CALCIUM CHANNEL BLOCKER DOSING

• ACRONYMS AND DEFINITIONS

• AAP - American Academy of Pediatrics
• ARB - Angiotensin II receptor blockers
• AUC - Area under the curve
• CCB - Calcium channel blocker
• ER - Extended-release
• HCTZ - Hydrochlorothiazide
• IR - Immediate release
• P = Drugs with pediatric dosing

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• CALCIUM CHANNEL BLOCKERS

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• Kidney disease dosing
• Amlodipine (Norvasc)
• No dose adjustment necessary in kidney disease
• Diltiazem (Cardizem, Cardizem CD, Cartia XT)
• Diltiazem is excreted by the kidneys. Start low and titrate slowly.
• A single study in 9 patients with severe kidney disease showed no difference in diltiazem pharmacokinetics compared to those with normal function.
• Diltiazem (Cardizem LA)
• No dose adjustment is necessary
• Diltiazem (Dilacor XR)
• Patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function
• Diltiazem (Taztia XT, Tiazac)
• Use caution. Patients with severely impaired renal function (creatinine clearance < 50 mL/min) who received immediate-release diltiazem had modestly increased diltiazem concentrations compared to patients with normal renal function
• Felodipine (Plendil)
• No dose adjustment necessary
• Isradipine (Dynacirc)
• Mild renal impairment (creatinine clearance 30 - 80 mL/min) increases the AUC of isradipine by 45%. Progressive deterioration reverses this trend, and patients with severe renal failure (creatinine clearance < 10 mL/min) who have been on hemodialysis show a 20% - 50% lower AUC than healthy volunteers. Starting dose of 2.5 mg twice a day is recommended in mild renal impairment.
• Nicardipine (Cardene)
• Exposure is increased. Start with 20 mg three times a day and titrate slowly.
• Nifedipine (Procardia IR, Adalat CC, Afeditab CR, Procardia XL)
• Has not been studied. Use caution.
• Nisoldipine (Sular)
• Dose adjustments in mild to moderate renal impairment are not necessary
• Verapamil (Calan, Calan SR, Verelan. Verelan PM)
• About 70% of verapamil dose is excreted by the kidneys. Use caution in patients with impaired renal function and monitor for abnormal prolongation of the PR interval.

• Liver disease dosing
• Amlodipine (Norvasc)
• Amlodipine is extensively metabolized by the liver and the plasma elimination half-life is 56 hours in patients with impaired hepatic function. Use a starting dose of 2.5 mg once daily and titrate slowly.
• Diltiazem (Cardizem, Cardizem CD, Cartia XT)
• Diltiazem should be used with caution in patients with significant liver disease
• In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
• Diltiazem (Cardizem LA)
• Child Pugh A and B: no dose adjustment is likely to be needed
• Child Pugh C: manufacturer makes no recommendation. In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
• Diltiazem (Dilacor XR)
• Diltiazem should be used with caution in patients with significant liver disease
• In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
• Diltiazem (Taztia XT, Tiazac)
• Use caution. In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
• Felodipine (Plendil)
• Clearance is reduced by about 60%. Starting dose should be 2.5 mg and blood pressure should be monitored closely while titrating.
• Isradipine (Dynacirc)
• In patients with hepatic impairment, AUC is increased by 52%. Recommended starting dose is 2.5 mg twice a day.
• Nicardipine (Cardene)
• Exposure is increased. Use caution. In severe liver disease, start with 20 mg twice a day and titrate slowly while maintaining twice daily dosing.
• Nifedipine (Procardia IR, Adalat CC, Afeditab CR, Procardia XL)
• Exposure is increased. Use caution.
• Nisoldipine (Sular)
• Exposure is increased. Use a starting dose of 8.5 mg and titrate slowly.
• Verapamil (Calan, Calan SR, Verelan, Verelan PM)
• Exposure is increased. For patients with severe liver disease, the dose of verapamil should be about 30% of the dose given to patients with normal liver function.

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• DRUG INTERACTIONS

• NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).


• All CCB
• Clarithromycin (Biaxin®) - Hypotension and acute kidney injury have been reported in patients taking CCBs with the antibiotic clarithromycin. Most reports have occurred in patients ≥ 65 years [55]
• Nitroglycerin - marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination [54]


• Amlodipine
• Cyclosporine - amlodipine may increase cyclosporine levels. Monitor cyclosporine levels closely.
• CYP3A4 inhibitors - amlodipine is a sensitive CYP3A4 substrate. Moderate and strong CYP3A4 inhibitors may increase exposure to amlodipine and lead to hypotension and/or edema. Monitor patients closely when combining.
• Simvastatin (Zocor®) - Simvastatin dose should not exceed 20 mg/day while taking amlodipine
• Tacrolimus - tacrolimus blood levels may increase when taken with amlodipine. Monitor tacrolimus blood levels and adjust dose accordingly.


