Although calcium-channel blockers are effective drugs for treating angina, nifedipine has rarely been associated with increased angina (<= 1%). This reaction may be a result of excessive lowering of blood pressure, coronary steal, or reflex tachycardia. Peripheral edema (4%—30%) has been attributed to nifedipine therapy and appears to be dose-related and related to the mechanism of action, which involves peripheral vasodilation. Peripheral edema occurred in about one in 25 patients (4%) at doses less than 60 mg/day, in about one in eight patients (12.5%) at >= 120 mg/day, and about 30% of patients at doses of 180 mg/day. This reaction reflects the potent vasodilatory effect of this drug because it occurs more frequently with nifedipine than with other calcium-channel blockers. This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. Although not readily distinguishable from the natural history of disease, congestive heart failure (2%) was reported in large uncontrolled experience in patients with vasospastic or resistant angina pectoris (about half had concomitant treatment with beta-blockers). In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, symptoms of congestive heart failure occurred in about 6.7% of patients. With patients whose angina is complicated by congestive heart failure, care should be taken to differentiate peripheral edema from the effects of increasing left ventricular dysfunction. In most patients the hypotensive effect of nifedipine is modest and well tolerated; however, some patients have had excessive and poorly tolerated hypotension (<1%—5%). These responses have usually occurred during initial titration or at the time of dose increase, and may be more likely in patients using concomitant beta-blockers. Other cardiovascular-related adverse events reported during nifedipine therapy include: flushing or heat sensation (< 3%—25%), palpitations (<1%—7%), syncope (0.5%—1%) (mostly with initial dosing and/or an increase in dose), erythromelalgia (0.5%), chest pain (unspecified) (<= 3%), substernal chest pain (< 1%), cardiac arrest (< 1%), phlebitis (< 1%), orthostatic hypotension (< 1%), cutaneous angiectases (< 1%), arrhythmia exacerbation (<= 1%), atrial fibrillation (< 1%), bradycardia (< 1%), sinus tachycardia (<= 1%), atrial or ventricular dysrhythmias (0.7%), extrasystole (i.e., premature ventricular contractions (PVCs))(< 1%), ventricular arrhythmias (< 0.5%), and conduction disturbances (0.5%).[29068] [42064] [31749]

Although not readily distinguishable from the natural history of hypertensive disease, myocardial infarction (4%) was reported in large uncontrolled experience in patients with vasospastic or resistant angina pectoris (about half had concomitant treatment with beta-blockers). In a subgroup of approximately 250 patients with a diagnosis of CHF as well as angina, myocardial infarction occurred in about 6.7% of patients. Patients with angina should be observed for worsening symptoms when nifedipine therapy is begun, particularly if beta-blocker therapy is being withdrawn. Serious adverse effects have been reported with the use of immediate-release nifedipine, primarily due to the unpredictable rate and degree of blood pressure lowering. Profound hypotension, myocardial infarction, and death have been reported when immediate-release nifedipine is used to lower blood pressure acutely, especially when used in elderly patients. Due to the risks associated with the immediate-release nifedipine capsules, this dosage formulation should not be used in patients with chronic hypertension, acute hypertensive crisis, acute myocardial infarction, or in the setting of acute coronary syndrome.[29068] [42064] [31749]

Common CNS-related adverse events reported during nifedipine therapy include: headache (10—23%; due to vasodilation) and dizziness or lightheadedness (4—27%) Other CNS-related adverse events reported during nifedipine therapy include weakness (10—12%), fatigue (4—5.9%), asthenia (< 1%—4%), tremor (<= 8%), paresthesias (<= 3%), vertigo (<= 3%), anxiety (<= 1%), nervousness; mood changes (<= 2%—7%), ataxia (<=1%), libido decrease (<= 1%), depression (<= 1%), hypertonia (<=1%), hypoesthesia (<=1%), migraine (<=1%), paroniria/nightmares (<= 1%), insomnia (< 3%), sleep disturbances (<= 2%), confusion (< 1%), drowsiness (< 3%), shakiness (<= 2%), jitteriness (<= 2%), difficulties in balance (<= 2%), and paranoia (<0.5%).[42064] [29068] [31749]

