Nifedipine

C08C - Selective calcium channel blockers with mainly vascular effects ATC C08CA05 Small molecule approved 1981 Oral Natural product

JFDA label: Myogard Retard 20 Tablets

Mechanism of Action

Blocker of Voltage-gated L-type calcium channel — Voltage-gated L-type calcium channel blocker

Target	Action	Gene / class
Voltage-gated L-type calcium channel efficacy	BLOCKER

Indications

Approved

Chronic kidney disease (CKD) and hypertension
Diabetes and hypertension
Hypertension

Off-label

Achalasia
High altitude pulmonary edema (prevention and treatment)
Hypertensive emergency in pregnancy
Preterm labor
Pulmonary hypertension
Raynaud phenomenon
Ureteral calculi (distal)

Contraindications

Source: Lexicomp · Curated

Additional contraindications (not in US labeling): Severe hypotension Absolute
Cardiogenic shock Absolute
Hypersensitivity to nifedipine or any component of the formulation Note: Considered contraindicated in patients with ST-elevation myocardial infarction (STEMI) (ACCF/AHA [O'Gara 2013]) Absolute
Kock pouch (ileostomy after proctocolectomy) Absolute
SOGC [Magee 2014]). Extended release only: Hypersensitivity to other dihydropyridine calcium antagonists Absolute
Yancy 2013) Absolute
avoid use (Elkayam 1990 Absolute
breast-feeding Absolute
cardiovascular shock Absolute
moderate or severe hepatic impairment Absolute
pregnancy or women of childbearing potential. Note: SOGC and ACOG guidelines recommend nifedipine as a preferred agent for maternal hypertension (ACOG 2013 Absolute
severe gastrointestinal obstructive disorders, concomitant use with rifampicin Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (6)

Very Common Flushing · peripheral edema

Common cardiac failure · Palpitations · Reflex tachycardia · transient hypotension

Vascular disorders (1)

Very Common Flushing

Nervous system disorders (12)

Very Common Dizziness · Headache · headache

Common chills · disturbed sleep · Dizziness · equilibrium disturbance · fatigue · jitteriness · Mood changes · nervousness · shakiness

Renal and urinary disorders (1)

Common Sexual difficulty

Gastrointestinal disorders (9)

Very Common Heartburn · nausea

Common abdominal cramps · Constipation · constipation · diarrhea · flatulence · Gingival hyperplasia · sore throat

Skin and subcutaneous tissue disorders (4)

Common Dermatitis · diaphoresis · pruritus · urticaria

Musculoskeletal and connective tissue disorders (3)

Common Muscle cramps · tremor · weakness

General disorders and administration site conditions (3)

Very Common Peripheral oedema

Common Fever · inflammation

Respiratory, thoracic and mediastinal disorders (5)

Common chest congestion · Cough · dyspnea · nasal congestion · wheezing

Dosing

Source: Lexicomp

Dosage adjustments should occur at 7- to 14-day intervals to allow for adequate assessment of new dose; however, if clinically indicated, titration may be done more rapidly with appropriate monitoring; when switching from immediate-release to sustained-release formulations, use same total daily dose. Chronic stable or vasospastic angina: Oral: Immediate release: Initial: 10 mg 3 times daily; usual dose: 10 to 20 mg 3 times daily; coronary artery spasm may require up to 20 to 30 mg 3 to 4 times daily; single doses >30 mg and total daily doses >120 mg are rarely needed; maximum: 180 mg daily; Note: Do not use for acute anginal episodes; may precipitate myocardial infarction Extended release: Initial: 30 or 60 mg once daily; titrate as clinically indicated. Doses >90 mg daily should be used with caution and only if necessary (maximum: 120 mg daily) Hypertension: Oral: Extended release: Initial: 30 or 60 mg once daily; usual dosage range (ASH/ISH [Weber 2014]): 30 to 90 mg daily; maximum: 90 to 120 mg daily Achalasia (off-label use): Sublingual: 10 to 30 mg administered 30 to 45 minutes before meals. Note: Clinical response is short acting and use does not provide complete relief of symptoms; consider risks before use (ACG [Vaezi 2013]). Hypertension emergency in pregnancy (systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg) (off-label dose): Oral: Immediate release: 10 mg; may repeat with a 20 mg dose in 20 minutes if needed. Also refer to administration protocols developed by the American College of Obstetricians and Gynecologists (ACOG 692 2017). High altitude pulmonary edema (off-label use): Oral: Prevention: ER: 30 mg every 12 hours starting the day before ascent and may be discontinued after staying at the same elevation for 5 days or if descent initiated (WMS [Luks 2014]). Treatment: ER: 30 mg every 12 hours (WMS [Luks 2014]). Pulmonary hypertension (off-label use): Oral: Note: Guidelines recommend the sustained-release formulation, which is not available in the US; dosing is provided empirically for the ER formulation. ER: Initial: 60 mg once daily (initiate after demonstrating acute vasoreactivity); may increase cautiously to 120 to 240 mg/day (ESC [Galie 2016]; Taichman 2014). Raynaud's phenomenon (off-label use): Oral: Extended release: Dosage range: 30 to 120 mg once daily (Thompson 2005; Wigley 2002) Immediate release: 10 to 30 mg 3 times daily (Thompson 2005; Wigley 2002) Ureteral calculi (distal) (off-label use): Oral: 10 to 30 mg 3 times daily for up to 4 weeks or until expulsion of lower stones (Ye 2011; Zhang 2009)

