Calcium channel blockers

Calcium channel blockers See also p 243, p 238 p 889 s Amlodipine p 231 Clevidipine p 862 Felodipine p 232 Lercanidipine p 232 Nifedipine p 232 Nimodipine p 233 Non-dihydropyridines Diltiazem p 231 Verapamil p 234 Mode of action Block inward current of calcium into cells in vascular smooth muscle, myocardium and cardiac conducting system via L-type calcium channels. Act on coronary arteriolar smooth muscle to reduce vascular resistance and myocardial oxygen requirements, relieving angina symptoms. s act mainly on arteriolar smooth muscle to reduce peripheral vascular resistance and BP. They have minimal effect on myocardial cells. Non-dihydropyridines: diltiazem and verapamil act on cardiac and arteriolar smooth muscle. They reduce cardiac contractility, heart rate and conduction, with verapamil having the greater effect. Diltiazem has a greater effect on arteriolar smooth muscle than verapamil. Myasthenia-like neuromuscular disease calcium channel blockers may increase risk of muscle weakness and respiratory depression (most case reports with verapamil). Cardiovascular Contraindicated in cardiogenic shock. Calcium channel blockers may further depress myocardial function in patients with systolic heart failure; diltiazem and verapamil are contraindicated (unless under specialist supervision); use dihydropyridines with caution. may worsen when starting a dihydropyridine, increasing the dose or stopping abruptly (possibly as a result of reflex cardiac stimulation, which increases heart rate and contractility); less likely with long-acting dihydropyridines, controlled release products or use with a betablocker. In aortic stenosis, dihydropyridines may cause coronary hypoperfusion and systemic hypotension. Hepatic May require dose reduction in impairment. Elderly Start treatment at a lower dose. Pregnancy Australian category C. Nifedipine is used to suppress preterm labour and for hypertension in pregnancy. Breastfeeding Limited data for diltiazem, nifedipine, nimodipine and verapamil but they appear safe to use. No data available for amlodipine, felodipine or lercanidipine. Most listed adverse effects occur with all calcium channel blockers. vary between the calcium channel blockers according to their relative effects on vascular, myocardial and conducting tissue. s have more pronounced vasodilatory effects than diltiazem and verapamil. Verapamil, and to a lesser extent, diltiazem, reduce cardiac contractility, heart rate and conduction. Common (>1%) nausea, vasodilatory effects, including headache, flushing, dizziness, hypotension, peripheral oedema (below) Infrequent (0.1 1%) palpitations, tachycardia and chest pain with dihydropyridines, see above; orthostatic hypotension, abdominal pain, dyspepsia, diarrhoea, constipation (common with verapamil), gingival hyperplasia (usually reversible), polyuria (including nocturia), tinnitus, rash, itch Rare (<0.1%) taste disturbance, elevation of hepatic enzymes, extrapyramidal reactions, gynaecomastia, hypersensitivity reactions, including Stevens-Johnson syndrome, exfoliative dermatitis, angioedema and vasculitis Peripheral oedema s commonly cause peripheral oedema due to redistribution of extracellular fluid (rather than fluid retention); this does not respond to treatment with diuretics, which may put patient at risk of volume depletion. Comparative information See Table 6 1 Comparison of calcium channel blockers p 231 Practice points vasodilatory adverse effects usually subside with continued treatment (may require dose reduction) www.amh.net.au AMH 2014

