Verapamil - Uses, Dosages, Side effects, brands

Verapamil (Isoptin) is a rate-limiting calcium channel blocker that belongs to the non-dihydropyridine group like diltiazem.

Verapamil is listed in WHO's list of essential medicine.

It is used to treat the following conditions:

Angina:
- Immediate-release tablet:
- It is used in the treatment of angina at rest i.e vasospastic (Prinzmetal variant) angina and unstable (crescendo, preinfarction) angina
- It is also used in the treatment of chronic stable angina.
For rate control in Atrial fibrillation:
- Immediate-release tablet:
  - It is used to control ventricular rate during rest and stress in chronic atrial flutter and fibrillation.
- Intravenous formulation:
  - It is used for temporary control of rapid ventricular rate in atrial flutter and atrial fibrillation.
  - It is not used when the atrial flutter and atrial fibrillation are associated with accessory bypass tracts [Wolff-Parkinson-White and Lown-Ganong-Levine syndromes]).
Hypertension:
- Immediate-release tablet/ ER capsule and tablet:
  - It is also used fo management of hypertension.
Guideline recommendations:
- 2017 Guidelines also recommends that if monotherapy is needed, in the absence of comorbidities (eg, cerebrovascular disease, diabetes, chronic kidney disease, heart failure, ischemic heart disease, etc), then thiazide-like diuretics or dihydropyridine calcium channel blockers are preferred due to improved cardiovascular endpoints.
- Combination therapy might be needed to achieve blood pressure goals and is initially preferred in patients at high risk.
- When a calcium channel blocker is chosen, the dihydropyridine class (eg, amlodipine) is usually preferred, if tolerated, over the non-dihydropyridine class (eg, diltiazem or verapamil).
Paroxysmal supraventricular tachycardia prophylaxis:
- Immediate-release tablet:
  - It is also used for prophylaxis of repetitive paroxysmal supraventricular tachycardia (PSVT).
Supraventricular tachycardias:
- It is used for rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia, also including those associated with accessory bypass tracts (Wolff-Parkinson-White and Lown-Ganong-Levine syndromes).
Guideline recommendations:
- ACC guidelines also recommend intravenous verapamil for the acute treatment (ie, conversion) of a number of SVTs i.e atrioventricular reentrant tachycardia [AVRT], atrioventricular nodal reentrant tachycardia [AVNRT], focal atrial tachycardia [AT], multifocal atrial tachycardia [MAT]) in patients who are hemodynamically stable.
- Oral verapamil is useful and recommended for the ongoing management of hemodynamically stable patients who have symptomatic supraventricular tachycardia (AVNRT, AVRT, focal AT, MAT) without pre-excitation in patients who usually are not candidates for catheter ablation.
- Oral verapamil is also useful for acute rate control in hemodynamically-stable patients with atrial flutter.
Off Label Usage of Verapamil in Adults:
- It is used as off label agent in following
  - Acute coronary syndrome (ACS)
  - Cluster headaches
  - Hypertrophic cardiomyopathy
  - Idiopathic ventricular tachycardia

Verapamil (Isoptin) Dose in Adults

Dosage in the treatment of Angina:

When we switch from immediate-release to extended-release formulations, the total daily dosage remains the same unless formulation strength does not allow for equal conversion.

Immediate release:

80 to 160 mg orally thrice daily.

Manufacturer’s labeling:

80 to 120 mg thrice daily
In patients with increased response to verapamil (eg, small stature), it is given as 40 mg thrice daily
The maximum dose is 480 mg/day

Dosage in the treatment of Atrial fibrillation (rate control):

An initial bolus of 0.075 to 0.15 mg/kg I/V is given over at least 2 minutes
The usual dose is 5 to 10 mg
If no response occurs, then give an additional 10 mg bolus after 15 to 30 minutes
If the patient is responding to the initial or repeat bolus dose, then continuous infusion can be given.

Dosage in the treatment of Continuous infusion:

Initially, 5 mg/hour is given
It is then titrated to goal heart rate.

Extended-release (off-label usage):

Usual maintenance dose is180 to 480 mg orally once a day.

Immediate-release:

240 to 480 mg orally daily is given in 3 - 4 divided doses
The maximum dose is 480 mg/day

Dosage in the treatment of Cluster headaches:

Immediate-release:

Initially, 240 mg is given in 3 divided doses
Dosage may be increased by 80 mg every 1 to 2 weeks until headaches diminish or adverse reactions are seen
The maximum daily dose is 960 mg/day.
Some physicians recommend ECGs at baseline and after the dosage is increased above 480 mg/day.

Dosage in the treatment of Hypertension:

When switching from immediate-release to extended-release formulations, the total daily dosage remains the same except formulation strength does not allow for equal conversion.

