Verapamil

C08D - Selective calcium channel blockers with direct cardiac effects ATC C08DA01 Small molecule approved 1981 Oral Parenteral Natural product

JFDA label: Aver

Mechanism of Action

Inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization; produces relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina; slows automaticity and conduction of AV node.

Indications

Approved

Acute coronary syndrome (ACS)
Angina
Atrial fibrillation (rate control)
Chronic kidney disease (CKD) and hypertension
Coronary artery disease (CAD) and hypertension
Hypertension
IV
Immediate-release tablet
Paroxysmal supraventricular tachycardia prophylaxis
Supraventricular tachycardia
Supraventricular tachycardias

Off-label

Cluster headaches
Hypertrophic cardiomyopathy

Contraindications

Source: Lexicomp · Curated

Additional contraindications: Complicated myocardial infarction (ventricular failure manifested by pulmonary congestion) Absolute
Concomitant IV beta-blocker administration Absolute
Oral: Hypersensitivity to verapamil or any component of the formulation Absolute
Severe left ventricular dysfunction or congestive heart failure Absolute
Sick sinus syndrome or second/third-degree AV block without pacemaker Absolute
atrial flutter or fibrillation and an accessory bypass tract (WPW syndrome, Lown-Ganong-Levine syndrome) Absolute
concurrent use of IV beta blocking agents Absolute
concurrent use of ivabradine. IV: Hypersensitivity to verapamil or any component of the formulation Absolute
hypotension (systolic pressure Absolute
marked bradycardia Absolute
second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker) Absolute
severe heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil) Absolute
severe hypotension or cardiogenic shock Absolute
severe left ventricular dysfunction Absolute
sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker) Absolute
ventricular tachycardia 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 (5)

Common atrioventricular block · bradycardia, dizziness, lethargy, pain, paresthesia, sleep disorder, confusion, drowsiness, alopecia, diaphoresis, erythema multiforme, hyperkeratosis, macular eruption, Stevens-Johnson syndrome, urti · cardiac failure · hypotension · Peripheral edema

Nervous system disorders (1)

Very Common Headache

Hepatobiliary disorders (1)

Common Increased liver enzymes

Renal and urinary disorders (2)

Common Impotence · Polyuria

Blood and lymphatic system disorders (2)

Common Bruise · purpuric vasculitis

Metabolism and nutrition disorders (4)

Common Galactorrhea · gynecomastia · hyperprolactinemia · spotty menstruation

Gastrointestinal disorders (8)

Very Common constipation · Gingival hyperplasia

Common abdominal distress · diarrhea · Dyspepsia · gastrointestinal distress · nausea · xerostomia

Musculoskeletal and connective tissue disorders (4)

Common arthralgia · muscle cramps · Myalgia · weakness

Eye disorders (1)

Common Blurred vision

Ear and labyrinth disorders (1)

Common Tinnitus

Respiratory, thoracic and mediastinal disorders (3)

