka AV, et al. Diabetogenic effects of nifedipine. BMJ 1984; 289: 437–8
4. Charles S, et al. Hyperglycaemic effect of nifedipine. BMJ 1981; 283: 19–20
5. Harrower ADB, Donnelly T. Hyperglycaemic effect of nifedipine. BMJ 1981; 283: 796
6. Greenwood RH. Hyperglycaemic effect of nifedipine. BMJ 1982; 284: 50
7. Abadie E, Passa P. Diabetogenic effects of nifedipine. BMJ 1984; 289: 438
8. Dante A. Nifedipine and fasting glycemia. Ann Intern Med 1986; 104: 125–6
9. Whitcroft I, et al. Calcium antagonists do not impair long-term glucose control in hypertensive non-insulin dependent diabetics (NIDDS). Br J Clin Pharmacol 1986; 22: 208P
10. Tentorio A, et al. Insulin secretion and glucose tolerance in noninsulin dependent diabetic patients after chronic nifedipine treatment. Eur J Clin Pharmacol 1989; 36: 311–13.

Effects on the ears.

There have been isolated reports1 of tinnitus associated with several calcium-channel blockers including nifedipine, nicardipine, nitrendipine, diltiazem, verapamil, and cinnarizine.
1. Narváez M, et al. Tinnitus with calcium-channel blockers. Lancet 1994; 343: 1229–30.

Effects on the eyes.

Individual reports have implicated nifedipine in the development of transient retinal ischaemia and blindness,1 and of periorbital oedema.2 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.3 Nifedipine has also been suggested as a risk factor in the development of cataract,4,5 but the numbers involved in this analysis are small6 and it is possible that the risk, if it exists,7 relates to hypertension rather than nifedipine treatment.6
1. Pitlik S, et al. Transient retinal ischaemia induced by nifedipine. BMJ 1983; 287: 1845–6
2. Silverstone PH. Periorbital oedema caused by nifedipine. BMJ 1984; 288: 1654
3. Coulter DM. Eye pain with nifedipine and disturbance of taste with captopril: a mutually controlled study showing a method of postmarketing surveillance. BMJ 1988; 296: 1086–8
4. van Heyningen R, Harding JJ. Do aspirin-like analgesics protect against cataract? Lancet 1986; i: 1111–13
5. Harding JJ, van Heyningen R. Drugs, including alcohol, that act as risk factors for cataract, and possible protection against cataract by aspirin-like analgesics and cyclopenthiazide. Br J Ophthalmol 1988; 72: 809–14
6. van Heyningen R, Harding JJ. Aspirin-like analgesics and cataract. Lancet 1986; ii: 283
7. Kewitz H, et al. Aspirin and cataract. Lancet 1986; ii: 689.

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,1and sudden circulatory collapse has been reported in 4 patients receiving nifedipine who underwent routine coronary bypass surgery.2 One patient died despite all attempts at resuscitation.2However, 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.3-6 Such cases appear to be chiefly associated with a too-rapid fall in blood pressure after the use of sublingual nifedipine for hypertensive urgencies or emergencies,5,6 or occur in patients with a history of ischaemic heart disease.3,4 For discussion of the effects of calcium-channel blockers on cardiovascular mortality, see above.
1. Chopra DA, Maxwell RT. Complete heart block with low dose nifedipine. BMJ 1984; 288: 760
2. Goiti JJ. Calcium channel blocking agents and the heart. BMJ 1985; 291: 1505
3. Sia STB, et al. Aggravation of myocardial ischaemia by nifedipine. Med J Aust 1985; 142: 48–50
4. Boden WE, et al. Nifedipine-induced hypotension and myocardial ischemia in refractory angina pectoris. JAMA 1985; 253: 1131–5
5. O’Mailia JJ, et al. Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987; 107: 185–6
6. Leavitt AD, Zweifler AJ. Nifedipine, hypotension, and myocardial injury. Ann Intern Med 1988; 108: 305–6.
WITHDRAWAL. Exacerbation of coronary ischaemia and thrombosis of arteriovenous graft could have resulted from withdrawal of nifedipine in a patient.1 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.2 It was postulated that the withdrawal effect could be due to an increase in sensitivity of vascular α2 adrenoceptors to circulating adrenaline.
1. Mysliwiec M, et al. Calcium antagonist withdrawal syndrome. BMJ 1983; 286: 1898
2. Mehta J, Lopez LM. Calcium-blocker withdrawal phenomenon: increase in affinity of alpha adrenoceptors for agonist as a potential mechanism. Am J Cardiol 1986; 58: 242–6.