Respiratory-related adverse reactions reported during nifedipine therapy include: nasal congestion (<=2%—6%), chest congestion (<= 2%), dyspnea (<= 2%—6%), cough (< 1%—6%), wheezing (6%), throat irritation (6%), epistaxis (<= 1%—3%), rhinitis (<= 3%), rales (< 1%), pharyngitis (< 1%), stridor (< 1%), upper respiratory tract infection (<= 1%), respiratory disorder (<= 1%), and sinusitis (<= 1%).[31749] [29068] [42064]

Dermatologic and allergic adverse reactions reported during administration of nifedipine include: rash (unspecified) (<= 3%), pruritus (< 3%), dermatitis (<= 2%), urticaria (<= 2%), hyperhidrosis (<= 2%), photosensitivity reaction (< 1%), petechiae (< 1%), alopecia (<=1%), and purpura (<=1%). In post-marketing experience, there have been rare reports of exfoliative dermatitis (< 0.5%) caused by nifedipine. There have also been rare reports of exfoliative or bullous skin adverse events (such as erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis). Angioedema (< 1%), allergic reaction (< 1%), cellulitis (< 1%), facial edema (<= 1%), and anaphylactoid reactions have been reported during nifedipine therapy.[29068] [31749] [42064] Nifedipine has also been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with elevated body temperature above 38 degrees C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2—3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, itching, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.[27736]

Gynecomastia has been reported in < 1% of patients receiving nifedipine. Breast enlargement or engorgement (< 1%) and breast pain or mastalgia (<= 1%) have also been reported.[29068] [42064] [31749]

Gingival hyperplasia (<=1%) gum disorder (< 1%), and gum hemorrhage (< 1%) have been reported with nifedipine.[29068] [42064] [31749]

Gastrointestinal-related adverse reactions reported during the use of all dosage forms of nifedipine include: nausea (2—11%), pyrosis (heartburn) (11%), diarrhea (< 3%), constipation (<= 3.3%), cramps (<= 2%), xerostomia (< 3%), dysphagia(< 1%), dyspepsia (< 3%), eructation (<= 1%), esophagitis (< 1%), flatulence (< 3%), gastrointestinal disorder (< 1%), GI bleeding (< 1%), vomiting (<= 1%), weight loss (< 1%), dysgeusia (<= 1%), abdominal pain (< 3%), gastrointestinal irritation (< 1%), gastroesophageal reflux (<= 1%), melena (<= 1%), and weight gain (<= 1%).[29068] [42064] [31749] GI obstruction (even in patients with no prior history of gastrointestinal disease, see Contraindications), tablet adherence to the gastrointestinal wall resulting in peptic ulcer, and, rarely, bezoar have been reported in association with extended-release nifedipine formulations. In some cases, hospitalization and surgical intervention have been required.[42064]

Urogenital-related adverse reactions reported during nifedipine therapy include: sexual difficulties (<= 2%), impotence (erectile dysfunction) (< 1%—3%), nocturia (< 0.5%—1%), polyuria (< 3%), increased urinary frequency (<= 3%), pelvic pain (< 1%), dysuria (<= 1%), nephrolithiasis (< 1%), urogenital disorder (< 1%), gout (<= 1%), and hematuria (<= 1%).[29068] [31749] [42064]

Musculoskeletal-related adverse reactions reported during nifedipine therapy include: muscle cramps (<= 2%—8%), inflammation (<= 2%), joint stiffness (<= 2%), arthritis with positive ANA (< 1%), myalgia (< 0.5—1%), pain (< 3%), leg pain (<= 3%), neck pain (< 1%), back pain (<= 1%), leg cramps (<= 3%), arthralgia (< 3%), joint disorder (< 1%), and myasthenia (< 1%).[29068] [42064] [31749]