Common dyspnea · Flu-like symptoms · pulmonary edema

Dosing

Source: Lexicomp

Angina: Oral: Note: When switching from immediate-release to extended-release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion. Immediate release: Manufacturer’s labeling: 80 to 120 mg 3 times daily; in patients with increased response to verapamil (eg, small stature): 40 mg 3 times daily; may titrate at daily (patients with unstable angina) or weekly intervals based on patient response; maximum: 480 mg/day Alternate recommendations: Usual dose range (ACC/AHA [Gibbons 2003]): 80 to 160 mg 3 times daily Atrial fibrillation (rate control): IV: Initial bolus: 0.075 to 0.15 mg/kg (usual dose: 5 to 10 mg) over at least 2 minutes; if no response, may give an additional 10 mg bolus after 15 to 30 minutes; if patient responds to the initial or repeat bolus dose, then may begin a continuous infusion (AHA/ACC/HRS [January 2014]; Phillips 1997) Continuous infusion: Initial: 5 mg/hour; titrate to goal heart rate (Barbarash, 1986; Phillips, 1997) Oral: Extended release (off-label use): Usual maintenance dose: 180 to 480 mg once daily (AHA/ACC/HRS [January 2014]) Immediate release: 240 to 480 mg daily in 3 to 4 divided doses (maximum: 480 mg/day) Cluster headaches: Oral: Immediate release: Initial: 240 mg in 3 divided doses; may increase dose by 80 mg every 1 to 2 weeks until headaches subside or adverse reactions develop; maximum dose 960 mg/day (EFNS [May 2006]; Obermann 2015). Some experts recommend ECGs at baseline and after dose increases above 480 mg/day (Koppen 2016). Additional data may be necessary to further define the role of verapamil in this condition. Hypertension: Oral: Note: When switching from immediate-release to extended-release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion. Immediate release: Initial: 80 mg 3 times daily; in patients with increased response to verapamil (eg, small stature): 40 mg 3 times daily; maximum: 480 mg/day; usual dose range (ASH/ISH [Weber 2014]): 240 to 480 mg daily Extended release: Usual dose range (ASH/ISH [Weber 2014]): 240 to 480 mg daily; Note: There is no evidence of additional benefit with doses >360 mg daily. Calan SR, Isoptin SR (Canadian product): Initial: 180 mg once daily in the morning; in patients with increased response to verapamil (eg, small stature): 120 mg once daily; if inadequate response to 180 mg once daily, may increase dose at weekly intervals to 240 mg once daily, then 180 mg twice daily (or 240 mg in the morning followed by 120 mg in the evening), up to 240 mg twice daily; maximum: 480 mg/day. Verelan: Usual dosage: 240 mg once daily in the morning; in patients with increased response to verapamil (eg, small stature): 120 mg once daily; if inadequate response to 120 mg once daily, may increase dose at weekly intervals in the following manner: 180 mg once daily; 240 mg once daily; 360 mg once daily; 480 mg once daily; maximum: 480 mg/day Verelan PM: Usua

(For additional information see "Verapamil: Pediatric drug information") SVT: Note: Verapamil is not included in the Pediatric Advanced Life Support (PALS) tachyarrhythmia algorithm. Optimal interval for subsequent doses is unknown and must be individualized for each specific patient. Children and Adolescents 1 to 15 years: IV, Intraosseous: 0.1 to 0.3 mg/kg/dose over 2 minutes; maximum: 5 mg/dose, may repeat dose in 15 to 30 minutes if inadequate response; maximum for second dose: 10 mg (Kliegman 2016; PALS [Kleinman 2010]; Park 2014) Adolescents >15 years: IV: Initial: Manufacturer labeling: 5 to 10 mg (0.075 to 0.15 mg/kg) PALS guidelines: 0.1 to 0.3 mg/kg/dose; maximum dose: 5 mg/dose (PALS [Kleinman 2010]; Park 2014) Repeat dose: May repeat dose in 15 to 30 minutes if adequate response not achieved; maximum for second dose: 10 mg/dose (Kliegman 2015; PALS [Kleinman 2010]; Park 2014)

Hypertension: Oral: Note: When switching from immediate-release to extended-release formulations, the total daily dose remains the same unless formulation strength does not allow for equal conversion. Manufacturer's labeling: Immediate release: Initial: 40 mg 3 times daily Extended release: Initial: 120 mg once daily in the morning (Calan SR, Isoptin SR [Canadian product] Verelan) or 100 mg once daily at bedtime (Verelan PM) Alternate recommendations: Consider lower initial doses and titrating to response (ACCF/AHA [Aronow 2011]) Other indications: Refer to adult dosing.

Manufacturer's labeling: Oral: Verelan PM: Initial: 100 mg once daily at bedtime. There are no dosage adjustments provided in the manufacturer’s labeling for the other products; however, use with caution and consider additional ECG monitoring. Injection: There are no dosage adjustments provided in the manufacturer’s labeling; however, repeated injections in patients with renal failure may lead to accumulation and excessive pharmacologic effects and should be avoided. If repeated injections are essential, monitor blood pressure and PR interval closely and use smaller repeat doses. Alternate recommendations: A multiple dose study in adults suggests reduced renal clearance of verapamil and its metabolite (norverapamil) with advanced renal failure (Storstein 1984). Additionally, several clinical papers report adverse effects of verapamil in patients with chronic renal failure receiving recommended doses of verapamil (Pritza 1991; Váquez 1996). In contrast, a number of single dose studies show no difference in verapamil (or norverapamil metabolite) disposition between chronic renal failure and control patients (Beyerlein 1990; Hanyok 1988; Mooy 1985; Zachariah 1991). Dialysis: Not removed by hemodialysis (Mooy 1985); supplemental dose is not necessary.