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 reported1 in 4 patients with underlying renal insufficiency receiving nifedipine,1 and in another report2 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,3 and nocturia in 9 patients referred for prostatic surgery was also attributed to nifedipine.4
1. Diamond JR, et al. Nifedipine-induced renal dysfunction: alterations in renal hemodynamics. Am J Med 1984; 77: 905–9
2. Demarie BK, Bakris GL. Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med 1990; 113: 987–8
3. Antonelli D, et al. Excessive nifedipine diuretic effect. BMJ 1984; 288: 760
4. Williams G, Donaldson RM. Nifedipine and nocturia. Lancet 1986; i: 738.

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.1-4
1. Rotmensch HH, et al. Lymphocyte sensitisation in nifedipineinduced hepatitis. BMJ 1980; 281: 976–7
2. Davidson AR. Lymphocyte sensitisation in nifedipine-induced hepatitis. BMJ 1980; 281: 1354
3. Abramson M, Littlejohn GO. Hepatic reactions to nifedipine. Med J Aust 1985; 142: 47–8
4. Shaw DR, et al. Nifedipine hepatitis. Aust N Z J Med 1987; 17: 447–8.

Effects on the menstrual cycle.

Menorrhagia in 2 women1and menstrual irregularity with heavy bleeding in another2 have been reported in association with nifedipine treatment.
1. Rodger JC, Torrance TC. Can nifedipine provoke menorrhagia? Lancet 1983; ii: 460
2. Singh G, et al. Can nifedipine provoke menorrhagia? Lancet 1983; ii: 1022.

Effects on mental function.

Insomnia, hyperexcitability, pacing, agitation, and depression were reported1 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.2 Although 2 epidemiological studies suggested that calciumchannel blockers may promote suicide,3 a subsequent study4found no evidence of an association between depression and the use of calcium-channel blockers, and the number of suicides was low. Further studies5,6 have also failed to find an increased risk of suicide with calcium-channel blockers compared with other antihypertensive drugs.
1. Ahmad S. Nifedipine-induced acute psychosis. J Am Geriatr Soc 1984; 32: 408
2. Hullett FJ, et al. Depression associated with nifedipine-induced calcium channel blockade. Am J Psychiatry 1988; 145: 1277–9
3. Lindberg G, et al. Use of calcium channel blockers and risk of suicide: ecological findings confirmed in population based cohort study. BMJ 1998; 316: 741–5
4. Dunn NR, et al. Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression. Br J Clin Pharmacol 1999; 48: 230–3
5. Gasse C, et al. Risk of suicide among users of calcium channel blockers: population based, nested case-control study. BMJ 2000; 320: 1251
6. Sørensen HT, et al. Risk of suicide in users of beta-adrenoceptor blockers, calcium channel blockers and angiotensin converting enzyme inhibitors. Br J Clin Pharmacol 2001; 52: 313–8.

Effects on the mouth.

GINGIVAL HYPERPLASIA. A number of reports have implicated nifedipine in the development of gingival hyperplasia.1-4 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.5 Amlodipine has also induced gingival overgrowth.6 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.7 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.8
1. Ramon Y, et al. Gingival hyperplasia caused by nifedipine—a preliminary report. Int J Cardiol 1984; 5: 195–204
2. van der Wall EE, et al. Gingival hyperplasia induced by nifedipine, an arterial vasodilating drug. Oral Surg 1985; 60: 38–40
3. Shaftic AA, et al. Nifedipine-induced gingival hyperplasia. Drug Intell Clin Pharm 1986; 20: 602–5
4. Jones CM. Gingival hyperplasia associated with nifedipine. Br Dent J 1986; 160: 416–17
5. Johnson RB. Nifedipine-induced gingival overgrowth. Ann Pharmacother 1997; 31: 935
6. Ellis JS, et al. Gingival sequestration of amlodipine and amlodipine-induced gingival overgrowth. Lancet 1993; 341: 1102–3
7. Steele RM, et al. Calcium antagonist-induced gingival hyperplasia. Ann Intern Med 1994; 120: 663–4
8. Adverse Drug Reactions Advisory Committee (ADRAC). Druginduced gingival overgrowth. Aust Adverse Drug React Bull 1999; 18: 6–7. Also available at: http://www.tga.gov.au/adr/ aadrb/aadr9906.pdf (accessed 25/07/08)
PAROTITIS. Acute swelling of the parotid glands occurred in a patient after sublingual administration of nifedipine.1
1. Bosch X, et al. Nifedipine-induced parotitis. Lancet 1986; ii: 467.