Immediate-release:

The usual dosage is 120 to 360 mg per day orally in 3 divided doses
Maximum dosage is 480 mg/day

Extended-release:

There is no data of additional benefit with doses greater than 360 mg/day orally are given.

Calan SR, Isoptin SR :

Initially 180 mg orally once a day is given in the morning
In patients who have increased response to verapamil (eg, small stature) dosage is 120 mg once daily
If there is an inadequate response to 180 mg once daily, then it may be increased at weekly intervals to 240 mg once a day, followed by 180 mg twice daily (or 240 mg in the morning and 120 mg in the evening), up to 240 mg twice a day
Maximum dosage is 480 mg/day.

Verelan:

The usual dosage is 240 mg orally once daily given in the morning
In patients who have increased response to verapamil (eg, small stature) dosage is 120 mg once daily.
If there is an inadequate response to 120 mg once daily, then increase the dose at weekly intervals in the following manner: 180 mg once daily followed by 240 mg once daily then 360 mg once daily and 480 mg once daily
Maximum dosage is 480 mg/day

Verelan PM:

The usual dosage is 200 mg orally once daily given at bedtime
In patients with increased response to verapamil (eg, small stature) dosage is 100 mg once daily
If there is an inadequate response to 200 mg once daily, then increase dosage at weekly intervals to 300 mg once daily, followed by 400 mg once daily
The maximum dose is 400 mg daily

Off Label Dosage in the treatment of Idiopathic ventricular tachycardia:

It is given 5 to 5 mg Intravenous every 15 to 30 minutes.

Immediate-release:

It is given as 360 mg/day orally in 3 divided doses

Extended-release:

Dosage is 240 to 480 mg orally once daily

Dosage in the treatment of PSVT prophylaxis:

When switching from immediate-release to extended-release formulations, the total daily dosage remains the same except that formulation strength does not allow for equal conversion.

Immediate release:

It is given as 240 to 480 mg orally daily in 3 to 4 divided doses
The maximum dose is 480 mg/day

Dosage in the treatment of Supraventricular tachycardia (ongoing management):

Initially, 120 mg daily is given in divided doses as immediate release
It can also be given 120 mg once daily as extended-release
The maximum maintenance dose is 480 mg/day in divided doses (immediate-release) or once daily (extended-release)

Intravenous Off label dosage in the treatment of acute Supraventricular tachycardia (SVT):

ACLS guidelines :

5 to 5 mg is given over 2 minutes (over 3 minutes in elderly patients)
The second dose of 5 to 10 mg (~0.15 mg/kg) is given 15 to 30 minutes after the initial dose if the patient tolerates, but if not responds to initial dose
The maximum total dose is 20 to 30 mg

ACC/AHA/HRS SVT guidelines:

5 to 10 mg (0.075 to 0.15 mg/kg) is administered over 2 minutes
If there is no response, then the second dose of 10 mg (0.15 mg/kg) can be given 30 minutes after the initial dose
It is followed by an infusion at 0.005 mg/kg/minute.

Verapamil (Isoptin) Dose in Childrens

Dose in the treatment of Supraventricular tachycardia (SVT):

Infants:

It can decrease cardiac output which results in hypotension and even cardiac arrest in infants
Some physicians consider verapamil use contraindicated.
If it is used, then it should only be with expert consultation and continuous ECG monitoring with IV calcium at the bedside
0.1 to 0.2 mg/kg/dose is given (usual: 0.75 to 2 mg/dose)
The dose can be repeated after at least 30 minutes if the response is inadequate

Children and Adolescents 1 to 15 years:

Initial dose is 1 to 0.3 mg/kg/dose Intravenous (usual dose: 2 to 5 mg/dose)
The maximum dose is 5 mg/dose
The repeat dose is given in 15 to 30 minutes if the response is inadequate
The maximum dose for the second dose is 10 mg/dose.
It may also be administered intraosseous.

Adolescents ≥16 years:

Initial dose:

PALS guidelines:

It is given as 1 to 0.3 mg/kg/dose
The maximum dose is 5 mg/dose

Manufacturer's labeling:

5 to 10 mg is administered (0.075 to 0.15 mg/kg/dose)
The maximum dose is 10 mg/dose
Similar dosing is recommended in the adult i.e 5 to 10 mg (0.075 to 0.15 mg/kg) over 2 minutes

Repeat dose:

It can be repeated in 15 to 30 minutes if an adequate response is not achieved
The maximum dose for the second dose is 10 mg/dose

Children and Adolescents:

Immediate release:
- 2 to 8 mg/kg/day orally is given in 3 divided doses
- Maximum daily dose is 480 mg/day

Verapamil Pregnancy Risk Factor: C

Verapamil crosses the placenta.
Use of it during pregnancy can have adverse effects on the fetus (bradycardia and heart block, hypotension).
Verapamil is a treatment that can be used to control hypertrophic cardiomyopathy in women who have been treated before becoming pregnant.
However, it is recommended that fetal monitoring be increased.
Verapamil IV can be used to treat supraventricular tachycardia in pregnant women when beta-blockers or adenosine are not effective or contraindicated.
Verapamil can also be used to manage SVT in patients with severe symptoms.
Usually, the lowest dose of effective medication is recommended
If possible, avoid it during the first trimester.
Other agents may be preferred if hypertension is treated during pregnancy.