Oral: In cirrhosis, reduce dose to 20% of normal and monitor ECG (Somogyi 1981). Calan, Calan SR, Verelan: Administer 30% of the normal dose in severe hepatic impairment. Verelan PM: Initial: 100 mg once daily at bedtime. Injection: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and consider additional ECG monitoring in severe impairment. In cirrhosis, reduce dose to 50% of normal and monitor ECG (Somogyi, 1981). Repeated injections in patients with hepatic failure may lead to accumulation and excessive pharmacologic effects and should be avoided. If repeated injections are essential, monitor blood pressure and PR interval closely and use smaller repeat doses.

Warnings & Precautions

Source: Lexicomp

Conduction abnormalities

May cause first-degree AV block or sinus bradycardia. Higher degrees of AV block may also occur (rare) and in extreme cases, asystole; more likely to occur in patients with a sick sinus syndrome. If marked first degree block, progressive development to second- or third-degree AV block, or unifascicular, bifascicular, or trifascicular bundle branch block occurs, consider a dosage reduction or discontinue therapy.

Hepatic effects

Elevations of hepatic transaminases, alkaline phosphatase, and bilirubin have been reported; hepatocellular injury has been proven by rechallenge. Periodically monitor liver function. Some elevations have been transient and disappeared with continued therapy.

Hypotension/syncope

Symptomatic hypotension with or without syncope may occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Disease-related concerns:

Arrhythmia

Considered contraindicated in patients with wide complex tachycardias unless known to be supraventricular in origin; severe hypotension likely to occur upon administration (ACLS 2010).

Attenuated neuromuscular transmission

Decreased neuromuscular transmission has been reported; use with caution in patients with attenuated neuromuscular transmission (Duchenne muscular dystrophy, myasthenia gravis); dosage reduction may be required.

Heart failure

The ACCF/AHA heart failure guidelines recommend to avoid use in patients with heart failure 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; dosage reduction may be required; monitor hemodynamics and possibly ECG in severe impairment. Avoid repeated injections of IV verapamil in patients with significant hepatic failure.

Hypertrophic cardiomyopathy (HCM)

Use with caution in patients with HCM with outflow tract obstruction (especially those with high gradients, advanced heart failure, or sinus bradycardia); may be used in patients who cannot tolerate beta-blockade. Verapamil should not be used in those with systemic hypotension or severe dyspnea at rest (Gersh 2011; Nishimura 2004).

Increased intracranial pressure

IV verapamil has increased intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction; use with caution in these patients.

Renal impairment

Use with caution in patients with renal impairment; monitor hemodynamics and possibly ECG in severe impairment, particularly if concomitant hepatic impairment. Avoid repeated injections of IV verapamil in patients with significant renal failure. 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 Special populations:

Pediatric

In neonates and young infants, avoid IV use for SVT due to severe apnea, bradycardia, hypotensive reactions, and cardiac arrest; in older children, use IV with caution as myocardial depression and hypotension may occur (PALS [Kleinman 2010]).

Pregnancy & Lactation

Pregnancy

FDA category C

Adverse events have been observed in some animal reproduction studies in doses, which also caused maternal toxicity. Verapamil crosses the placenta. Use during pregnancy may cause adverse fetal effects (bradycardia, heart block, hypotension) (Tan 2001). Women with hypertrophic cardiomyopathy who are controlled with verapamil prior to pregnancy may continue therapy, but increased fetal monitoring is recommended (Gersh 2011). Verapamil may be used IV for the acute treatment of supraventricular tachycardia (SVT) in pregnant women when adenosine or beta-blockers are ineffective or contraindicated. Verapamil may also be used for the ongoing management of SVT in highly symptomatic patients. The lowest effective dose is recommended; avoid use during the first trimester if possible (Page [ACC/AHA/HRS 2015]). Untreated chronic maternal hypertension is associated with adverse events in the fetus, infant, and mother. If treatment for hypertension during pregnancy is needed, other agents are prefe

Lactation

Verapamil is excreted in breast milk; the estimated exposure to the nursing infant is

Monitoring

Clinical pearl	Monitor blood pressure and heart rate; periodic liver function tests; ECG, especially with renal and/or hepatic impairment Consult individual institutional policies and procedures.