Effects on the neuromuscular system.

Severe muscle cramps have been reported in a few patients taking nifedipine;1,2in one patient2 the cramps were associated with widespread paraesthesia. Reversible myoclonic dystonia associated with nifedipine has been reported in a patient.3 Severe rhabdomyolysis developed in a patient with a transplanted kidney who was receiving an intravenous infusion of nifedipine.4 The patient recovered rapidly once the infusion was stopped. There has also been a report5 of myopathy, myalgia, and arthralgia associated with amlodipine, and of arthralgia in a patient6 receiving diltiazem. Parkinsonism is a recognised adverse effect of flunarizine and cinnarizine, which have calcium-channel blocking properties. It has also been reported with diltiazem and with amlodipine.7,8
1. Keidar S, et al. Muscle cramps during treatment with nifedipine. BMJ 1982; 285: 1241–2
2. Macdonald JB. Muscle cramps during treatment with nifedipine. BMJ 1982; 285: 1744
3. de Medina A, et al. Nifedipine and myoclonic dystonia. Ann Intern Med 1985; 104: 125
4. Horn S, et al. Severe rhabdomyolysis in a kidney-transplant recipient receiving intravenous nifedipine. Lancet 1995; 346: 848–9
5. Phillips BB, Muller BA. Severe neuromuscular complications possibly associated with amlodipine. Ann Pharmacother 1998; 32: 1165–7
6. Smith KM. Arthralgia associated with calcium-channel blockers. Am J Health-Syst Pharm 2000; 57: 55–7
7. Sempere AP, et al. Parkinsonism induced by amlodipine. Mov Disord 1995; 10: 115–6
8. Teive HA, et al. Parkinsonian syndrome induced by amlodipine: case report. Mov Disord 2002; 17: 833–5.

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 study1 found that calcium-channel blockers may also precipitate or exacerbate gastro-oesophageal reflux disease.
1. Hughes J, et al. Do calcium antagonists contribute to gastrooesophageal reflux disease and concomitant noncardiac chest pain? Br J Clin Pharmacol 2007; 64: 83–9.

Effects on the peripheral circulation.

An erythromelalgialike 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.1 Similar effects have been reported in other patients on nifedipine.2-4 Erythromelalgia has also been reported with nicardipine.5 This type of erythromelalgia may be termed secondary erythermalgia.6
1. Fisher JR, et al. Nifedipine and erythromelalgia. Ann Intern Med 1983; 98: 671–2
2. Grunwald Z. Painful edema, erythematous rash, and burning sensation due to nifedipine. Drug Intell Clin Pharm 1982; 16: 492
3. Brodmerkel GJ. Nifedipine and erythromelalgia. Ann Intern Med 1983; 99: 415
4. Sunahara JF, et al. Possible erythromelalgia-like syndrome associated with nifedipine in a patient with Raynaud’s phenomenon. Ann Pharmacother 1996; 30: 484–6
5. Levesque H, et al. Erythromelalgia induced by nicardipine (inverse Raynaud’s phenomenon?) BMJ 1989; 298: 1252–3
6. Drenth JPH, Michiels JJ. Three types of erythromelalgia. BMJ 1990; 301: 454–5.

Effects on the respiratory system.

There have been some reports of pulmonary oedema being precipitated by nifedipine therapy in patients with aortic stenosis.1,2 Nifedipine has also been reported to exacerbate impaired tissue oxygenation in patients with cor pulmonale secondary to obstructive airways disease.3 For a report of exacerbation of laryngeal oedema, see under Hypersensitivity, below.
1. Gillmer DJ, Kark P. Pulmonary oedema precipitated by nifedipine. BMJ 1980; 280: 1420–1
2. Aderka D, Pinkhas J. Pulmonary oedema precipitated by nifedipine. BMJ 1984; 289: 1272
3. Kalra L, Bone MF. Nifedipine and impaired oxygenation in patients with chronic bronchitis and cor pulmonale. Lancet 1989; i: 1135–6.

Effects on the skin and nails.