Table 6 1 Comparison of calcium channel blockers Drug Forms Doses/day Comments s amlodipine hypertension tablet 1 felodipine hypertension CR tablet 1 lercanidipine hypertension tablet 1 nifedipine nimodipine Non-dihydropyridines diltiazem verapamil CR = controlled release hypertension preterm labour (p 747) aneurysmal subarachnoid haemorrhage hypertension (CR) AF hypertension SVT, AF, atrial flutter prevention of cluster headache (p 703) tablet, CR tablet tablet, injection tablet, CR capsule tablet, CR tablet/capsule, injection 2 (tablet) 1 (CR) 6 (tablet) continuous infusion 3 or 4 (tablet) 1 (CR) 2 or 3 (tablet) 1 (CR) Calcium channel blockers effect on arterial pressure is similar to that of other antihypertensives may be used with beta-blockers in stable angina minimal effect on cardiac conduction system and myocardial contractility use with caution in systolic heart failure (amlodipine or felodipine may be considered if necessary) peripheral vasodilation causes adverse effects, eg peripheral oedema, flushing, headache mainly selective for the cerebral vasculature used post-acs and in stable angina when beta-blockers are contraindicated or not tolerated reduce heart rate and depress myocardial contractility (verapamil more than diltiazem) contraindicated in systolic heart failure less peripheral vasodilation than dihydropyridines Amlodipine p 889, Amlodipine p 889 (includes combinations with olmesartan (p 257), olmesartan (p 257) with hydrochlorothiazide, telmisartan (p 258), valsartan (p 258), valsartan (p 258) with hydrochlorothiazide) Combination with atorvastatin Treatment of patients stabilised on atorvastatin and at least 5 mg of amlodipine daily Combination with perindopril See Perindopril p 253 if already maintained on perindopril and amlodipine Stable coronary heart disease if already maintained on perindopril and amlodipine Adult, child >6 years, initially 2.5 5 mg once daily, increasing if necessary after at least 1 2 weeks to a maximum of 10 mg once daily. Child <6 years, initially 0.1 0.2 mg/kg once daily, increasing if necessary over 1 2 weeks to a maximum of 0.4 mg/kg or 10 mg once daily. Elderly, hepatic impairment Adult, initially 2.5 mg once daily. Combination with atorvastatin For additional information see Atorvastatin p 290 Adult, 1 tablet once daily (of any strength). tab, 5 mg, 30, Amlodipine (DO, GQ, RZ), PBS tab, 5 mg (scored), 30, Amlo (ZP), Nordip (AL), Norvapine (PF), Norvasc (PF), Ozlodip (RA), Amlodipine (CH, PF, SZ, TA, TW, TX), PBS tab, 10 mg, 30, Amlodipine (CH, DO, GQ, RZ, TW, TX), PBS tab, 10 mg (scored), 30, Amlo (ZP), Nordip (AL), Norvapine (PF), Norvasc (PF), Ozlodip (RA), Amlodipine (PF, SZ, TA), PBS Combination products tab, amlodipine 5 mg, atorvastatin 10 mg, 30, Cadatin 5/10 (PF), Caduet 5/10 (PF), PBS-R 1 tab, amlodipine 5 mg, atorvastatin 20 mg, 30, Cadatin 5/20 (PF), Caduet 5/20 (PF), PBS-R 1 tab, amlodipine 5 mg, atorvastatin 40 mg, 30, Cadatin 5/40 (PF), Caduet 5/40 (PF), PBS-R 1 tab, amlodipine 5 mg, atorvastatin 80 mg, 30, Cadatin 5/80 (PF), Caduet 5/80 (PF), PBS-R 1 tab, amlodipine 10 mg, atorvastatin 10 mg, 30, Cadatin 10/10 (PF), Caduet 10/10 (PF), PBS-R 1 tab, amlodipine 10 mg, atorvastatin 20 mg, 30, Cadatin 10/20 (PF), Caduet 10/20 (PF), PBS-R 1 tab, amlodipine 10 mg, atorvastatin 40 mg, 30, Cadatin 10/40 (PF), Caduet 10/40 (PF), PBS-R 1 tab, amlodipine 10 mg, atorvastatin 80 mg, 30, Cadatin 10/80 (PF), Caduet 10/80 (PF), PBS-R 1 1 patients with hypertension and/or angina meeting the criteria in the PBS General Statement for Lipid-Lowering Drugs Diltiazem Non-dihydropyridine See also Atrial fibrillation p 276 p 889, Diltiazem p 889 (controlled release) Accepted AF or atrial flutter (ventricular rate control) AMH 2014 www.amh.net.au