• Diltiazem
• CYP3A inhibitors/inducers/substrates - may affect the metabolism of diltiazem and vice versa
• Digoxin - diltiazem may increase digoxin levels. Monitor digoxin levels when starting or changing diltiazem therapy.
• Ivabradine (Corlanor®) - diltiazem may increase blood levels of ivabradine and cause severe bradycardia. Diltiazem should not be given with ivabradine.
• Lovastatin (Mevacor®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
• Medications that slow the heart rate - verapamil and diltiazem slow the heart rate. When they are taken with other medications that slow the heart rate, the effect may be potentiated.
• Common medications that slow the heart rate
• Amiodarone (Cordarone®)
• Beta blockers
• Clonidine (Catapres®)
• Digoxin (Lanoxin®)
• Fingolimod (Gilenya®)
• Ivabradine (Corlanor®)
• Siponimod (Mayzent®)
• Simvastatin (Zocor®) - Simvastatin dose should not exceed 10 mg/day. Diltiazem dose should not exceed 240 mg/day.
• Topiramate (Topamax®) - topiramate may decrease diltiazem levels, and diltiazem may increase topiramate levels


• Felodipine
• CYP3A inhibitors/inducers/substrates - may affect the metabolism of felodipine and vice versa
• Oxcarbazepine (Trileptal®) - oxcarbazepine may decrease Felodipine levels by 28%


• Isradipine
• Cimetidine - cimetidine may increase exposure to isradipine. Monitor for adverse events and adjust dose if necessary.
• Rifampicin - rifampicin may decrease exposure to isradipine. Concomitant use is not recommended.


• Nicardipine
• Cyclosporine - nicardipine inhibits cyclosporine metabolism and increases its exposure. Monitor cyclosporine levels closely when given concomitantly.
• Tacrolimus - nicardipine inhibits tacrolimus metabolism and increases its exposure. Monitor tacrolimus levels closely when given concomitantly.


• Nifedipine
• CYP3A inhibitors/inducers/substrates - may affect the metabolism of nifedipine and vice versa


• Nisoldipine
• CYP3A inhibitors/inducers/substrates - may affect the metabolism of nisoldipine and vice versa


• Verapamil
• CYP3A inhibitors/inducers/substrates - may affect the metabolism of verapamil and vice versa
• Digoxin - verapamil may increase digoxin levels. Monitor digoxin levels when starting or changing verapamil therapy.
• Disopyramide (Norpace®) - Manufacturer recommends disopyramide not be administered 48 hours before or 24 hours after verapamil is administered
• Ethanol (beverage alcohol) - verapamil may inhibit the metabolism and ethanol and increase blood alcohol levels
• Inhalation anesthetics - inhaled anesthetics may depress cardiac activity and potentiate the effects of verapamil. Use caution when combining.
• Ivabradine (Corlanor®) - verapamil may increase blood levels of ivabradine and cause severe bradycardia. Verapamil should not be given with ivabradine.
• Lovastatin (Mevacor®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
• Medications that slow the heart rate - verapamil and diltiazem slow the heart rate. When they are taken with other medications that slow the heart rate, the effect may be potentiated.
• Common medications that slow the heart rate
• Amiodarone (Cordarone®)
• Beta blockers
• Clonidine (Catapres®)
• Digoxin (Lanoxin®)
• Fingolimod (Gilenya®)
• Ivabradine (Corlanor®)
• Siponimod (Mayzent®)
• mTOR inhibitors (e.g. temsirolimus, sirolimus, everolimus) - verapamil increases blood levels of mTOR inhibitors and mTOR inhibitors increase blood levels of verapamil. In one study, co-administration of verapamil and sirolimus increased sirolimus Cmax and AUC by 130% and 120%, respectively. Plasma S (-) verapamil Cmax and AUC were both increased 50%. In another study, co-administration of verapamil with everolimus increased the Cmax and AUC of everolimus by 130% and 250%, respectively. Consider reducing doses of both medications when combining.
• Neuromuscular blocking agents - verapamil may potentiate the effects of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of one or both drugs when combining.
• Oxcarbazepine (Trileptal®) - verapamil may decrease oxcarbazepine levels by 20%
• P-glycoprotein substrates/inducers/inhibitors - may affect the metabolism of verapamil and vice versa
• Simvastatin (Zocor®) - simvastatin dose should not exceed 10 mg/day while taking verapamil
• Theophylline - verapamil may inhibit the clearance of theophylline and increase its levels

• Metabolism and clearance
• Amlodipine (Norvasc®, Katerzia®)
• CYP3A4 - Sensitive substrate and weak inhibitor


• Diltiazem (Cardizem®, Cartia®, Dilacor®, etc.)
• CYP2D6 - Weak inhibitor
• CYP3A4 - Substrate and inhibitor
• P-glycoprotein - Substrate and inhibitor


• Felodipine (Plendil®)
• CYP3A4 - Substrate
• P-glycoprotein - Substrate


• Isradipine (Dynacirc®)
• CYP3A4 - Substrate and inhibitor


• Nicardipine (Cardene®)
• CYP2D6 - Substrate and inhibitor
• CYP2C8 - Substrate and inhibitor
• CYP2C19 - Inhibitor
• CYP3A4 - Substrate and weak inhibitor
• P-glycoprotein - Inhibitor


• Nifedipine (Adalat®, Procardia®, Afeditab®)
• CYP3A4 - Substrate and inhibitor


• Nisoldipine (Sular®)
• CYP3A4 - Substrate


• Verapamil (Calan®, Verelan®, Isoptin®)
• CYP1A2 - Substrate and weak inhibitor
• CYP2D6 - Weak inhibitor
• CYP2C8 - Substrate
• CYP2C9 - Substrate
• CYP2C18 - Substrate
• CYP3A4 - Sensitive substrate and inhibitor
• P-glycoprotein - Substrate and inhibitor

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• PRICE ($) INFO

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• BIBLIOGRAPHY

• Manufacturer's package insert
• 2 - PMID 28827377 - Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents, Pediatrics (2017)
• 3 - PMID 24346990
• 4 - Nitromist® PI