Clinically significant, but usually transient, elevated hepatic enzymes have been reported rarely during nifedipine therapy. A causal relationship to nifedipine has not been established. These laboratory abnormalities have rarely been associated with clinical symptoms; cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have also been reported.[29068] [42064] [31749]

Blurred vision (<= 2%), visual impairment (i.e., abnormal vision (<= 1%) or transient blindness at the peak of plasma level (< 0.5%)), amblyopia (< 1%), conjunctivitis (< 1%), diplopia (< 1%), eye disorder (< 1%), ocular hemorrhage (< 1%), periorbital edema (<= 1%), and abnormal lacrimation (<= 1%) have been reported during nifedipine therapy.[29068] [42064] [31749]

Tinnitus (<= 1%) has been reported during nifedipine therapy.[29068] [42064] [31749]

Hematologic changes have been reported with nifedipine therapy. Eosinophilia and lymphadenopathy have been reported in < 1% of nifedipine-treated patients. Thrombocytopenia, anemia, and leukopenia have been reported in < 0.5% of nifedipine-treated patients. Positive direct Coombs Test with/without hemolytic anemia has been reported but a causal relationship between nifedipine administration and positivity of this laboratory test, including hemolysis, could not be determined.[29068] [42064] [31749]

General effects, such as fever (<= 2%), chills (<= 2%), malaise (<= 1%), and rigors (<= 1%) have been reported during nifedipine therapy.[29068] [42064] [31749]

Nifedipine may produce hyperglycemia and may lead to loss of glucose control.[31749]

Hot flashes have been reported in <= 1% of nifedipine-treated patients, and may be related to vasodilation.[42064]

Nifedipine is a dihydropyridine calcium-channel blocker and is contraindicated in patients with known serious dihydropyridine hypersensitivity.

Nifedipine should be used cautiously in patients with severe bradycardia. It also should be used cautiously in patients with congestive heart failure (or left ventricular dysfunction) because nifedipine can precipitate or exacerbate heart failure due to its negative inotropic effects, particularly in patients receiving concomitant beta-blocker therapy. The development or worsening of pulmonary edema is a marker for discontinuation of nifedipine. The manufacturer of Adalat CC (extended-release nifedipine) states that use in patients in cardiogenic shock is contraindicated. Immediate-release nifedipine should be avoided in certain coronary artery disease states which include cardiogenic shock or acute myocardial infarction (or other acute coronary syndromes such as unstable angina) due to its negative inotropic effects and the reflex sympathetic activation, tachycardia, and hypotension associated with its use. Although immediate-release nifedipine (including sublingual or 'bite and swallow' administration) was frequently used for the treatment of hypertensive urgencies prior to 1995,[24121] serious adverse effects have been reported with its use, primarily due to the unpredictable rate and degree of blood pressure lowering. Profound hypotension, myocardial infarction, and death have been reported when immediate-release nifedipine was used to lower blood pressure acutely. Therefore, according to recommendations of the Joint National Committee on Prevention, Detection Evaluation, and Treatment of High Blood Pressure (JNC-VI), nifedipine liquid-filled capsules are contraindicated in the setting of hypertensive urgency, hypertensive crisis, or hypertensive emergency. The routine, sporadic use of nifedipine liquid-filled capsules whenever blood pressure rises above a predetermined level is not considered appropriate.[24732] The immediate-release nifedipine dosage form is currently only indicated for the treatment of chronic stable angina or vasospastic angina.

Nifedipine should be avoided in patients with advanced aortic stenosis because the drug can worsen the abnormal pressure gradient associated with this condition.