Cardiovascular Contraindicated in severe bradycardia, sick sinus syndrome, second- or third-degree atrioventricular block (without pacemaker); hypotension (systolic BP <90 mm Hg); AF or atrial flutter associated with an accessory conduction pathway (eg Wolff-Parkinson- White syndrome). Diltiazem may worsen first-degree atrioventricular block, but risk is less than with verapamil. Other drugs Treatment with drugs that slow cardiac conduction, cause bradycardia or arrhythmias may potentiate the adverse cardiac effects of diltiazem; use combinations, eg with beta-blockers, carefully and monitor cardiac function. Common (>1%) bradycardia Infrequent (0.1 1%) atrioventricular block, development or worsening of heart failure, AF, atrial flutter Conventional product, adult, initially 30 mg 3 or 4 times daily; increase as required; maximum 360 mg daily in 3 or 4 divided doses. Controlled release products, adult, initially 180 mg once daily; increase as required up to 360 mg once daily. Controlled release products, adult, initially 180 240 mg once daily; increase as required up to 360 mg once daily. Dose conversion When converting to controlled release product, use the strength nearest the total daily dose of conventional product. Swallow the capsules whole; do not open or chew them. tab, 60 mg (scored), 90, Cardizem (AV), Coras (AL), Dilzem (TA), Vasocardol (AV), Diltiazem (CH, SZ, TW, TX), PBS cap, 180 mg (controlled release), 30, Cardizem CD (AV), Vasocardol CD (AV), Diltiazem CD (SZ, TX), PBS cap, 240 mg (controlled release), 30, Cardizem CD (AV), Vasocardol CD (AV), Diltiazem CD (SZ, TX), PBS cap, 360 mg (controlled release), 30, Cardizem CD (AV), Vasocardol CD (AV), Diltiazem CD (SZ), PBS Felodipine p 889, Felodipine p 890 (includes combination with ramipril (p 254)) Adult, initially 5 mg once daily; maintenance dose 5 10 mg once daily; maximum dose 20 mg once daily. Elderly, hepatic impairment Adult, initially 2.5 mg once daily. Swallow tablet whole; do not crush or chew. Avoid grapefruit juice as it may increase the risk of side effects with felodipine. tab, 2.5 mg (controlled release), 30, Felodur ER (AP), Fendex ER (AL), Plendil ER (AP), PBS tab, 5 mg (controlled release), 30, Felodil XR (AS), Felodur ER (AP), Fendex ER (AL), Plendil ER (AP), PBS tab, 10 mg (controlled release), 30, Felodil XR (AS), Felodur ER (AP), Fendex ER (AL), Plendil ER (AP), PBS Lercanidipine p 889, Lercanidipine p 890 (includes combination with enalapril (p 252)) Treatment with cyclosporin manufacturer contraindicates combination. Renal Use cautiously in severe impairment (manufacturer contraindicates use when CrCl <12 ml/minute). Hepatic Use cautiously in severe impairment (manufacturer contraindicates use). Adult, initially 10 mg once daily; if necessary, increase after at least 2 weeks. Maximum 20 mg once daily. This medicine is absorbed best if you take it at least 15 minutes before a meal. tab, 10 mg (scored), 28, Ledip (RA), Lercadip (AB), Lercan (AB), Zanidip (AB), Zircol (AL), Lercanidipine (CH, GQ, SZ, TX, TW), PBS tab, 20 mg, 28, Lercadip (AB), Lercan (AB), Zanidip (AB), PBS tab, 20 mg (scored), 28, Ledip (RA), Zircol (AL), Lercanidipine (CH, GQ, SZ, TX, TW), PBS Nifedipine p 889, Nifedipine p 890 Accepted Preterm labour (see Nifedipine p 747) Severe GI stenosis use controlled release tablet cautiously; tablet is non-deformable. www.amh.net.au AMH 2014

Adult Conventional tablet, initially 10 20 mg twice daily, increase to 20 40 mg twice daily. Controlled release tablet, initially 20 mg or 30 mg once daily, increase to a maximum of 90 mg once daily (angina) or 120 mg once daily (hypertension). To change from conventional tablets to controlled release, choose the nearest daily dose initially, then adjust according to response, eg if converting from 20 mg twice daily conventional tablets, choose 30 mg once daily controlled release. Child Initially 0.25 0.5 mg/kg daily in 1 or 2 doses depending on product used; maximum 3 mg/kg (not to exceed 120 mg daily in 1 or 2 doses). See above for changing from conventional to controlled release tablets. Conventional tablet: do not stop taking this medicine suddenly unless your doctor tells you to. Controlled release tablet: swallow whole; do not crush or chew. Avoid grapefruit juice