Verapamil use during breastfeeding:

Breast milk also contains verapamil, norverapamil and verapamil
When the RID of your medication is less that 10%, breastfeeding is considered acceptable.
Some manufacturers do not recommend breastfeeding, but breastfeeding is compatible with verapamil.

Verapamil dose in Renal Disease:

Manufacturer's labeling:

Oral: Verelan PM:

Initially, 100 mg once daily at bedtime is given.
No dosage adjustments are given in the manufacturer’s labeling for the other products

Injection:

There are no dosage adjustments given in the manufacturer’s labeling
But repeated injections in patients with renal failure can lead to accumulation and excessive pharmacologic effects and should be avoided.
If repeated injections are necessary then monitor blood pressure and PR interval closely and use smaller repeat doses.

Alternate recommendations:

A study suggests that renal clearance of verapamil and its metabolite is reduced with advanced renal failure.

Dialysis:

It is not removed by hemodialysis
Supplemental dose is usually not necessary.

Verapamil dose in Liver disease:

Oral:

In cirrhosis, decrease the dose to 20% of normal and monitor ECG.

Calan, Calan SR, Verelan:

Give 30% of the normal dose in severe hepatic impairment.

Verelan PM:

Initially, 100 mg once daily is given at bedtime.

Injection:

There are no dosage adjustments given in the manufacturer’s labeling
Use cautiously and consider additional ECG monitoring in severe impairment.
In cirrhosis, decrease dose to half of normal and monitor ECG.
Repeated injections in patients with hepatic failure can lead to accumulation and excessive pharmacologic effects and should be avoided.
If repeated injections are necessary then monitor blood pressure and PR interval closely and use smaller repeat doses.

Common Side Effects of Verapamil Include:

Central nervous system:
- Headache
Gastrointestinal:
- Gingival hyperplasia
- Constipation

Less Common Side Effects of Verapamil Include:

Cardiovascular:
- Peripheral Edema
- Hypotension
- Cardiac Failure
- Atrioventricular Block
- Bradycardia
- Flushing
- Angina Pectoris
- Atrioventricular Dissociation
- Cerebrovascular Accident
- Chest Pain
- Claudication
- ECG Abnormality
- Myocardial Infarction
- Palpitations
- Syncope
Central Nervous System:
- Fatigue
- Dizziness
- Lethargy
- Pain
- Paresthesia
- Sleep Disorder
- Confusion
- Drowsiness
- Equilibrium Disturbance
- Extrapyramidal Reaction
- Insomnia
- Psychosis
- Shakiness
Dermatologic:
- Skin Rash
- Alopecia
- Diaphoresis
- Erythema Multiforme
- Hyperkeratosis
- Macular Eruption
- Stevens-Johnson Syndrome
- Urticaria
Endocrine & Metabolic:
- Galactorrhea
- Gynecomastia
- Hyperprolactinemia
- Spotty Menstruation
Gastrointestinal:
- Dyspepsia
- Nausea
- Diarrhea
- Abdominal Distress
- Gastrointestinal Distress
- Xerostomia
Genitourinary:
- Impotence
Hematologic & Oncologic:
- Bruise
- Purpuric Vasculitis
Hepatic:
- Increased Liver Enzymes
Neuromuscular & Skeletal:
- Myalgia
- Arthralgia
- Muscle Cramps
- Weakness
Ophthalmic:
- Blurred Vision
Otic:
- Tinnitus
Renal:
- Polyuria
Respiratory:
- Flu-Like Symptoms
- Pulmonary Edema
- Dyspnea

Contraindication to Verapamil Include:

Hypersensitivity to verapamil and any component of the formulation
Hypotension, severe left ventricular dysfunction and cardiogenic shock are all contraindicated.
It is also contraindicated for sick sinus syndromes (unless the patient currently has an artificial ventricular pacemaker). Second- and third-degree Atrioventricular Block (AV) blocks (unless the patient currently has an artificial ventricular pacemaker).
It is contraindicated in atrial flutter or fibrillation and an accessory bypass tract (Wolff-Parkinson-White [WPW] syndrome, Lown-Ganong-Levine syndrome).
Other contraindications include complex myocardial injury (MI), ventricular failure caused by pulmonary congestion, severe bradycardia, and concurrent use of vabradine.

