Trandolapril + Verapamil

Oral
Hypertension

Should be taken with food.

Cardiogenic shock, hypotension (systolic blood pressure <90 mm Hg), heart failure, 2nd- or 3rd-degree AV block (unless pacemaker is fitted), sick-sinus syndrome, tachycardia, severe left ventricular dysfunction, atrial flutter or atrial fibrillation, accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes), hereditary/idiopathic angioedema, history of angioedema related to previous ACE inhibitor treatment. Pregnancy, lactation. Concomitant use with aliskiren in patient with diabetes mellitus or renal impairment. Concomitant use with neprilysin inhibitor (e.g. sacubitril).

Patient with aortic stenosis, bradycardia or 1st-degree AV block, attenuated neuromuscular transmission, collagen vascular disease, ischaemic heart disease, cerebrovascular disease, hypertrophic cardiomyopathy, unstented unilateral or bilateral renal artery stenosis. Patients on haemodialysis and dietary salt restriction. Renal and hepatic impairment.

Significant: Hypotension with or without syncope, cerebrovascular accident, conduction abnormalities (e.g. 1st-degree AV block, bradycardia), cough, neutropaenia with myeloid hypoplasia, agranulocytosis, anaemia, thrombocytopaenia, elevated transaminases, hyperkalaemia, increased BUN and serum creatinine, proteinuria, taste disturbance. Rarely, rash, photosensitivity.
Gastrointestinal disorders: Constipation, nausea.
General disorders and administration site conditions: Chest pain, fatigue.
Infections and infestations: Influenza.
Metabolism and nutrition disorders: Hyperlipidaemia, peripheral oedema.
Musculoskeletal and connective tissue disorders: Back pain, joint pain, pain in extremities.
Nervous system disorders: Dizziness, headache, dyspnoea.
Respiratory, thoracic and mediastinal disorders: Upper respiratory tract infection and congestion, bronchitis.
Potentially Fatal: Anaphylactic reactions, angioedema, hepatotoxicity (e.g. fulminant hepatic necrosis).

PO: D

This drug may cause hypotension, if affected, do not drive or operate machinery.

Monitor blood pressure, heartrate, BUN, serum creatinine, electrolytes, and CBC with differential periodically.

Symptoms: Severe hypotension, bradycardia, AV block and asystole, negative inotropy, shock, stupor, electrolyte disturbance, renal failure, tachycardia, palpitations, dizziness, anxiety and cough. Management: Supportive treatment. Consider gastric lavage and administer activated charcoal. May administer dopamine or dobutamine for inotropic support; IV angiotensin II infusion or catecholamines for hypotension. Maintain adequate circulation volume with plasma replacements.

Trandolapril: Additive hyperkalaemic effect with K-sparing diuretics, K-containing salt substitutes and supplements. May increase serum levels and toxicity of lithium. May increase hypoglycaemic effect of antidiabetics. Increased risk of renal function deterioration with NSAIDs.
Verapamil: May increase plasma level with CYP3A4 inhibitors (e.g. erythromycin, ritonavir), cimetidine. May decrease plasma level with CYP3A4 inducers (e.g. rifampicin), phenobarbital, sulfinpyrazone. Increased risk of bleeding with aspirin. May increase bradycardic and hypotensive effect with telithromycin. Increased AV blocking effect with clonidine. May increase plasma level of cardiac glycosides (e.g. digoxin, digitoxin), β-blockers (e.g. propranolol, metoprolol), α-blockers (e.g. terazosin, prazosin), immunosuppressants (e.g. sirolimus, ciclosporin, tacrolimus, everolimus), lipid lowering agents (e.g. simvastatin, atorvastatin), colchicines, quinidine, carbamazepine, imipramine, glibenclamide, doxorubicin, midazolam, buspirone, almotriptan, theophylline. May potentiate hypotensive effect with diuretics, antihypertensives, vasodilators. May increase neurotoxic effect of lithium.
Potentially Fatal: Increased risk of hypotension, hyperkalaemia, and changes in renal function (including acute renal failure) with aliskiren in diabetic patients. Increased risk of angioedema with sacubitril and racedotril.

May increase blood ethanol levels. May increase plasma level of verapamil with grapefruit juice.

Description: Trandolapril, a prodrug of trandolaprilat, competitively inhibits ACE from converting angiotensin I to angiotensin II (a potent vasoconstrictor) resulting in increased plasma renin activity and reduced aldosterone (a hormone that causes water and Na retention) secretion. This promotes vasodilation and BP reduction.
Verapamil inhibits entry of Ca ions into the slow channels or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarisation. It relaxes coronary vascular smooth muscle and coronary vasodilation, increases myocardial oxygen delivery, and slows automaticity and AV node conduction.
Onset: Trandolapril: 1-2 hours.
Verapamil: Within 1-2 hours (oral); 3-5 minutes (IV).
Duration: Verapamil: 6-8 hours (oral); 0.5-6 hours (IV).
Pharmacokinetics:
Absorption: Trandolapril: Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 70% (trandolaprilat); approx 10% (trandolapril). Time to peak plasma concentrations: 4-10 hours (trandolaprilat).
Verapamil: Well absorbed from the gastrointestinal tract. Bioavailability: 20-35% (oral). Time to peak plasma concentration: 1-2 hours (oral).
Distribution: Trandolapril: Volume of distribution: Approx 18 L. Plasma protein binding: >80% (trandolapril); 65-94% (trandolaprilat).
Verapamil: Crosses the placenta; enters breast milk. Volume of distribution: 3.89 L/kg. Plasma protein binding: Approx 90%.
Metabolism: Trandolapril: Metabolised in the liver via hydrolysis to its active metabolite, trandolaprilat and to some inactive metabolites.
Verapamil: Extensively metabolised in the liver by CYP isoenzymes to its primary metabolite, norverapamil, and to at least 12 metabolites.
Excretion: Trandolapril: Via urine (approx 33%); faeces (approx 66%). Elimination half-life: Approx 6 hours (trandolapril); 22.5 hours (trandolaprilat).
Verapamil: Mainly via urine (approx 70% as metabolites, 3-4% as unchanged drug); faeces (approx 16%). Elimination half-life: Approx 12 hours (extended-release).

Source: National Center for Biotechnology Information. PubChem Database. Trandolapril, CID=5484727, https://pubchem.ncbi.nlm.nih.gov/compound/Trandolapril (accessed on Jan. 23, 2020)

Source: National Center for Biotechnology Information. PubChem Database. Verapamil, CID=2520, https://pubchem.ncbi.nlm.nih.gov/compound/Verapamil (accessed on Jan. 23, 2020)

Store between 15-25°C.

ACE Inhibitors/Direct Renin Inhibitors / Calcium Antagonists

C09BB10 - trandolapril and verapamil ; Belongs to the class of ACE inhibitors and calcium channel blockers. Used in the treatment of cardiovascular diseases.

Anon. Trandolapril and Verapamil. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/03/2018.

Anon. Trandolapril. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/03/2018.

Anon. Verapamil. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/03/2018.

Buckingham R (ed). Trandolapril. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/03/2018.

Buckingham R (ed). Verapamil Hydrochloride. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/03/2018.

McEvoy GK, Snow EK, Miller J et al (eds). Trandolapril. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 05/03/2018.

McEvoy GK, Snow EK, Miller J et al (eds). Verapamil Hydrochloride. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 05/03/2018.

Trandolapril and Verapamil Hydrochloride ER Film-Coated, Extended Release (Greenstone LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 05/03/2018.