The commonest skin reactions to nifedipine have been rash, pruritus, urticaria, alopecia, and exfoliative dermatitis;1 there have been a few reports of erythema multiforme and the Stevens-Johnson syndrome.1 Erythema multiforme occurred in a patient after substitution of amlodipine for nifedipine2 and cross-sensitivity, manifest as a pruritic maculopapular rash, has been reported between amlodipine and diltiazem.3 Generalised pruritus has been reported with amlodipine.4 Other skin reactions that have been reported with nifedipine include severe photosensitivity reactions,5 nonthrom bocytopenic purpuric rashes,6 and telangiectasias,7 including photodistributed telangiectasias,8 and pemphigoid nodularis.9Photodistributed telangiectasias have also been reported with amlodipine,10,11 and in one case10 recurred 3 years later. Amlodipine has also been associated12 with a case of lichen planus. For reference to erythromelalgia, see under Effects on the Peripheral Circulation, above. Nail and periungual pigmentation developed13 in a 75-year-old man 18 months after starting amlodipine; it was much improved 2 years after the drug was stopped.
1. Stern R, Khalsa JH. Cutaneous adverse reactions associated with calcium channel blockers. Arch Intern Med 1989; 149: 829–32
2. Bewley AP, et al. Erythema multiforme following substitution of amlodipine for nifedipine. BMJ 1993; 307: 241
3. Baker BA, Cacchione JG. Dermatologic cross-sensitivity between diltiazem and amlodipine. Ann Pharmacother 1994; 28: 118–19
4. Orme S, et al. Generalised pruritus associated with amlodipine. BMJ 1997; 315: 463
5. Thomas SE, Wood ML. Photosensitivity reactions associated with nifedipine. BMJ 1986; 292: 992
6. Oren R, et al. Nifedipine-induced nonthrombocytopenic purpura. DICP Ann Pharmacother 1989; 23: 88
7. Tsele E, Chu AC. Nifedipine and telangiectasias. Lancet 1992; 339: 365–6
8. Collins P, Ferguson J. Photodistributed nifedipine-induced facial telangiectasia. Br J Dermatol 1993; 129: 630–3
9. Ameen M, et al. Pemphigoid nodularis associated with nifedipine. Br J Dermatol 2000; 142: 575–7
10. Basarab T, et al. Calcium antagonist-induced photo-exposed telangiectasia. Br J Dermatol 1997; 136: 974–5
11. Grabczynska SA, Cowley N. Amlodipine induced-photosensitivity presenting as telangiectasia. Br J Dermatol 2000; 142: 1255–6
12. Swale VJ, McGregor JM. Amlodipine-associated lichen planus. Br J Dermatol 2001; 144: 920–1
13. Sladden MJ, et al. Longitudinal melanonychia and pseudoHutchinson sign associated with amlodipine. Br J Dermatol 2005; 153: 219–20.

Effects on taste.

Distortion of taste and smell has been reported in 2 patients taking nifedipine,1 but a large survey involving 922 patients receiving nifedipine and 343 taking captopril did not show any association of taste disturbances with nifedipine.2 Sudden loss of taste has also been reported3 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.
1. Levenson JL, Kennedy K. Dysomia, dysgeusia, and nifedipine. Ann Intern Med 1985; 102: 135–6
2. Coulter DM. Eye pain with nifedipine and disturbance of taste with captopril: a mutually controlled study showing a method of postmarketing surveillance. BMJ 1988; 296: 1086–8
3. Sadasivam B, Jhaj R. Dysgeusia with amlodipine—a case report. Br J Clin Pharmacol 2007; 63: 253.

Gynaecomastia.

Unilateral gynaecomastia developed in 3 men 4, 6, and 26 weeks after starting nifedipine therapy.1
1. Clyne CAC. Unilateral gynaecomastia and nifedipine. BMJ 1986; 292: 380.

Haemorrhage.

See Effects on the Blood, above.

Hypersensitivity.

Nifedipine is associated with various hypersensitivity 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.1
1. Silfvast T, et al. Laryngeal oedema after isosorbide dinitrate spray and sublingual nifedipine. BMJ 1995; 311: 232.

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.1 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.2 The oedema may respond to simple measures such as elevation of the feet or to a reduction in dosage but if it persists the calciumchannel blocker should be withdrawn.1 Generalised oedema3 and facial and upper extremity oedema4have been reported in patients taking amlodipine, but in both cases symptoms resolved on withdrawal of the drug.
1. Maclean D, MacConnachie AM. Selective side-effects: peripheral oedema with dihydropyridine calcium antagonists. Prescribers’ J 1991; 31: 4–6
2. Williams SA, et al. Dependent oedema and attenuation of postural vasoconstriction associated with nifedipine therapy for hypertension in diabetic patients. Eur J Clin Pharmacol 1989; 37: 333–5
3. Şener D, et al. Anasarca edema with amlodipine treatment. Ann Pharmacother 2005; 39: 761–3
4. Ganeshalingham A, Wong W. Amlodipine-induced bilateral upper extremity edema. Ann Pharmacother 2007; 41: 1536–8.