Warnings and precautions

Conductivity abnormalities
- It can cause a first-degree AV block, or sinus bradycardia.
- Rarer might be a higher degree of AV block
- Asystole can occur in extreme cases in patients suffering from sick sinus syndrome.
- If there is a marked first-degree block, progressive progression to second- or three-degree AV block or unifascicular bundle block block or unifascicular bundle block block, dosage reduction should be considered.
Hepatic effects
- Reports indicate an increase in liver transaminases and alkalinephosphatase as well as bilirubin
- Rechallenge has also been shown to show hepatocellular injury.
- Tests of liver function are recommended.
- Sometimes elevation can be temporary.
Syncope and hypotension:
- Also, symptoms of hypotension can occur with or without syncope
- The patient's clinical condition dictates that blood pressure should be lowered.
Accessory bypass tract (eg, Wolff-Parkinson-White [WPW] syndrome):
- It has been shown to increase anterograde conduction down an accessory pathway, which can lead to ventricular fibrillation in an episode of atrial fibrillation.
- Patients with such conditions should avoid its use.
Arrhythmia:
- Patients with complex tachycardias, other than those known to be supraventricular, are not advised.
- Administration of severe hypotension can lead to severe hypotension.
Attenuated neuromuscular transmission
- It has been reported that there is a decrease in neuromuscular transmission.
- Patients with impaired neuromuscular transmission (Duchenne muscular Dystrophy, myasthenia Gravis) should be cautious.
- It may be advisable to reduce dosage.
Hepatic impairment
- Patients with hepatic impairment should be cautious
- It may be a good idea to reduce dosage
- In severe impairment, monitor hemodynamics and even ECG.
- Patients with a severe hepatic impairment should avoid IV verapamil injections.
Increased intracranial pressure
- IV verapamil caused intracranial pressure for patients with supratentorial tumors during anesthesia induction
- These patients should be used with caution
Left ventricular dysfunction:
- Caution in left ventricular dysfunction
- Negative inotropic effects may make the condition worse.
- Patients with heart disease should avoid it. It is not recommended for patients with severe cardiac problems.
Renal impairment
- Patients with impaired renal function should be cautious
- Monitor hemodynamics and ECG for severe impairment, especially if
- In severe impairment, monitor hemodynamics and even ECG.
- Patients with severe renal impairment should avoid IV verapamil injections.