(For additional information see "Nifedipine: Pediatric drug information") High altitude pulmonary edema (off-label use; Pollard, 2001): Oral: Note: Treatment with NIFEdipine is only necessary if response to oxygen and/or descent is unsatisfactory; extended release preparation is preferred, but with proper dose and frequency adjustment: Immediate release: 0.5 mg/kg/dose (maximum: 20 mg/dose) every 8 hours Hypertension (off-label use): Oral: Children 1 to 17 years: Extended release tablet: Initial: 0.2 to 0.5 mg/kg/day once daily or in 2 divided doses; maximum: 3 mg/kg/day up to 120 mg daily

Refer to adult dosing. In the management of hypertension, consider lower initial doses and titrate to response (Aronow 2011).

There are no dosage adjustments provided in manufacturer's labeling (has not been studied); the pharmacokinetics of nifedipine are not significantly influenced by the degree of renal impairment (only trace amounts of unchanged drug are found in urine). Hemodialysis: Supplemental dose is not necessary. Peritoneal dialysis effects: Supplemental dose is not necessary.

There are no dosage adjustments provided in manufacturer's labeling (has not been studied); use with caution. Clearance of nifedipine is reduced in cirrhotic patients, which may lead to increased systemic exposure; monitor closely for adverse effects/toxicity and consider dose adjustments.

Warnings & Precautions

Source: Lexicomp

Angina/MI

Increased angina and/or MI have occurred with initiation or dosage titration of dihydropyridine calcium channel blockers. Reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease, especially in the absence of concurrent beta-blockade. In patients with unstable angina/non-STEMI, the use of immediate-release nifedipine is not recommended except with concomitant beta-blockade (ACCF/AHA [Anderson 2013]).

Hypotension/syncope

Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. The use of immediate release nifedipine (sublingually or orally) in hypertensive emergencies and urgencies is neither safe nor effective. Serious adverse events (eg, death, cerebrovascular ischemia, syncope, stroke, acute myocardial infarction, and fetal distress) have been reported. Immediate release nifedipine should not be used for acute blood pressure reduction. Guidelines are available when immediate release nifedipine is required for acute treatment in pregnant or postpartum women (ACOG 692 2017; Magee 2014).

Peripheral edema

The most common side effect is peripheral edema; occurs within 2 to 3 weeks of starting therapy. Disease-related concerns:

Aortic stenosis

Use with extreme caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in myocardial ischemia.

GI strictures

Alterations in GI anatomy (eg, severe GI narrowing, history of GI cancer, obstruction, bowel resection, gastric bypass, vertical banded gastroplasty) and underlying hypomotility disorders have led to bezoar formation with extended release forms.

Heart failure

The ACCF/AHA heart failure guidelines recommend to avoid use in patients with HF due to lack of benefit and/or worse outcomes with calcium channel blockers in general (Yancy 2013).

Hepatic impairment

Use with caution in patients with hepatic impairment. Clearance of nifedipine is reduced in cirrhotic patients leading to increased systemic exposure; monitor closely for adverse effects/toxicity and consider dose adjustments.

Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction

Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Extended release formulation

Consists of drug within a nondeformable matrix; following drug release/absorption, the matrix/shell is expelled in the stool. The use of nondeformable products in patients with known stricture/narrowing of the GI tract (eg, severe gastrointestinal narrowing, colon cancer, obstruction, bowel resection, gastric bypass, vertical banded gastroplasty) has been associated with symptoms of obstruction (pharmacobezoar).

Immediate release formulation

Immediate release formulations should not be used to manage primary hypertension, adequate studies to evaluate outcomes have not been conducted.