as it may increase the risk of side effects with nifedipine. Practice points if using nifedipine without a beta-blocker to treat angina, controlled release tablets are more appropriate than conventional tablets as they do not appear to worsen angina tab, 10 mg, 60, Adalat (BN), Adefin 10 (AL), PBS tab, 20 mg, 60, Adalat (BN), Adefin 20 (AL), Nifehexal (SZ), PBS tab, 20 mg (controlled release), 30, Adalat Oros (BN), PBS tab, 30 mg (controlled release), 30, Adalat Oros (BN), Addos XR (AS), Adefin XL (AL), Nifedipine (AS), PBS tab, 60 mg (controlled release), 30, Adalat Oros (BN), Addos XR (AS), Adefin XL (AL), Nifedipine (AS), PBS Nimodipine p 889, Nimodipine p 890 Mode of action Unclear; may reduce influx of calcium into neurones and vascular smooth muscle cells; prevents ischaemic damage from cerebral vasospasm. Prevention and treatment of ischaemic neurological deficits following aneurysmal subarachnoid haemorrhage Ethanol content infusing at 2 mg/hour for 24 hours will deliver about 50 g ethanol. Cerebral oedema or severely raised intracranial pressure manufacturer suggests cautious use with close monitoring. Hypotension risk of aggravation. Other drugs The manufacturer contraindicates use of oral nimodipine with rifampicin, phenobarbitone, phenytoin or carbamazepine, as treatment with AMH 2014 drugs that affect CYP3A4 may affect nimodipine s clearance and activity, see Table B 4 Drugs and CYP enzymes p 974. Treatment with disulfiram or metronidazole may cause reactions with ethanol (p 866) as nimodipine infusion contains ethanol (about 25%). Hepatic Requires lower dosage in hepatic impairment; monitor BP and pulse rate. Rare (<0.1%) ileus Refer to local protocols. Start nimodipine as soon as possible or within 4 days of subarachnoid haemorrhage; duration of treatment usually up to 21 days. Oral Adult, 60 mg every 4 hours. Hepatic impairment, 30 mg every 4 hours. IV infusion Co-infuse with a compatible solution, eg glucose 5%, sodium chloride 0.9%, dextran 40. Adult >70 kg, 1 mg/hour for the first 2 hours; give co-infusion solution at a rate of 20 ml/hour. If well tolerated (ie BP stable), increase dosage up to 2 mg/hour (with an increase in the rate of coinfusion solution to 40 ml/hour). Adult <70 kg or labile BP or hepatic impairment, initially 0.5 mg/hour; give co-infusion solution at a rate of 10 ml/hour. Maximum 1 mg/hour. Administration advice Give infusion via a central catheter using an infusion pump. Do not use PVC giving sets because of the loss of nimodipine and contamination by plasticisers; use polyethylene sets. Tablets: avoid grapefruit juice as it may increase the risk of side effects with nimodipine. Practice points high morbidity and mortality after aneurysmal subarachnoid haemorrhage is associated with neurological damage from bleeding (initial and recurrent) and cerebral ischaemia due to reactive vasospasm; early medical treatment aims to prevent vasospasm and re-bleeding and to stabilise the patient for surgery tab, 30 mg, 100, Nimotop (BN) inj, 0.2 mg/ml, 50 ml, 5, Nimotop (BN) www.amh.net.au

Verapamil Non-dihydropyridine See also Tachyarrhythmias p 276, Migraine p 701 p 889, Verapamil p 890 SVT AF or atrial flutter (ventricular rate control), including combination with trandolapril Accepted Prophylaxis of cluster headache Cardiovascular Contraindicated in severe bradycardia, sick sinus syndrome, second- or third-degree atrioventricular block (without pacemaker); hypotension (systolic BP <90 mm Hg); AF or atrial flutter associated with an accessory conduction pathway (eg Wolff- Parkinson-White syndrome), wide complex tachycardia or ventricular tachycardia. Verapamil may worsen first-degree atrioventricular block (greater risk than with diltiazem). Other drugs Treatment with antiarrhythmics increases risk of heart failure, bradycardia and proarrhythmic effect; avoid such combinations