Verapamil: Drug Interaction

Risk Factor C (Monitor therapy)
Abemaciclib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Abemaciclib.
Alcohol (Ethyl)	Verapamil may increase the serum concentration of Alcohol (Ethyl).
Alfuzosin	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Aliskiren	Verapamil may increase the serum concentration of Aliskiren.
Alpha1-Blockers	May enhance the hypotensive effect of Calcium Channel Blockers.
Amiodarone	Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Amiodarone. Sinus arrest has been reported.
AmLODIPine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine.
Amphetamines	May diminish the antihypertensive effect of Antihypertensive Agents.
Antipsychotic Agents (Second Generation [Atypical])	Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]).
Apixaban	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban.
ARIPiprazole	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations.
Aspirin	Calcium Channel Blockers (Nondihydropyridine) may enhance the antiplatelet effect of Aspirin.
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.
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.
Barbiturates	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Benperidol	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Benzhydrocodone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased.
Beta-Blockers	Calcium Channel Blockers (Nondihydropyridine) may enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Levobunolol; Metipranolol.
Blonanserin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Bosentan	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details.
Bradycardia-Causing Agents	May enhance the bradycardic effect of other Bradycardia-Causing Agents.
Brentuximab Vedotin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Bretylium	May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
Brexpiprazole	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer.
Brimonidine (Topical)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
BusPIRone	Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of BusPIRone.
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).
Calcium Salts	May diminish the therapeutic effect of Calcium Channel Blockers.
Cannabidiol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabidiol.
Cannabis	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.
Cardiac Glycosides	Calcium Channel Blockers (Nondihydropyridine) may enhance the AVblocking effect of Cardiac Glycosides. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Cardiac Glycosides.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CloNIDine	May enhance the AV-blocking effect of Calcium Channel Blockers (Nondihydropyridine). Sinus node dysfunction may also be enhanced.
Clopidogrel	Calcium Channel Blockers may diminish the therapeutic effect of Clopidogrel.
CloZAPine	CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Codeine	CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Codeine.
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
CYP3A4 Substrates (High risk with Inhibitors)	CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); Praziquantel; Trabectedin; Vinorelbine.
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Dexmethylphenidate	May diminish the therapeutic effect of Antihypertensive Agents.
Diazoxide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Dronabinol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.
DULoxetine	Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine.
Duvelisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Efavirenz	May decrease the serum concentration of Calcium Channel Blockers.
Erdafitinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Erdafitinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Erdafitinib	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Estrogen Derivatives	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Estrogen Derivatives.
Fexofenadine	Verapamil may increase the serum concentration of Fexofenadine.
Fingolimod	Verapamil may enhance the bradycardic effect of Fingolimod.
Flecainide	Verapamil may enhance the adverse/toxic effect of Flecainide. In particular, this combination may significantly impair myocardial contractility and AV nodal conduction.
Fluconazole	May increase the serum concentration of Calcium Channel Blockers.
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Grapefruit Juice	May increase the serum concentration of Verapamil.
Halofantrine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Management: Extreme caution, with possibly increased monitoring of ECGs, should be used if halofantrine is combined with moderate CYP3A4 inhibitors. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs.
Herbs (Hypertensive Properties)	May diminish the antihypertensive effect of Antihypertensive Agents.
Herbs (Hypotensive Properties)	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
HYDROcodone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone.
Hypotension-Associated Agents	Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents.
Ifosfamide	CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.
Imatinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib.
Lacosamide	Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide.
Larotrectinib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Larotrectinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib.
Levodopa-Containing Products	Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products.
Lithium	Calcium Channel Blockers (Nondihydropyridine) may enhance the neurotoxic effect of Lithium. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Lithium. Decreased or unaltered lithium concentrations have also been reported with this combination.
Lormetazepam	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
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.
Manidipine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Manidipine.
MetFORMIN	Verapamil may diminish the therapeutic effect of MetFORMIN.
Methylphenidate	May diminish the antihypertensive effect of Antihypertensive Agents.
Midodrine	May enhance the bradycardic effect of Bradycardia-Causing Agents.
Mirodenafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil.
Molsidomine	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Naftopidil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Naldemedine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naldemedine.
Naldemedine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.
Nalfurafine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Nalfurafine.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Neuromuscular-Blocking Agents (Nondepolarizing)	Calcium Channel Blockers may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).
Nicergoline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Nicorandil	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
NiMODipine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine.
Nintedanib	Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib.
Nitroprusside	Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside.
Opioids (Anilidopiperidine)	May enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine). Opioids (Anilidopiperidine) may enhance the hypotensive effect of Calcium Channel Blockers (Nondihydropyridine).
OxyCODONE	CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased.
Palbociclib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Pentoxifylline	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
P-glycoprotein/ABCB1 Substrates	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide.
Pholcodine	Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine.
Phosphodiesterase 5 Inhibitors	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Pimecrolimus	CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus.
Propafenone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Prostacyclin Analogues	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
Prucalopride	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.