💊 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 nondihydropyridines such as verapamil or diltiazem, treatment of overdosage is similar for all calcium-channel blockers.1-4 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 suggested5 as a specific antagonist, and successful use of vasopressin6 or terlipressin7 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.8-11 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.12 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.13 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.
1. Salhanick SD, Shannon MW. Management of calcium channel antagonist overdose. Drug Safety 2003; 26: 65–79
2. DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev 2004; 23: 223–38
3. Olson KR, et al. Calcium channel blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2005; 43: 797–822
4. Shepherd G. Treatment of poisoning caused by beta-adrenergic and calcium-channel blockers. Am J Health-Syst Pharm 2006; 63: 1828–35
5. Stevens JJWM, Ghosh S. Overdose of calcium channel blockers. BMJ 1994; 309: 193
6. Kanagarajan K, et al. The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose. Clin Toxicol 2007; 45: 56–9
7. Leone M, et al. Terlipressin: a new therapeutic for calciumchannel blockers overdose. J Crit Care 2005; 20: 114–15
8. Yuan TH, et al. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999; 37: 463–74
9. Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med 2001; 344: 1721–2
10. Mégarbane B, et al. The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta-blocker poisoning. Toxicol Rev 2004; 23: 215–22
11. Shepherd G, Klein-Schwartz W. High-dose insulin therapy for calcium-channel blocker overdose. Ann Pharmacother 2005; 39: 923–30
12. Ferner RE, et al. Pharmacokinetics and toxic effects of nifedipine in massive overdose. Hum Exp Toxicol 1990; 9: 309–11
13. Wells TG, et al. Nifedipine poisoning in a child. Pediatrics 1990; 86: 91–4.

💊 Precautions

Nifedipine should be used with caution in patients with hypotension, in patients whose cardiac reserve is poor, and in those with heart failure since deterioration of heart failure has been noted. Nifedipine should not be used in cardiogenic shock, in patients who have suffered a myocardial infarction in the previous 2 to 4 weeks, or in acute unstable angina. Nifedipine should not be used to treat an anginal attack in chronic stable angina. In patients with severe aortic stenosis nifedipine may increase the risk of developing heart failure. Sudden withdrawal of nifedipine might be associated with an exacerbation of angina. The dose may need to be reduced in patients with hepatic impairment. Nifedipine should be stopped in patients who experience ischaemic pain after use. Nifedipine is reported to be teratogenic in animals and may inhibit labour, but it has been used in hypertension in pregnancy (see Hypertension, under Uses and Administration, below).

Breast feeding.

Nifedipine is distributed into breast milk1,2 but the amount present is probably too small to be harmful. There have been no reports of any clinical effects in breast-fed infants whose mothers were receiving nifedipine and the American Academy of Pediatrics therefore considers3 that it is usually compatible with breast feeding.
1. Ehrenkranz RA, et al. Nifedipine transfer into human milk. J Pediatr 1989; 114: 478–80
2. Penny WJ, Lewis MJ. Nifedipine is excreted in human milk. Eur J Clin Pharmacol 1989; 36: 427–8
3. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 06/07/04)

Diabetes mellitus.

Nifedipine may modify insulin and glucose responses (see Effects on Carbohydrate Metabolism under Adverse Effects, above) calling for adjustments in antidiabetic therapy. Also some studies have suggested that nifedipine may worsen proteinuria and renal dysfunction in diabetic patients with some degree of renal insufficiency,1,2 but other studies, (see Kidney Disorders under Uses and Administration, below), have suggested that nifedipine may have a beneficial effect on proteinuria. Some studies have suggested that patients with diabetes mellitus3,4 or impaired glucose metabolism5 may be more susceptible to adverse cardiovascular effects of calcium-channel blockers. The calcium-channel blockers used in these studies were nisoldipine, amlodipine, and isradipine (long-acting or intermediate-acting calcium-channel blockers). However, two of the studies3,4 compared the calcium-channel blocker with an ACE inhibitor and it has been suggested that ACE inhibitors may have a protective effect in patients with diabetes that is additional to their antihypertensive action. Thus, ACE inhibitors may be particularly beneficial in these patients rather than calcium-channel blockers being particularly harmful.6
1. Mimran A, et al. Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy. J Hypertens 1988; 6: 919–23
2. Demarie BK, Bakris GL. Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med 1990; 113: 987–8
3. Estacio RO, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998; 338: 645–52. Correction. ibid.; 339: 1339
4. Tatti P, et al. Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998; 21: 597–603
5. Byington RP, et al. Isradipine, raised glycosylated haemoglobin, and risk of cardiovascular events. Lancet 1997; 350: 1075–6
6. Poulter NR. Calcium channel blockers and cardiovascular risk in diabetes. Lancet 1998; 351: 1809–10.