Lactose

Adalat CC tablets contain lactose; do not use with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndromes. Other warnings/precautions:

Surgery

Use with caution before major surgery. Cardiopulmonary bypass, intraoperative blood loss or vasodilating anesthesia may result in severe hypotension and/or increased fluid requirements. Consider withdrawing nifedipine (>36 hours) before surgery if possible.

Withdrawal

Abrupt withdrawal may cause rebound angina in patients with CAD.

Pregnancy & Lactation

Pregnancy

FDA category C

Safe

Second-line after labetalol/methyldopa for chronic hypertension; first-line tocolytic (preterm labour). Avoid with magnesium sulphate (potentiates neuromuscular blockade)

Lactation

RID 0.27%

Nifedipine is present in breast milk. The relative infant dose (RID) of nifedipine is 0.27% to 3.2% when calculated using the highest breast milk concentration located and compared to an infant therapeutic dose of 0.25 to 3 mg/kg/day. In general, breastfeeding is considered acceptable when the RID is Milk concentrations reached a peak within 1 hour of maternal administration of immediate release capsules (Ehrenkrantz 1989; Penny 1989). The half-life of nifedipine in breast milk has been report

Monitoring

Clinical pearl	Heart rate, blood pressure, signs and symptoms of CHF, peripheral edema

Chemistry & Properties

Formula	C17H18N2O6
Molecular weight	346.34 g/mol
IUPAC name	dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
CAS	21829-25-4
PubChem CID	4485
InChIKey	`HYIMSNHJOBLJNT-UHFFFAOYSA-N`
logP	2.18 (XLogP 2.2)
Polar surface area	107.77 Å²
H-bond acceptors / donors	7 / 1
Drug-likeness (QED)	0.51
Lipinski violations	0

SMILES

COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.687 h
Volume of distribution	1.496 L/kg
Protein binding	97.8%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	IC₅₀ 0.8306623862918078 µM
CYP1A2	Substrate	—
CYP2C19	Inhibitor	IC₅₀ 5.420000000000002 µM
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	IC₅₀ 4.080000000000001 µM
CYP2D6	Substrate	—
CYP3A4	Inhibitor	IC₅₀ 13.055161485691356 µM
CYP3A4	Substrate	—

Receptor binding (top 5)

Target	Action	Affinity
Cav1.3 (CACNA1D)	Gating inhibitor	pIC50 7.7
5-HT2A (HTR2A)	Binding	pKi 6.5
Cav1.4 (CACNA1F)	Gating inhibitor	pIC50 6.0
glycine receptor β subunit (GLRB)	Antagonist	pIC50 5.9
glycine receptor α1 subunit (GLRA1)	Antagonist	pIC50 5.5

Transporters

ASBT (Inhibitor)BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)ENT1 (Inhibitor)ENT2 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)NTCP (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCTN1 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Apalutamide	major
Ceritinib	major
Cisapride	major
Dolasetron	major
Enzalutamide	major
Lumacaftor	major
Mitotane	major
Siponimod	major
Venetoclax	major
Acalabrutinib	moderate
Acetylsalicylic acid	moderate
Adalimumab	moderate
Aldesleukin	moderate
Alefacept	moderate
Alimemazine	moderate
Amifostine	moderate
Anagrelide	moderate
Anakinra	moderate
Apixaban	moderate
Aprepitant	moderate
Axitinib	moderate
Betamethasone	moderate
Betrixaban	moderate
Bexarotene	moderate
Binimetinib	moderate
Bosutinib	moderate
Brigatinib	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Budesonide	moderate
Budesonide (nasal)	moderate
Bupropion	moderate
Cabazitaxel	moderate
Calcium Phosphate	moderate
Calcium acetate	moderate
Calcium carbonate	moderate
Calcium chloride	moderate
Calcium citrate	moderate
Calcium glubionate anhydrous	moderate
Calcium glucoheptonate	moderate

Showing 40 of 100+.

Registered Products (6)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Epilat Retard 20 mg. Tab	Tablet 20 mg	20 tab pack varies	Reda Jardaneh Drug Store	2.000
Myogard Retard 20 Tablets	Tablet 20 mg	30 tab pack varies	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	4.440
Adalat LA	Tablet 30 mg	30 tab	Khoury Drug Store	5.920
Adalat LA	Tablet 60 mg	30 tab	Khoury Drug Store	12.930
Epilat Retard 20 mg. Tab	Tablet 20 mg	1000 tab pack varies	Reda Jardaneh Drug Store	60.610
Myogard Retard 20 Tablets	Tablet 20 mg	1000 tab pack varies	UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN	125.800