Quinagolide	May enhance the hypotensive effect of Blood Pressure Lowering Agents.
QuiNIDine	May enhance the hypotensive effect of Verapamil. Verapamil may increase the serum concentration of QuiNIDine.
Red Yeast Rice	Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin (and possibly other related compounds) may be increased.
Regorafenib	May enhance the bradycardic effect of Calcium Channel Blockers (Nondihydropyridine).
RifAXIMin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.
RisperiDONE	Verapamil may increase the serum concentration of RisperiDONE.
Rupatadine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Rupatadine.
Ruxolitinib	May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible.
Ruxolitinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ruxolitinib.
Salmeterol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
SAXagliptin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin.
Sildenafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil.
Silodosin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin.
Silodosin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Silodosin.
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Tacrolimus (Systemic)	Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus (Systemic).
Tacrolimus (Topical)	Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Tacrolimus (Topical).
Tamsulosin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tamsulosin.
Tegaserod	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod.
Terlipressin	May enhance the bradycardic effect of Bradycardia-Causing Agents.
Tetrahydrocannabinol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.
Ticagrelor	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Tofacitinib	May enhance the bradycardic effect of Bradycardia-Causing Agents.
Trabectedin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin.
Udenafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil.
Vilazodone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone.
Vindesine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine.
Yohimbine	May diminish the antihypertensive effect of Antihypertensive Agents.
Zuclopenthixol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol.
Risk Factor D (Consider therapy modification)
Acalabrutinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Acalabrutinib. Management: Reduce acalabrutinib dose to 100 mg once daily with concurrent use of a moderate CYP3A4 inhibitor. Monitor patient closely for both acalabrutinib response and evidence of adverse effects with any concurrent use.
Afatinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib.
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.
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.
AtorvaSTATin	May increase the serum concentration of Verapamil. Verapamil may increase the serum concentration of AtorvaSTATin. Management: Consider using lower atorvastatin doses when used together with verapamil.
Avanafil	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects.
Betrixaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor.
Bilastine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors.
Brigatinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with moderate CYP3A4 inhibitors when possible. If such a combination cannot be avoided, reduce the dose of brigatinib by approximately 40% (ie, from 180 mg to 120 mg, from 120 mg to 90 mg, or from 90 mg to 60 mg).
Bromocriptine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations.
Budesonide (Topical)	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased.
CarBAMazepine	Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Consider empiric reductions in carbamazepine dose with initiation of nondihydropyridine calcium channel blockers. Monitor for increased toxic effects of carbamazepine and reduced therapeutic effects of the calcium channel blocker.
Celiprolol	Verapamil may enhance the bradycardic effect of Celiprolol. Verapamil may increase the serum concentration of Celiprolol. Management: Concomitant use of verapamil and celiprolol is not recommended, particularly in patients with pre-existing conduction abnormalities. When switching from one agent to the other, a drug-free period is recommended, and heart rate should be monitored closely.
Ceritinib	Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Exceptions are discussed in separate monographs.
Cilostazol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4.
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.
Colchicine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. See full monograph for details. Use extra caution in patients with impaired renal and/or hepatic function.
Colchicine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details.
CycloSPORINE (Systemic)	Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine).
CYP3A4 Inducers (Strong	May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
CYP3A4 Inhibitors (Strong)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Dabigatran Etexilate	Verapamil may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Consider giving dabigatran 2 hrs before oral verapamil; other dose reductions may be needed. Specific recommendations vary by US vs Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling.
Dabrafenib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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).
Dapoxetine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg per day when used together with a moderate inhibitor of CYP3A4.
Deflazacort	CYP3A4 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor.
DOXOrubicin (Conventional)	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
DOXOrubicin (Conventional)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
Dronedarone	Calcium Channel Blockers (Nondihydropyridine) may enhance the AV-blocking effect of Dronedarone. Other electrophysiologic effects of Dronedarone may also be increased. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Dronedarone. Dronedarone may increase the serum concentration of Calcium Channel Blockers (Nondihydropyridine). Management: Use lower starting doses of the nondihydropyridine calcium channel blockers (i.e., verapamil, diltiazem), and only consider increasing calcium channel blocker dose after obtaining ECG-based evidence that the combination is being well-tolerated.
Edoxaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation.
Eletriptan	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided.
Eliglustat	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details.
Encorafenib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and moderate CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose prior to initiation of the CYP3A4 inhibitor. See full monograph for details.
Enzalutamide	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.
Eplerenone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details.
Esmolol	Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Esmolol. Management: Administration of IV verapamil or diltiazem together with esmolol is contraindicated if one agent is given while the effects of the other are still present. Canadian esmolol labeling specifies that use within 24 hours is contraindicated.
Everolimus	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations.
Everolimus	Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for most indications. See full monograph or prescribing information for specific dose adjustment and monitoring recommendations.
FentaNYL	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary.
Fosphenytoin	Calcium Channel Blockers may increase the serum concentration of Fosphenytoin. Management: Monitor for phenytoin toxicity with concomitant use of a calcium channel blocker (CCB) or decreased phenytoin effects with CCB discontinuation. Monitor for decreased CCB therapeutic effects. Nimodipine Canadian labeling contraindicates use with phenytoin.
GuanFACINE	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination.
Ibrutinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: When treating B-cell malignancies, decrease ibrutinib to 280 mg daily when combined with moderate CYP3A4 inhibitors. When treating graft versus host disease, monitor patients closely and reduce the ibrutinib dose as needed based on adverse reactions.
Ivacaftor	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumacaftor with a moderate CYP3A4 inhibitor.
Ivosidenib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivosidenib. Management: Avoid use of moderate CYP3A4 inhibitors with ivosidenib whenever possible. If combined, monitor for increased ivosidenib toxicities. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Lovastatin	Verapamil may increase the serum concentration of Lovastatin. Management: Initiate lovastatin at a maximum adult dose of 10 mg/day, and do not exceed 20 mg/day, in patients receiving verapamil. Monitor closely for signs of HMG-CoA reductase inhibitor toxicity (e.g., myositis, rhabdomyolysis).
Lurasidone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: Lurasidone US labeling recommends reducing lurasidone dose by half with a moderate CYP3A4 inhibitor. Some non-US labeling recommends initiating lurasidone at 20 mg/day and limiting dose to 40 mg/day; avoid concurrent use of grapefruit products.
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.
MiFEPRIStone	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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.
Mitotane	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
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.
Olaparib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily.
Phenytoin	Calcium Channel Blockers may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Calcium Channel Blockers. Management: Avoid use of nimodipine or nifedipine with phenytoin. Monitor for phenytoin toxicity and/or decreased calcium channel blocker effects with any concurrent use.
Pitolisant	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant.
Protease Inhibitors	May decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If used, monitor for CCB toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Saquinavir, tipranavir, and darunavir/cobicistat use with bepridil is contraindicated.
Ranolazine	Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Ranolazine. Management: Limit ranolazine dose to a maximum of 500 mg twice daily when used with diltiazem or verapamil.
Ranolazine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.).
Rifamycin Derivatives	May decrease the serum concentration of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers. Management: The labeling for some US and Canadian calcium channel blockers contraindicate use with rifampin, however recommendations vary. Consult appropriate labeling.
Rivaroxaban	Inhibitors of CYP3A4 (Moderate) and P-glycoprotein may increase the serum concentration of Rivaroxaban. Management: No action is needed in patients with normal renal function. US labeling recommends avoidance in patients with estimated creatinine clearance 15 to 80 mL/min unless prospective benefits outweigh the risks. Other non-US labels may differ.
Simvastatin	Verapamil may increase the serum concentration of Simvastatin. Management: Avoid concurrent use of verapamil with simvastatin when possible. If used together, limit adult maximum simvastatin dose to 10 mg/day, and avoid Simcor (simvastatin/niacin) because fixed simvastatin doses in the product exceed this maximum.
Sincalide	Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction.
Siponimod	Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia.
Sirolimus	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sirolimus. Management: Monitor for increased serum concentrations of sirolimus if combined with a moderate CYP3A4 inhibitor. Lower initial sirolimus doses or sirolimus dose reductions will likely be required.
Sonidegib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions).
St John's Wort	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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.
Suvorexant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Management: The recommended dose of suvorexant is 5 mg daily in patients receiving a moderate CYP3A4 inhibitor. The dose can be increased to 10 mg daily (maximum dose) if necessary for efficacy.
Talazoparib	Verapamil may increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. After a period of 3 to 5 times the half-life of verapamil, increase the talazoparib dose to the dose used before initiation of verapamil.
Telithromycin	May enhance the bradycardic effect of Verapamil. Telithromycin may enhance the hypotensive effect of Verapamil.
Tezacaftor	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tezacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor should be given in the morning, every other day. Ivacaftor alone should be given in the morning, every other day on alternate days from tezacaftor/ivacaftor.
TiZANidine	CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions.
Tolvaptan	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Management: Jynarque dose requires adjustment when used with a moderate CYP3A4 inhibitor. See labeling or full interaction monograph for specific recommendations. Use of Samsca with moderate CYP3A4 ihibitors should generally be avoided.
Venetoclax	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations.
Venetoclax	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors.
Zopiclone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined.
Risk Factor X (Avoid combination)
Aprepitant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant.
Asunaprevir	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir.
Bosutinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib.
Bromperidol	Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents.
Budesonide (Systemic)	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic).
Cobimetinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily.
Conivaptan	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Dantrolene	May enhance the hyperkalemic effect of Calcium Channel Blockers (Nondihydropyridine). Dantrolene may enhance the negative inotropic effect of Calcium Channel Blockers (Nondihydropyridine). Management: This interaction has only been described with intravenous dantrolene administration.
Disopyramide	Verapamil may enhance the adverse/toxic effect of Disopyramide. Of particular concern is the potential for profound depression of myocardial contractility. Management: Concurrent use of disopyramide within 48 hours prior to or 24 hours after verapamil should be avoided.
Dofetilide	Verapamil may increase the serum concentration of Dofetilide.
Domperidone	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Flibanserin	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin.
Fosaprepitant	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Fosaprepitant.
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ivabradine	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine.
Ivabradine	Calcium Channel Blockers (Nondihydropyridine) may enhance the bradycardic effect of Ivabradine. Ivabradine may enhance the QTc-prolonging effect of Calcium Channel Blockers (Nondihydropyridine). Specifically, the QTc prolonging effects of bepridil may be enhanced. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Ivabradine. Specifically, verapamil or diltiazem may increase serum ivabradine concentrations.
Lomitapide	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide.
Naloxegol	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol.
Neratinib	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Neratinib.
PAZOPanib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib.
Pimozide	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide.
Simeprevir	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir.
Topotecan	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.
Ulipristal	CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity.
VinCRIStine (Liposomal	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).