Interference with la

boratory estimations. Nifedipine may give falsely elevated spectrophotometric values of urinary vanillylmandelic acid; HPLC estimations are unaffected.

Porphyria.

Nifedipine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Withdrawal.

Sudden withdrawal of nifedipine might be associated with an exacerbation of angina. For a report of life-threatening coronary vasospasm occurring after withdrawal of nifedipine before a revascularisation procedure, see under Effects on the Heart, in Diltiazem.

💊 Interactions

Nifedipine may enhance the antihypertensive effects of other antihypertensive drugs such as beta blockers although the combination is generally well tolerated. Enhanced antihypertensive effects may also be seen if used with drugs such as aldesleukin and antipsychotics that cause hypotension. Nifedipine may modify insulin and glucose responses (see Effects on Carbohydrate Metabolism, above) and therefore diabetic patients may need to adjust their antidiabetic treatment when receiving nifedipine. Nifedipine is extensively metab olised in the liver by the cytochrome P450 isoenzyme CYP3A4, and interactions may occur with other drugs, such as quinidine, sharing the same metabolic pathway, and with enzyme inducers, such as carbamazepine, phenytoin, and rifampicin, and enzyme inhibitors, such as cimetidine, erythromycin, and HIVprotease inhibitors.

Alcohol.

A study involving 10 healthy subjects showed that the area under the concentration-time profile for nifedipine 20 mg was increased by 54% when taken orally with alcohol, and maximum pulse rate was achieved more rapidly, which was in line with animal and in-vitro studies suggesting that the metabolism of nifedipine is inhibited by alcohol.1
1. Qureshi S, et al. Nifedipine-alcohol interaction. JAMA 1990; 264: 1660–1.

Antiarrhythmics.

Nifedipine and quinidine probably have a common metabolic pathway in the liver and might be expected to interact if given concurrently. In one study,1 quinidine appeared to inhibit nifedipine metabolism resulting in increased serum concentrations of nifedipine; quinidine concentrations were unchanged. However, conflicting effects on serum-quinidine concentrations have been reported.
1. Bowles SK, et al. Evaluation of the pharmacokinetic and pharmacodynamic interaction between quinidine and nifedipine. J Clin Pharmacol 1993; 33: 727–31.

Antibacterials.

The macrolide antibacterials are inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may inhibit the metabolism of calcium-channel blockers. Two days after clarithromycin was started,1 vasodilatory shock and heart block occurred in a 77-year-old man whose antihypertensive medication included nifedipine. Clarithromycin was continued and when his condition improved nifedipine was reintroduced at half the previous dose; his blood pressure was stable on discharge.
1. Gerónimo-Pardo M, et al. Clarithromycin–nifedipine interaction as possible cause of vasodilatory shock. Ann Pharmacother 2005; 39: 538–42.

Antidiabetics.

See Diabetes Mellitus under Precautions and Effects on Carbohydrate Metabolism under Adverse Effects, above.

Antiepileptics.

The effects of dihydropyridine calcium-channel blockers may be reduced by enzyme-inducing antiepileptics such as carbamazepine, phenobarbital, and phenytoin.1-4 In contrast, sodium valproate has been reported to increase plasma-nimodipine concentrations.3 For reports of an interaction between dihydropyridines and phenytoin resulting in raised serum-phenytoin concentration.
1. Capewell S, et al. Reduced felodipine bioavailability in patients taking anticonvulsants. Lancet 1988: ii: 480–2
2. Schellens JHM, et al. Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design. J Pharmacol Exp Ther 1989; 249: 638–45
3. Tartara A, et al. Differential effects of valproic acid and enzymeinducing anticonvulsants on nimodipine pharmacokinetics in epileptic patients. Br J Clin Pharmacol 1991; 32: 335–40
4. Yasui-Furukori N, Tateishi T. Carbamazepine decreases antihypertensive effect of nilvadipine. J Clin Pharmacol 2002; 42: 100–103.

Antifungals.