Because calcium channel blockers relax the lower esophageal sphincter, nifedipine should be used cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis.[41457] Nifedipine extended-release formulations have been associated with rare reports of obstructive symptoms in patients with known strictures as well as in patients with no known gastrointestinal disease. In some cases hospitalization and surgical intervention have been necessary. Use caution in patients at increased risk of GI obstruction including those with an alteration in gastrointestinal anatomy such as severe gastrointestinal narrowing (e.g., esophageal stricture), gastric cancer, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, colostomy, diverticulitis, diverticulosis, and inflammatory bowel disease), hypomotility disorders (constipation, gastroesophageal reflux disease (GERD), ileus, obesity, hypothyroidism, and diabetes mellitus) and aggravating concomitant medications (H2-histamine blockers, opiate agonists, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, levothyroxine, and neuromuscular blocking agents).[42064]

Nifedipine should generally only be used during pregnancy if the potential benefit justifies the potential risk.Available data have not shown nifedipine to pose a risk for major teratogenecity in humans and experts consider nifedipine an option for treating hypertension during pregnancy.[65551] For the long-term treatment of pregnant women who require drug therapy, nifedipine (extended-release) is considered a reasonable option by the American College of Obstetricians and Gynecologists (ACOG), and along with labetalol, is recommended above all other antihypertensive drugs. Nifedipine (immediate-release) may also be considered an option for urgent blood pressure control, as long as sublingual use is avoided.[63903] Per the manufacturers, nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin. Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Nifedipine use was associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a mg/kg basis, all the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (5 to 50 times) than the maximum recommended human dose (MRHD) of 120 mg/day. On a mg/m² basis, some doses were higher and some were lower than the MRHD, but all are within an order of magnitude of it. The doses associated with placentotoxic effects in monkeys were equivalent to or lower than the MRHD on a mg/m² basis.[29068] [42064]

Nifedipine is compatible with breast-feeding. Nifedipine is present in breast milk in small amounts with a relative infant dose of 2.3% to 3.4%. Due to limited infant ingestion, it is not expected to cause infant adverse effects, and no infant adverse effects due to nifedipine exposure in breast milk have been reported.[70364] [70365] The American College of Obstetricians and Gynecologists (ACOG) states nifedipine may be continued during breast-feeding in lactating individuals.[63903] After study of a single infant-mother pair, one article concluded that the amount of nifedipine transferred into human milk is an insignificant fraction of the maternal dose; over 24 hours, it appears to amount to less than 5% of a pediatric therapeutic dose. Nifedipine administration did not appear to alter milk composition. The authors concluded that breast-feeding during nifedipine therapy appears to pose little risk to an infant, even a very low birth weight infant.[48512] Nifedipine has been used to treat Raynaud's phenomenon of the nipple to decrease the pain associated with breast-feeding.[66515] [66516]

Nifedipine plasma concentrations are significantly increased in patients with hepatic disease such as cirrhosis. These patients may be at greater risk for drug accumulation and toxicity. It is unknown how systemic exposure may be altered in patients with moderate or severe hepatic impairment. Careful monitoring and dose reduction may be necessary; consider initiating therapy with the lowest dose available (see Dosage).

The manufacturer also notes a report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. There are published reports of reversible infertility in men taking nifedipine for hypertension.[66517] [66518]

The use of nifedipine immediate-release dosage forms in geriatric adults (71 years of age and older) for the treatment of hypertension has been associated with a nearly 4-fold increase in risk for all-cause mortality when compared to other antihypertensives (beta-blockers, ACE inhibitors, or non-dihydropyridine calcium channel blockers).[24546] Age also appears to have a significant effect on the pharmacokinetics of nifedipine. The clearance is decreased resulting in a higher AUC in the geriatric adult. These changes are not due to changes in renal function.[42064] According to the Beers Criteria, immediate-release nifedipine is considered a potentially inappropriate medication for geriatric adults; avoid use due to the potential for hypotension and the risk of precipitating myocardial ischemia.[63923]

According to the manufacturer of Adalat CC, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take nifedipine formulations that contain lactose.[31749]