Monitor:

Blood pressure and heart rate
Repeated liver function tests
ECG, especially with renal and/ or hepatic impairment

How to administer Verapamil (Isoptin)?

Oral formulation:

Do not crush or chew its extended-release products.

Calan SR and Isoptin SR :

Give with food.
Isoptin SR 240 mg tablet can be split in half.

Verelan and Verelan PM:

Capsules can be opened and the contents sprinkled on 1 tablespoonful of applesauce
Then swallow immediately (without chewing)
It is followed by a glass of cool water.
Do not subdivide the contents of capsules.

Intravenous formulation:

Give over at least 2 minutes
Administer over 3 minutes in older patients for the acute treatment of SVT.

Mechanism of action of Verapamil (Isoptin):

It prevents calcium ions from entering "slow channels" and select voltage-sensitive areas in vascular smooth muscles and myocardium during depolarization.
It also results in relaxation of coronary smooth muscle and coronary blood vasodilation
It increases myocardial oxygen delivery in patients with vasospastic gina.
It reduces the automaticity and conduction speed of the AV Node.
Verapamil pharmacokinetics are mainly affected by lean body weight.

Peak effect:

Oral: Immediate release in 1 to 2 hours
IV bolus: in 3 to 5 minutes

Duration:

Oral: Immediate-release tablets in 6 - 8 hours
intravenous in 0.5 - 6 hours

Absorption:

It is well absorbed orally(more than 90%)

Protein binding:

almost 90%

Metabolism:

Mostly hepatic (extensive first-pass effect) via multiple CYP isoenzymes.
The primary metabolite is norverapamil (possesses about 20% pharmacologic activity of verapamil)

Bioavailability:

Orally 20% to 35%

Half-life elimination:

Injection: Terminal: 2 - 5 hours.
Oral:
- Immediate-release:
  - Single-dose in 2.8 to 7.4 hours
  - Multiple doses in 4.5 to 12 hours
- Extended-release: almost 12 hours
Severe hepatic impairment: 14 - 16 hours

The time to reach peak serum concentration after oral administration is:

Immediate release in 1 to 2 hours
Extended-release:
- Calan SR in 5.21 hours
- Verelan in 7 to 9 hours
- Verelan PM: almost 11 hours;
Drug release delayed almost 4 to 5 hours

Excretion:

Mainly urine (~70% as metabolites, 3% to 4% as unchanged drug).

International Brands of Verapamil:

APO-Verap
APO-Verap SR
DOM-Verapamil SR
Isoptin SR
MYLAN-Verapamil
MYLAN-Verapamil SR
NOVO-Veramil SR
NOVO-Veramil
PHL-VERAPAMIL SR
PMS-Verapamil SR
PRO-Verapamil SR
RIVA-Verapamil SR
Verelan
Angimil
Anpec
Beaptin SR
Calan SR
Calaptin
Cardiolen
Cardiomil
Caveril
Cordilat
Cordilox SR
Cronovera
Devincil
Dilacoran
Dilacoran Retard
Fibrocard
Flamon
Hexasoptin
Hypover
Ikacor
Ikapress
Isoptin
Isoptin Retard
Isoptin RR
Isoptin SR
Isoptine
Isoptino
Lekoptin
Lexoptin
Librapamil
Manidon
Manidon Retard
Quasar
Securon
Vasolan
Vasomil
Vasopten
Vepiltax
Verahexal
Verahexal 240SR
Veraloc
Veramet
Veramex
Veramil
Verap
Verapamil Hydrochloride
Verapamil Pharmavit
Verapil
Verapress 240 SR
Verapress MR
Veratad
Veratens
Verelan
Vermine
Verpamil
Vetrimil
Zolvera

Verapamil (Isoptin) Brands in Pakistan:

Verapamil (Hcl) [Inj 10 Mg/Ml]
Canocil	Pharmedic (Pvt) Ltd.

Verapamil (Hcl) [Inj 50 Mg/Ml]
Canocil	Pharmedic (Pvt) Ltd.

Verapamil (Hcl) [Inj 2.5 Mg/Ml]
Isoptin	Abbott Laboratories (Pakistan) Limited.

Verapamil (Hcl) [Tabs 40 Mg]
Calan	Searle Pakistan (Pvt.) Ltd.
Geopress	Geofman Pharmaceuticals
Isoptin	Abbott Laboratories (Pakistan) Limited.
Zavera	Zafa Pharmaceutical Laboratories (Pvt) Ltd.
Zeyar	Zephyr Pharmatec (Pvt) Ltd.

Verapamil (Hcl) [Tabs 80 Mg]
Calan	Searle Pakistan (Pvt.) Ltd.
Geopress	Geofman Pharmaceuticals
Isocardin	Pharmedic (Pvt) Ltd.
Isoptin	Abbott Laboratories (Pakistan) Limited.
Veramil	Caraway Pharmaceuticals
Veramil	Caraway Pharmaceuticals
Zeyar	Zephyr Pharmatec (Pvt) Ltd.