if possible. Treatment with drugs that cause bradycardia may further decrease heart rate and cause hypotension; monitor cardiac function. Treatment with beta-blockers increases risk of severe bradycardia, heart block and left ventricular failure; avoid combination (unless under specialist supervision). The manufacturer of dabigatran contraindicates combination with verapamil in certain circumstances, see Dabigatran p 314. Common (>1%) constipation, bradycardia Infrequent (0.1 1%) atrioventricular block, development or worsening of heart failure Rare (<0.1%) ileus Conventional tablet, adult, initially 80 mg 2 or 3 times daily; maintenance dose, 160 mg 2 or 3 times daily. Controlled release capsule, adult, initially 160 240 mg once daily, increasing if necessary to a maximum of 480 mg once daily. Controlled release tablet, adult, initially 180 240 mg once daily, increasing if necessary to a maximum of 240 mg twice daily. Give daily doses >240 mg in 2 doses. SVT, AF or atrial flutter IV injection Refer to local protocols. Adult, 2.5 10 mg over 2 3 minutes. Oral Conventional tablet, adult, initially 40 80 mg 2 or 3 times daily; maintenance dose, 160 mg 2 or 3 times daily. Controlled release capsule, initially 160 240 mg once daily, increasing if necessary to a maximum of 480 mg once daily. Controlled release tablet, initially 120 240 mg once daily, increasing if necessary to a maximum of 240 mg twice daily. Give daily doses >240 mg in 2 doses. Conventional tablet, adult, initially 80 mg 2 or 3 times daily; maintenance dose, 160 mg 2 or 3 times daily. Controlled release capsule, adult, initially 160 240 mg once daily, increasing if necessary to a maximum of 480 mg once daily. Controlled release tablet, adult, initially 120 180 mg once daily; usual maintenance dose 240 mg once daily; increase if necessary to a maximum of 240 mg twice daily. Give daily doses >240 mg in 2 doses. Controlled release verapamil with trandolapril For additional information see Trandolapril p 255 Do not start treatment with these products; it is important to titrate the dose of both drugs first. Adult, 1 tablet once daily (of either strength). Prophylaxis of cluster headache Use under specialist supervision; individualise dose according to response. Monitor ECG regularly. Adult, initially 240 mg daily; usual range 240 960 mg daily in 1 4 doses depending on formulation. Administration advice Give IV injections slowly under continuous ECG and BP monitoring over 2 3 minutes; rapid IV administration may result in hypotension, bradycardia, heart block and asystole. Controlled release capsules: swallow whole (do not crush or chew), or you can open the capsule and sprinkle the contents in soft food; take immediately without chewing, followed by a glass of water. Verapamil may increase the effects of alcohol so that you are more easily affected and the effects last longer. Limit your alcohol intake until you know whether you are affected like this. Avoid grapefruit juice as it may increase the risk of side effects with verapamil. tab, 40 mg, 100, Isoptin (AB), PBS tab, 40 mg (scored), 100, Anpec (AL), PBS tab, 80 mg (scored), 100, Anpec (AL), Isoptin (AB), PBS tab, 120 mg (scored), 100, Isoptin (AB), PBS tab, 180 mg (controlled release, scored), 30, Cordilox SR (AB), Isoptin SR (AB), PBS tab, 240 mg (controlled release, scored), 30, Cordilox SR (AB), Isoptin SR (AB), PBS cap, 160 mg (controlled release), 30, Veracaps SR (AS), PBS cap, 240 mg (controlled release), 30, Veracaps SR (AS), PBS inj, 2.5 mg/ml, 2 ml, 5, Isoptin (AB), PBS www.amh.net.au AMH 2014

Combination products tab, verapamil (controlled release) 180 mg, trandolapril 2 mg, 28, Tarka 2/180 (AB), PBS-R 1 tab, verapamil (controlled release) 240 mg, trandolapril 4 mg, 28, Tarka 4/240 (AB), PBS-R 1 1 hypertension inadequately controlled by either drug alone AMH 2014 www.amh.net.au