Skip to main content

Drug Interactions between diltiazem and enfortumab vedotin

This report displays the potential drug interactions for the following 2 drugs:

Edit list (add/remove drugs)

Interactions between your drugs

Moderate

dilTIAZem enfortumab vedotin

Applies to: diltiazem and enfortumab vedotin

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations and effects of unconjugated monomethyl auristatin E (MMAE). Enfortumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE, a microtubule-disrupting agent believed to induce cell cycle arrest and apoptosis, via proteolytic cleavage. MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4. According to physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumab vedotin with ketoconazole, a dual P-gp and strong CYP450 3A4 inhibitor, is predicted to increase unconjugated MMAE peak plasma concentration (Cmax) by 15% and systemic exposure (AUC) by 38%, with no change in ADC exposure. In one case report, a 70-year-old man on stable doses of raltegravir and the CYP450 3A4 inhibitors darunavir and ritonavir, experienced severe toxicity after receiving 2 infusions of enfortumab vedotin (1.25 mg/kg on days 1 and 8 of his 28-day cycle). He was hospitalized with a severe generalized pruritic rash, thrush, mucositis, anorexia, diarrhea, acute kidney injury, and pancytopenia. Enfortumab vedotin was withheld and the patient returned to baseline after being treated with supportive measures. About a year later, he was rechallenged with enfortumab vedotin while on an antiretroviral regimen consisting of dolutegravir, doravirine, and valacyclovir. He was able to tolerate a reduced dose of 1 mg/kg, with mild expected toxicity including skin blisters and peripheral neuropathy. It is not known if, and to what extent, enfortumab vedotin may interact with less potent CYP450 3A4 inhibitors.

MANAGEMENT: Patients should be closely monitored for development or exacerbation of toxicities including, but not limited to skin reactions (maculopapular rash, pruritus, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, palmar-plantar erythrodysesthesia, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)); hyperglycemia (including diabetic ketoacidosis); pneumonitis or interstitial lung disease; peripheral neuropathy; and ocular disorders (dry eyes, keratitis, blurred vision, limbal stem cell deficiency). Refer to the product labeling for dose adjustment or discontinuation of therapy recommendations depending on the severity or Grade of the adverse reactions, should they occur.

References (7)
  1. Han TH, Gopal AK, Ramchandren R, et al. (2013) "CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies." J Clin Pharmacol, 53, p. 866-77
  2. (2023) "Product Information. Padcev (enfortumab vedotin)." Astellas Pharma Australia Pty Ltd
  3. (2023) "Product Information. Padcev (enfortumab vedotin)." Seagen Inc
  4. (2021) "Product Information. Padcev (enfortumab vedotin)." Seagen Canada Inc
  5. (2022) "Product Information. Padcev (enfortumab vedotine)." ASTELLAS PHARMA
  6. (2022) "Product Information. Padcev (enfortumab vedotin)." Astellas Pharma Ltd
  7. Azizi A, Houshyar R, Mar N (2022) "Use of enfortumab vedotin in an HIV-positive patient with urothelial carcinoma." J Oncol Pharm Pract, 28, p. 1226-9

Drug and food interactions

Moderate

dilTIAZem food

Applies to: diltiazem

MONITOR: Like many CNS-active agents, alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a study of ten healthy male volunteers, administration of a single 120 mg oral dose of immediate-release diltiazem in combination with 250 mL of grapefruit juice increased the diltiazem peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 22% and 20%, respectively, compared to administration with water. The time to reach Cmax (Tmax) and the terminal half-life were not affected, and no statistically significant differences in blood pressure and heart rate were observed during administration with grapefruit juice relative to water. In a different study, repeated administration of 200 mL of grapefruit juice at 0, 2, 4, 8 and 12 hours had no significant effect on the Cmax or AUC of a single 120 mg oral dose of diltiazem, but increased its half-life from 4.1 to 5.1 hours. The ratios for the N-demethyl and deacetyl metabolites to diltiazem were also not affected by grapefruit juice. However, because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

References (5)
  1. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  2. Sigusch H, Henschel L, Kraul H, Merkel U, Hoffmann A (1994) "Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects." Pharmazie, 49, p. 675-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  4. Christensen H, Asberg A, Holmboe AB, Berg KJ (2002) "Coadministration of grapefruit juice increases systemic exposure of diltiazem in healthy volunteers." Eur J Clin Pharmacol, 58, p. 515-520
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics."
Moderate

dilTIAZem food

Applies to: diltiazem

MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

References (14)
  1. Henry M, Kay MM, Viccellio P (1985) "Cardiogenic shock associated with calcium-channel and beta blockers: reversal with intravenous calcium chloride." Am J Emerg Med, 3, p. 334-6
  2. Moller IW (1987) "Cardiac arrest following intravenous verapamil combined with halothane anaesthesia." Br J Anaesth, 59, p. 522-6
  3. Oszko MA, Klutman NE (1987) "Use of calcium salts during cardiopulmonary resuscitation for reversing verapamil-associated hypotension." Clin Pharm, 6, p. 448-9
  4. Schoen MD, Parker RB, Hoon TJ, et al. (1991) "Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with intravenous calcium chloride pretreatment in normal subjects." Am J Cardiol, 67, p. 300-4
  5. O'Quinn SV, Wohns DH, Clarke S, Koch G, Patterson JH, Adams KF (1990) "Influence of calcium on the hemodynamic and anti-ischemic effects of nifedipine observed during treadmill exercise testing." Pharmacotherapy, 10, p. 247
  6. Woie L, Storstein L (1981) "Successful treatment of suicidal verapamil poisoning with calcium gluconate." Eur Heart J, 2, p. 239-42
  7. Morris DL, Goldschlager N (1983) "Calcium infusion for reversal of adverse effects of intravenous verapamil." JAMA, 249, p. 3212-3
  8. Guadagnino V, Greengart A, Hollander G, Solar M, Shani J, Lichstein E (1987) "Treatment of severe left ventricular dysfunction with calcium chloride in patients receiving verapamil." J Clin Pharmacol, 27, p. 407-9
  9. Luscher TF, Noll G, Sturmer T, Huser B, Wenk M (1994) "Calcium gluconate in severe verapamil intoxication." N Engl J Med, 330, p. 718-20
  10. Bar-Or D, Gasiel Y (1981) "Calcium and calciferol antagonise effect of verapamil in atrial fibrillation." Br Med J (Clin Res Ed), 282, p. 1585-6
  11. Lipman J, Jardine I, Roos C, Dreosti L (1982) "Intravenous calcium chloride as an antidote to verapamil-induced hypotension." Intensive Care Med, 8, p. 55-7
  12. McMillan R (1988) "Management of acute severe verapamil intoxication." J Emerg Med, 6, p. 193-6
  13. Perkins CM (1978) "Serious verapamil poisoning: treatment with intravenous calcium gluconate." Br Med J, 2, p. 1127
  14. Moroni F, Mannaioni PF, Dolara A, Ciaccheri M (1980) "Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning." Clin Toxicol, 17, p. 395-400

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

See also

Report options

Loading...
QR code containing a link to this page

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer