Nifedipine

In multiple-dose United States and foreign controlled studies in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of PROCARDIA.

There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with betaadrenergic blocking agents. The most common adverse events were:

Incidence Approximately 10%

Cardiovascular: peripheral edema

Central Nervous System: dizziness or lightheadedness

Gastrointestinal: nausea

Systemic: headache and flushing, weakness

Incidence Approximately 5%

Cardiovascular: transient hypotension

Incidence 2% or Less

Cardiovascular: palpitation

Respiratory: nasal and chest congestion, shortness of breath

Gastrointestinal: diarrhea, constipation, cramps, flatulence

Musculoskeletal: inflammation, joint stiffness, muscle cramps

Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance

Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties

Incidence Approximately 0.5%

Cardiovascular: syncope (mostly with initial dosing and/or an increase in dose), erythromelalgia

Incidence Less Than 0.5%

Hematologic: thrombocytopenia, anemia, leukopenia, purpura

Gastrointestinal: allergic hepatitis

Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia

CNS: depression, paranoid syndrome

Special Senses: transient blindness at the peak of plasma level, tinnitus

Urogenital: nocturia, polyuria

Other: arthritis with ANA (+), exfoliative dermatitis, gynecomastia

Musculoskeletal: myalgia

Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day or more. Transient hypotension, generally of mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more.

Very rarely, introduction of PROCARDIA therapy was associated with an increase in anginal pain, possibly due to associated hypotension. Transient unilateral loss of vision has also occurred.

In addition, more serious adverse events were observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients.

In a subgroup of over 1000 patients receiving PROCARDIA with concomitant beta blocker therapy, the pattern and incidence of adverse experiences were not different from that of the entire group of PROCARDIA (nifedipine) treated patients. (See PRECAUTIONS.)

In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina pectoris (about 10% of the total patient population), dizziness or lightheadedness, peripheral edema, headache, or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150.

In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported.

Nifedipine is a prescription medication used to treat chest pain. This medication belongs to a group of drugs called calcium channel blockers, which relax blood vessels, making it easier for the heart to pump blood.

Nifedipine comes in an immediate release capsule form and is taken 3 or 4 times a day, with or without food. This medication also comes in an extended release tablet form. It is taken once a day, with or without food.

Common side effects of nifedipine include swelling, headache, flushing, and nausea. Nifedipine can also cause dizziness. Do not drive or operate heavy machinery until you know how this medication will affect you.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• beta blockers such as metoprolol (Lopressor, Toprol XL), atenolol (Tenormin), propranolol (Inderal, Inderal LA), and carvedilol (Coreg)
• digoxin (Lanoxin)
• quinidine (Cardioquine, Quinact, Duraquin)
• warfarin (Coumadin, Jantoven)
• cimetidine (Tagamet)
• medications that increase the activity of the enzyme CYP3A4 such as carbamazepine (Tegretol, Equetro, Carbatrol), phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), St John's wort, and nimodipine (Nimotop)

This is not a complete list of nifedipine drug interactions. Ask your doctor or pharmacist for more information.

If you take too much nifedipine, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

In the U.S.

• Adalat CC
• Afeditab CR
• Nifediac CC
• Nifedical XL
• Procardia
• Procardia XL

Available Dosage Forms:

• Capsule, Liquid Filled
• Tablet, Extended Release
• Tablet
• Capsule

Therapeutic Class: Cardiovascular Agent

Pharmacologic Class: Calcium Channel Blocker

Chemical Class: Dihydropyridine

• Adalat CC
• Afeditab CR
• Nifediac CC [DSC]
• Nifedical XL [DSC]
• Procardia
• Procardia XL

Inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina; also reduces peripheral vascular resistance, producing a reduction in arterial blood pressure.

Metabolism

Hepatic via CYP3A4 to inactive metabolites

Excretion

Urine (60% to 80% as inactive metabolites); feces

Mean Cmax is 36% higher and plasma concentration is 70% greater in elderly patients.

Avoid grapefruit juice with all products.

Immediate release: Capsule is rapidly absorbed orally if it is administered without food, but may result in vasodilator side effects; if flushing is problematic, administration with low-fat meals may decrease. In general, can take with or without food.

Extended release: Adalat CC, Afeditab CR, Nifediac CC: Take on an empty stomach (manufacturer's labeling). Other extended release products may not have this recommendation; consult product labeling.

Alcohol (Ethyl): May increase the serum concentration of NIFEdipine. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Alpha1-Blockers: May enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs. Management: Concurrent use of felodipine or nisoldipine with itraconazole is specifically contraindicated. Frequent monitoring is warranted with any such combination; calcium channel blocker dose reductions may be required. Exceptions: Fluconazole; Isavuconazonium Sulfate. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Atosiban: Calcium Channel Blockers may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Barbiturates: May increase the metabolism of Calcium Channel Blockers. Management: Monitor for decreased therapeutic effects of calcium channel blockers with concomitant barbiturate therapy. Calcium channel blocker dose adjustments may be necessary. Nimodipine Canadian labeling contraindicates concomitant use with phenobarbital. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta-Blockers: NIFEdipine may enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): Calcium Channel Blockers (Dihydropyridine) may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine). Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Calcium Salts: May diminish the therapeutic effect of Calcium Channel Blockers. Monitor therapy

Cimetidine: May increase the serum concentration of Calcium Channel Blockers. Management: Consider alternatives to cimetidine. If no suitable alternative exists, monitor for increased effects of calcium channel blockers following cimetidine initiation/dose increase, and decreased effects following cimetidine discontinuation/dose decrease. Consider therapy modification

Cisapride: May increase the serum concentration of NIFEdipine. Reported with sustained release nifedipine product. Monitor therapy

Clopidogrel: Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CycloSPORINE (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of NIFEdipine. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of Calcium Channel Blockers. Monitor therapy

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Digoxin: NIFEdipine may increase the serum concentration of Digoxin. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Efavirenz: May decrease the serum concentration of Calcium Channel Blockers. Monitor therapy

Fluconazole: May increase the serum concentration of Calcium Channel Blockers. Monitor therapy

FLUoxetine: May enhance the adverse/toxic effect of NIFEdipine. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of NIFEdipine. Avoid combination

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Felodipine Canadian labeling specifically recommends avoiding its use in combination with clarithromycin. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Salts: Calcium Channel Blockers may enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers. Monitor therapy

Melatonin: May diminish the antihypertensive effect of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nafcillin: May decrease the serum concentration of NIFEdipine. Consider therapy modification

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phenytoin: NIFEdipine may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of NIFEdipine. Avoid combination

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

QuiNIDine: Calcium Channel Blockers (Dihydropyridine) may decrease the serum concentration of QuiNIDine. Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of QuiNIDine. QuiNIDine may increase the serum concentration of Calcium Channel Blockers (Dihydropyridine). Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of NIFEdipine. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): Calcium Channel Blockers (Dihydropyridine) may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

VinCRIStine: NIFEdipine may increase the serum concentration of VinCRIStine. Monitor therapy

VinCRIStine (Liposomal): NIFEdipine may increase the serum concentration of VinCRIStine (Liposomal). Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

May lead to false-negative aldosterone/renin ratio (ARR) (Funder 2016)

Take nifedipine exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may need to take an extended-release tablet on an empty stomach. Follow the directions on your medicine label about taking this medication with or without food.

Do not crush, chew, or break a nifedipine extended-release tablet. Swallow it whole.

Your blood pressure will need to be checked often and you may need other blood tests at your doctor's office.

Some tablet forms of nifedipine are made with a shell that is not absorbed or melted in the body. Part of the tablet shell may appear in your stool. This is a normal side effect of nifedipine and will not make the medication less effective.

If you need surgery, tell the surgeon ahead of time that you are using nifedipine. You may need to stop using the medicine at least 36 hours before surgery.

You may have very low blood pressure while taking this medication. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.

If you are also taking a beta-blocker (atenolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, propranolol, sotalol, and others) you should not stop using the beta-blocker suddenly or you could have serious heart problems that will not be prevented by nifedipine. Follow your doctor's instructions about tapering your beta-blocker dose.

You should not stop using nifedipine suddenly. Stopping suddenly may make your condition worse.

If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture, heat, and light.

Immediate-release capsules: Data not available

Extended-release tablets:
-Mild liver dysfunction: Data not available
-Moderate to severe liver dysfunction: Use with caution; frequent monitoring recommended. Providers should consider starting patients on the lowest available dose.

Administration advice:
-Immediate-release capsules should be swallowed whole, and may be taken with or without food.
-Modified-release formulations should be taken after meals.
-Extended-release formulations should be swallowed whole and should be taken on an empty stomach.
-Extended release formulations should not be divided, crushed, or chewed.
-Grapefruit juice should be avoided.

Storage requirements:
-Immediate-release capsules: Protect from light and moisture; avoid freezing.
-Extended-release tablets: Protect from light and moisture.

General:
-Patients may take sublingual nitroglycerin concomitantly for acute angina.
-Prolonged/modified/extended release formulations may not be bioequivalent to immediate-release formulations.

Monitoring:
-Cardiovascular: Blood pressure, heart rate, and signs/symptoms of angina, especially during initiation and titration

Patient advice:
-Inform patients that this drug may cause drowsiness, dizziness, lethargy, blindness, headache, or nausea, and they should avoid driving or operating machinery until the full effects of the drug are seen.
-Instruct patients to immediately report any signs/symptoms of Stevens-Johnson syndrome, hepatitis/jaundice, or hypersensitivity reactions.
-Patients receiving extended-release tablet formulations should be advised to not be concerned if they find a tablet in their stool.
-Patients should be advised to speak to a healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding.
-Patients should be advised to report all concurrent prescription and nonprescription medications or herbal products they are taking.

• Nifedipine inhibits the influx of calcium ions across cardiac (heart) and smooth muscle causing relaxation of these muscles and dilation (widening). The exact way nifedipine works in angina is not known; however, experts believe it helps prevent spasm of the coronary artery and reduces how hard the heart has to work to pump blood around the body, lowering its oxygen requirements. Nifedipine does not change levels of calcium in the blood.
• Nifedipine belongs to a class of medicines called calcium channel blockers (sometimes called calcium channel antagonists).

Nifedipine is quickly absorbed when taken orally and peak blood levels occur in approximately 30 minutes. It is relatively short-acting and needs to be taken three times a day.

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