Azole antifungals inhibit the cytochrome P450 enzyme system and may therefore interfere with metabolism of calcium-channel blockers. Two women who had been taking felodipine for about a year developed peripheral oedema a few days after starting treatment with itraconazole.1 Plasma-felodipine concentrations were measured in one of the women before and during a subsequent course of itraconazole and increased considerably when the two drugs were used together. A similar interaction occurred when itraconazole therapy was started in a patient already taking nifedipine.2 Potentiation of the effects of nifedipine by fluconazole has also been reported.3
1. Neuvonen PJ, Suhonen R. Itraconazole interacts with felodipine. J Am Acad Dermatol 1995; 33: 134–5
2. Tailor SAN, et al. Peripheral edema due to nifedipine-itraconazole interaction: a case report. Arch Dermatol 1996; 132: 350–2
3. Kremens B, et al. Loss of blood pressure control on withdrawal of fluconazole during nifedipine therapy. Br J Clin Pharmacol 1999; 47: 707–8.

Antihistamines.

Severe angina developed in a patient stabilised on nifedipine who took terfenadine 60 mg for seasonal allergy. The pain resolved within an hour or two.1
1. Falkenberg HM. Possible interaction report. Can Pharm J 1988; 121: 294.

Antineoplastics.

For reports of increased vincristine toxicity in children also receiving itraconazole and nifedipine concomitantly, see Antifungals under Interactions of Vincristine.

Antivirals.

The HIV-protease inhibitors are known to inhibit the cytochrome P450 isoenzyme CYP3A4 and may therefore interfere with the metabolism of calcium-channel blockers. A woman stable on felodipine developed oedema1 in both legs when she was given nelfinavir after a needle-stick injury. The oedema resolved on withdrawal of felodipine, and was attributed to inhibition of felodipine metabolism. A study2 in healthy subjects found that indinavir plus ritonavir increased exposure to both amlodipine and diltiazem.
1. Izzedine H, et al. Nelfinavir and felodipine: a cytochrome P450 3A4-mediated drug interaction. Clin Pharmacol Ther 2004; 75: 362–3
2. Glesby MJ, et al. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers. Clin Pharmacol Ther 2005; 78: 143–53.

Beta blockers.

Although nifedipine is often used with beta blockers without untoward effects, heart failure has been reported in a few patients with angina who were given nifedipine and a beta blocker.1,2 Severe hypotension has been reported in 1 of 15 angina patients given nifedipine and atenolol;3 withdrawal of the beta blocker precipitated severe unstable angina in this patient. Severe hypotension in a patient was attributed to the use of nifedipine with propranolol, and was thought to have contributed to fatal myocardial infarction.4
1. Anastassiades CJ. Nifedipine and beta-blocker drugs. BMJ 1980; 281: 1251–2
2. Robson RH, Vishwanath MC. Nifedipine and beta-blockade as a cause of cardiac failure. BMJ 1982; 284: 104
3. Opie LH, White DA. Adverse interaction between nifedipine and
β-blockade. BMJ 1980; 281: 1462.
4. Staffurth JS, Emery P. Adverse interaction between nifedipine and beta-blockade. BMJ 1981; 282:225.

Calcium-channel blockers.

Plasma concentrations of nifedipine were increased in a study in 6 healthy subjects when pretreated with diltiazem; the elimination half-life of nifedipine was prolonged from 2.54 hours to 3.40 hours after pretreatment with diltiazem 30 mg daily and to 3.47 hours after 90 mg daily. The effect was probably due to reduced hepatic metabolism of nifedipine.1 Nifedipine and diltiazem are reported to be metabolised by the same hepatic enzyme and, conversely, pretreatment with nifedipine has resulted in increased concentrations of diltiazem.2
1. Tateishi T, et al. Dose dependent effect of diltiazem on the pharmacokinetics of nifedipine. J Clin Pharmacol 1989; 29: 994–7
2. Tateishi T, et al. The effect of nifedipine on the pharmacokinetics and dynamics of diltiazem: the preliminary study in normal volunteers. J Clin Pharmacol 1993; 33: 738–40.

Digoxin.

For the effect of nifedipine and other dihydropyridine calcium-channel blockers on digoxin262.

Grapefruit juice.

Grapefruit juice inhibits the cytochrome P450 isoenzyme CYP3A4, particularly in the intestinal wall, and has been shown to increase markedly the bioavailability of oral calcium-channel blockers;1-3 calcium-channel blockers given intravenously appear to be unaffected.4 The interaction may be less significant with calcium-channel blockers such as amlodipine that have a higher bioavailability,5 but most calcium-channel blockers should not be taken orally at the same time as grapefruit juice.6 A stereoselective effect has also been reported.7
1. Bailey DG, et al. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991; 337: 268–9
2. Bailey DG, et al. Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics. Clin Pharmacol Ther 1993; 54: 589–94
3. Lundahl J, et al. Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects. Eur J Clin Pharmacol 1995; 49: 61–7
4. Rashid TJ, et al. Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol 1995; 40: 51–8
5. Vincent J, et al. Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine. Br J Clin Pharmacol 2000; 50: 455–63
6. Committee on Safety of Medicines/Medicines Control Agency. Drug interactions with grapefruit juice. Current Problems 1997; 23: 2. Also available at: http://www.mhra.gov.uk/home/ idcplg?IdcService=GET_FILE&dDocName=CON2015623& RevisionSelectionMethod=LatestReleased (accessed 16/06/06
7. Uno T, et al. Effect of grapefruit juice on the disposition of manidipine enantiomers in healthy subjects. Br J Clin Pharmacol 2006; 61: 533–7.

