Calcium channel blocker (benzothiazepine)
Diltiazem is a calcium channel blocker, used to lower blood pressure and to treat angina pectoris. It reduces the work of the heart and dilates blood vessels.
Also known as: Diltiazem, Tiazac
Tacrolimus + diltiazem: diltiazem reduces tacrolimus metabolism, increasing its levels and the nephrotoxicity risk (QUADRO 2).
Diltiazem inhibits CYP3A4, the main metabolic pathway of tacrolimus, increasing its plasma concentrations and the risk of nephrotoxicity. QUADRO 2 of Annex 7 records this interaction in the calcium channel blocker section. The rise in levels usually appears within the first days of starting diltiazem; stopping diltiazem has the opposite effect. The risk is higher in renal or hepatic transplant patients with a narrow therapeutic margin. Monitor tacrolimus levels and creatinine when starting, adjusting or stopping diltiazem, and consider reducing the tacrolimus dose (typically 30-50%).
Tacrolimus + diltiazem: CYP3A4 inhibition by diltiazem — increased tacrolimus; reduce dose and monitor levels and renal function.
Diltiazem (CYP3A4/P-gp inhibitor) reduces tacrolimus metabolism — increased concentrations and toxicity (QUADRO 2, Calcium channel blockers: "Tacrolimus: reduced tacrolimus metabolism with diltiazem, nicardipine, verapamil").
Monitor renal function and tacrolimus levels.
Elevated tacrolimus levels and rising creatinine after starting diltiazem.
Monitor tacrolimus levels when starting diltiazem; reduce the dose as needed.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 7, QUADRO 2 (Calcium channel blockers)
Grapefruit juice inhibits intestinal CYP3A4 and increases systemic exposure to diltiazem (a study in healthy volunteers documents increased exposure with coadministration). Diltiazem is metabolised by CYP3A4.
Avoid grapefruit juice during treatment; if intake is unavoidable, monitor effects (hypotension, bradycardia).
DailyMed/FDA (NIH/NLM) — approved Cardizem (diltiazem) label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3e7ecef-f360-4987-a4f5-933214130ab2 ; PubMed: Coadministration of grapefruit juice increases systemic exposure of diltiazem (Bailey et al.)
TIAZAC label (CONTRAINDICATIONS): contraindicated in sick sinus syndrome except in the presence of a functioning ventricular pacemaker, and in second-/third-degree AV block except with a functioning pacemaker.
Contraindicated in conduction disorders without a pacemaker; use with caution in first-degree AV block.
DailyMed/FDA (NIH/NLM) — Diltiazem (TIAZAC), CONTRAINDICATIONS: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c567fe7e-887e-4291-a0d1-2dd3f25cbf25
Reduce the dose in hepatic impairment.
Reduce the dose in hepatic impairment.
Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 3, Drugs and hepatic impairment: Reduce the dose in hepatic impairment.
TIAZAC label (CONTRAINDICATIONS): contraindicated in patients with severe hypotension (less than 90 mm Hg systolic).
Contraindicated in severe hypotension (< 90 mm Hg systolic).
DailyMed/FDA (NIH/NLM) — Diltiazem (TIAZAC), CONTRAINDICATIONS: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c567fe7e-887e-4291-a0d1-2dd3f25cbf25
TIAZAC label (Pregnancy): reproduction studies in mice, rats and rabbits (4-6× the upper limit of the optimum range, 480 mg/day) with embryo-fetal lethality and propensity for skeletal, heart, retina and tongue abnormalities; no well-controlled studies in pregnant women — use only if the potential benefit justifies the risk.
Use only if the potential benefit justifies the risk (embryo-fetal lethality and abnormalities in animals).
No specific breastfeeding data in the label; assess risk/benefit.
Not applicable (no specific contraception requirements in the label).
DailyMed/FDA (NIH/NLM) — approved Diltiazem label (TIAZAC), Pregnancy section: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c567fe7e-887e-4291-a0d1-2dd3f25cbf25 ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 2, Drugs and Breastfeeding: Significant amounts in milk. Avoid unless there is no safe alternative.
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Calcium channel blocker (benzothiazepine): inhibition of calcium influx in the myocardium and vascular smooth muscle — reduced contractility, AV conduction and vascular resistance; antihypertensive and antianginal (TIAZAC label).
L-type calcium channel blockade; P-gp and CYP3A4 substrate and inhibitor.
Well absorbed from the GI tract; oral bioavailability of ~40% (immediate-release formulation); only 2-4% of unchanged drug in urine (Pharmacokinetics and Metabolism).
Extensive first-pass hepatic metabolism; CYP3A4 substrate and inhibitor — interacts with midazolam/triazolam, cyclosporine, carbamazepine and statins (Drug Interactions).
Plasma elimination half-life of approximately 3.0-4.5 hours (immediate-release formulation).
