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Drug Interactions between etrasimod and Tofranil

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

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Interactions between your drugs

Major

imipramine etrasimod

Applies to: Tofranil (imipramine) and etrasimod

MONITOR CLOSELY: Due to the risk of bradycardia and atrioventricular (AV) block, the risk of QT prolongation and torsade de pointes arrhythmia may be increased during initiation of etrasimod treatment in patients receiving drugs that prolong the QT interval. Etrasimod may cause a transient decrease in heart rate during initiation of therapy, in the randomized placebo-controlled studies UC-1 and UC-2, following an initial dose of 2 mg, the greatest mean decrease from baseline in heart rate of 7.2 bpm occurred at hour 2 (UC-2) and hour 3 (UC-1) on day 1. In studies UC-2 and UC-3, bradycardia was reported on day 1 in 2.9% of patients on etrasimod compared to none in the placebo group. On Day 2, bradycardia was reported in 1 patient (0.3%) treated with etrasimod compared to none in the placebo group. Overall, subjects who experienced bradycardia were generally asymptomatic. Few subjects experienced symptoms such as dizziness, and these symptoms resolved without intervention. Initiation of etrasimod treatment has also resulted in transient AV conduction delays. In the UC-1 study, after 2 mg of etrasimod on day 1 of treatment, first- or second-degree Mobitz type I AV blocks were observed in 0.7% of etrasimod- treated subjects compared to none in the placebo group. In studies UC-2 and UC-3, Mobitz type I AV blocks were observed in 0.8% of etrasimod-treated subjects compared to none in the placebo group. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Because bradycardia and AV block are recognized risk factors for QT prolongation and torsade de pointes arrhythmia, advice from a cardiologist should be sought if treatment with etrasimod is considered in patients with significant QT prolongation (QTcF greater than 450 msec in males or 470 msec in females), patients on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction, or in patients with arrhythmias requiring treatment with Class 1a or Class III antiarrhythmic agents.

References

  1. (2023) "Product Information. Velsipity (etrasimod)." Pfizer U.S. Pharmaceuticals Group

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Drug and food interactions

Moderate

etrasimod food

Applies to: etrasimod

GENERALLY AVOID: Coadministration with moderate inhibitors of CYP450 3A4 such as grapefruit juice may increase the plasma concentrations of etrasimod in patients that are poor CYP450 2C9 metabolizers (e.g., *2/*3, *3/*3). Etrasimod is primarily metabolized by the CYP450 3A4, CYP450 2C8, and CYP450 2C9 isoenzymes. Pharmacokinetic studies reported that no single enzyme appears to dominate etrasimod elimination and that the involvement of multiple CYP450 isoforms reduces the likelihood of drug-drug interactions when only a single CYP450 isoform is strongly or moderately inhibited by a coadministered drug. In clinical drug interaction studies, when etrasimod was administered with the dual moderate CYP450 2C9 and 3A4 inhibitor fluconazole at steady-state levels, etrasimod systemic exposure (AUC) increased by 84%. However, concomitant use with the potent CYP450 3A4 inhibitor itraconazole increased the AUC of etrasimod by 32%, which was not considered by the manufacturer to be clinically significant. The effect on etrasimod systemic exposure in CYP450 2C9 intermediate metabolizers (e.g., *1/*2, *1/*3, *2/*2) treated with less potent CYP450 3A4 inhibitors is not known. Increased plasma concentrations of etrasimod may increase the risk of infection, bradyarrhythmia, AV conduction delays, elevated transaminase levels, and macular edema.

MANAGEMENT: Until further information is available, the consumption of grapefruit and grapefruit juice in combination with moderate to potent CYP450 2C8 inhibitors such as gemfibrozil should be avoided or limited during treatment with etrasimod in patients who are poor CYP450 2C9 metabolizers. Caution is recommended with grapefruit products consumption in patients who are intermediate CYP450 2C9 metabolizers. Patients should be advised to notify their physician if they experience potential adverse effects of etrasimod.

References

  1. (2023) "Product Information. Velsipity (etrasimod)." Pfizer U.S. Pharmaceuticals Group
  2. Lee C, Taylor C, Tang Y, Caballero LV, shan k, Randle A, Grundy JS (2022) Effects of fluconazole, gemfibrozil, and rifampin on the pharmacokinetics, safety, and tolerability of etrasimod https://gut.bmj.com/content/71/Suppl_1/A142.1

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Moderate

imipramine food

Applies to: Tofranil (imipramine)

GENERALLY AVOID: Concomitant use of ethanol and a tricyclic antidepressant (TCA) may result altered TCA plasma levels and efficacy, and additive impairment of motor skills, especially driving skills. Acute ethanol ingestion may inhibit TCA metabolism, while chronic ingestion of large amounts of ethanol may induce hepatic TCA metabolism.

MANAGEMENT: Patients should be advised to avoid alcohol during TCA therapy. Alcoholics who have undergone detoxification should be monitored for decreased TCA efficacy. Dosage adjustments may be required.

References

  1. Dorian P, Sellers EM, Reed KL, et al. (1983) "Amitriptyline and ethanol: pharmacokinetic and pharmacodynamic interaction." Eur J Clin Pharmacol, 25, p. 325-31
  2. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  3. Sandoz M, Vandel S, Vandel B, Bonin B, Allers G, Volmat R (1983) "Biotransformation of amitriptyline in alcoholic depressive patients." Eur J Clin Pharmacol, 24, p. 615-21
  4. Ciraulo DA, Barnhill JG, Jaffe JH (1988) "Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers." Clin Pharmacol Ther, 43, p. 509-18
  5. Seppala T, Linnoila M, Elonen E, Mattila MJ, Makl M (1975) "Effect of tricyclic antidepressants and alcohol on psychomotor skills related to driving." Clin Pharmacol Ther, 17, p. 515-22
  6. Ciraulo DA, Barnhill JG, Jaffe JH, Ciraulo AM, Tarmey MF (1990) "Intravenous pharmacokinetics of 2-hydroxyimipramine in alcoholics and normal controls." J Stud Alcohol, 51, p. 366-72
  7. Ciraulo DA, Alderson LM, Chapron DJ, Jaffe JH, Subbarao B, Kramer PA (1982) "Imipramine disposition in alcoholics." J Clin Psychopharmacol, 2, p. 2-7
View all 7 references

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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.

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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.

Further information

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