Histamine H2-antagonists.

Pharmacokinetic studies have indicated that use of nifedipine with cimetidine can increase the bioavailability of nifedipine.1-4 An increase in the area under the plasma concentration-time curve of between 77 and 92% has been reported.2,3 Potentiation of the hypotensive effect of nifedipine by cimetidine was also shown in 7 hypertensive patients.1The mechanism of the interaction was thought to be due to inhibition of the cytochrome P450 system by cimetidine and thus inhibition of the metabolism of nifedipine. Ranitidine was found to have little effect on the pharmacokinetics of nifedipine, although there was an increase in the bioavailability of nifedipine during use of ranitidine.5 Famotidine has been reported not to interact with nifedipine.6
1. Kirch W, et al. Einfluß von cimetidin und ranitidin auf pharmakokinetik und antihypertensiven effekt von nifedipin. Dtsch Med Wochensc hr 1983; 108: 1757–61
2. Renwick AG, et al. Factors affecting the pharmacokinetics of nifedipine. Eur J Clin Pharmacol 1987; 32: 351–5
3. Smith SR, et al. Ranitidine and cimetidine: drug interactions with single dose and steady-state nifedipine administration. Br J Clin Pharmacol 1987; 23: 311–15
4. Schwartz JB, et al. Effect of cimetidine or ranitidine administration on nifedipine pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1988; 43: 673–80
5. Kirch W, et al. Ranitidine increases bioavailability of nifedipine. Clin Pharmacol Ther 1985; 37: 204
6. Kirch W, et al. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 1989; 96: 1388–92.

Immunosuppressants.

Flushing, paraesthesias, and rashes were reported in 2 patients given nifedipine 40 mg daily while taking ciclosporin for psoriasis.1 A study in 8 psoriatic patients indicated that giving nifedipine with ciclosporin resulted in reduced recovery of the principal metabolite of nifedipine, presumably because ciclosporin reduced nifedipine metabolism through competition for the cytochrome P450 metabolising enzymes. For reference to the effects of calcium-channel blockers on ciclosporin concentrations in blood27. For the possible protective effect of nifedipine against ciclosporin-induced nephrotoxicity, see Transplantation under Uses and Administration, below. For the effect of nifedipine on tacrolimus.
1. McFadden JP, et al. Cyclosporin decreases nifedipine metabolism. BMJ 1989; 299: 1224.

Magnesium salts.

Profound hypotension has been reported in 2 women in whom a single oral dose of nifedipine 10 mg was added to treatment with magnesium sulfate infusion for pre-eclampsia; both women were also receiving methyldopa.1 Neuromuscular blockade has been reported in 2 women after use of nifedipine with intravenous magnesium sulfate. In one woman receiving nifedipine as a tocolytic, symptoms of neuromuscular blockade occurred immediately on injection of magnesium sulfate and resolved within 25 minutes of stopping the injection.2 In another woman who was receiving a magnesium sulfate infusion for pre-eclampsia, symptoms developed 30 minutes after the second of 2 doses of nifedipine had been given and improved after receiving calcium gluconate injection.3
1. Waisman GD, et al. Magnesium plus nifedipine: potentiation of hypotensive effect in pre-eclampsia? Am J Obstet Gynecol 1988; 159: 308–9
2. Snyder SW, Cardwell MS. Neuromuscular blockade with magnesium sulfate and nifedipine. Am J Obstet Gynecol 1989; 161: 35–6
3. Ben-Ami M, et al. The combination of magnesium sulphate and nifedipine: a cause of neuromuscular blockade. Br J Obstet Gynaecol 1994; 101: 262–3.

Melatonin.

Melatonin may cause a reduction in blood pressure and might be expected to have additive effects if given with antihypertensives. However, in a study1 in hypertensive patients taking nifedipine, giving melatonin led to an increase in both blood pressure and heart rate.
1. Lusardi P, et al. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol 2000; 49: 423–7.Published May 08, 2019.