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Drug Interactions between diltiazem and seladelpar

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

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Interactions between your drugs

Moderate

dilTIAZem seladelpar

Applies to: diltiazem and seladelpar

MONITOR: Concomitant use with a moderate to potent CYP450 3A4 inhibitor may significantly increase seladelpar's exposure in patients who are CYP450 2C9 poor metabolizers. The proposed mechanism is reduced clearance of seladelpar, which is primarily metabolized via CYP450 2C9 and to a lesser extent via CYP450 3A4 and 2C8. The activity of CYP450 2C9 is decreased in individuals with genetic variants of the isoenzyme. After a single dose of seladelpar (1 mg to 15 mg), dose-normalized systemic exposure (AUC) was 48% higher in CYP450 2C9 poor metabolizers (n=2) and 24% higher in CYP450 2C9 intermediate metabolizers (n=28) compared to normal metabolizers (n=84). However, the maximum plasma concentration (Cmax) was similar regardless of metabolizer status. These increases in AUC are not considered clinically relevant alone. Similarly, physiologically based pharmacokinetic model simulations predicted that coadministration with the potent CYP450 3A4 inhibitor itraconazole (300 mg daily) and the moderate CYP450 3A4 inhibitor erythromycin (500 mg 4 times daily) increased seladelpar's AUC by 34% and 24% and its Cmax by 18% and 14%, respectively. These changes were also not considered clinically relevant alone. However, use of a concomitant moderate to potent CYP450 3A4 inhibitor in a patient classified as a CYP450 2C9 poor metabolizer may result in clinically significant changes. While in vivo data specific to this scenario are lacking, coadministration with the moderate CYP450 2C9 and 3A4 inhibitor fluconazole (400 mg) increased the AUC of seladelpar (10 mg) by 2.4-fold, which was considered clinically significant.

MANAGEMENT: If concomitant use of a moderate to potent CYP450 3A4 inhibitor is clinically necessary during treatment with seladelpar, caution and determining the patient's CYP450 2C9 genotype may be advisable. Patients who are classified as poor CYP450 2C9 metabolizers should be monitored more closely for adverse reactions (e.g., abnormal liver function tests) during coadministration. Should adverse reactions occur, treatment with seladelpar may need to be held or permanently discontinued as indicated by the manufacturer. The labeling of the inhibitor should also be consulted as some inhibitors may continue to have effects on CYP450 3A4 even after the agent has been discontinued.

References (2)
  1. (2024) "Product Information. Livdelzi (seladelpar)." Gilead Sciences
  2. Cymabay Therapeutics Inc (2024) Center for drug evaluation and research. Application Number: 217899Orig1s000 integrated review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217899Orig1s000IntegratedR.pdf

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

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

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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.

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