Chemistry & Properties

Formula	C27H38N2O4
Molecular weight	454.61 g/mol
IUPAC name	2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile
CAS	52-53-9
PubChem CID	2520
InChIKey	`SGTNSNPWRIOYBX-UHFFFAOYSA-N`
logP	5.09 (XLogP 3.8)
Polar surface area	63.95 Å²
H-bond acceptors / donors	6 / 0
Drug-likeness (QED)	0.42
Lipinski violations	1

SMILES

COc1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	Yes (logBB -0.7)

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Substrate	—
CYP2C19	Inhibitor	IC₅₀ 21.80000000000001 µM
CYP2C19	Substrate	—
CYP2C8	Inhibitor	Ki 17.5 µM
CYP2C9	Substrate	—
CYP2D6	Inhibitor	IC₅₀ 43.30000000000001 µM
CYP2D6	Substrate	—
CYP3A4	Inhibitor	IC₅₀ 6.051225653043531 µM
CYP3A4	Substrate	—

Receptor binding (top 6)

Target	Action	Affinity
5-HT2A (HTR2A)	Binding	pKi 6.9
5-HT Transporter (SLC6A4)	Binding	pKi 6.6
Calcium channel verapamil binding site	Binding	pKi 6.5
IKr	Binding	pKi 6.3
CYP3A4 (CYP3A4)	Inhibitor	pKi 6.2
TPC2 (TPCN2)	Channel blocker	pIC50 5.0

Transporters

ASBT (Inhibitor)BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MATE2 (Inhibitor)MCT1 (Inhibitor)MDR1 (Inhibitor)MRP (Inhibitor)MRP1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)MRP5 (Inhibitor)MRP6 (Inhibitor)MRP7 (Inhibitor)OATP (Inhibitor)OATP1A2 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT(unspecified) (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)OCTN1 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)PEPT (Inhibitor)PEPT1 (Inhibitor)Proton-coupled organic cation antiporter (Inhibitor)Transporter(unspecified) (Inhibitor)MATE1 (Substrate)MATE2 (Substrate)MDR1 (Substrate)OCT(unspecified) (Substrate)OCTN1 (Substrate)OCTN2 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acalabrutinib	major
Betrixaban	major
Bosutinib	major
Brigatinib	major
Ceritinib	major
Cilostazol	major
Cisapride	major
Cobimetinib	major
Deflazacort	major
Docetaxel	major
Dolasetron	major
Edoxaban	major
Eliglustat	major
Encorafenib	major
Entrectinib	major
Erythromycin	major
Everolimus	major
Fingolimod	major
Halofantrine	major
Hydrocodone	major
Ibrutinib	major
Ivacaftor	major
Ivosidenib	major
Loperamide	major
Naloxegol	major
Neratinib	major
Olaparib	major
Pazopanib	major
Simvastatin	major
Siponimod	major
Sonidegib	major
Talazoparib	major
Venetoclax	major
Abemaciclib	moderate
Acetylsalicylic acid	moderate
Afatinib	moderate
Aldesleukin	moderate
Alectinib	moderate
Alimemazine	moderate
Alpelisib	moderate

Showing 40 of 100+.

Registered Products (5)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
ISOPTIN	Tablet 80 mg	20 tab	Sukhtian Group	2.750
ISOPTIN SR TAB	Tablet 240 mg	20 tab	Sukhtian Group	4.870
Tarka Tab	Tablet 2 mg, 180 mg	28 tab	Sukhtian Group	14.960
Aver	Vial 5.0 mg/2 ml	5 vial	MS-pharma jordan	—
Verapamil Injection BP	Injection 5 mg/2 ml	2 ml	مستودع أدوية جاودة الدولي	—