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Drug Interactions between capivasertib and Mellaril

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

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Interactions between your drugs

Major

thioridazine capivasertib

Applies to: Mellaril (thioridazine) and capivasertib

Consumer information for this interaction is not currently available.

CONTRAINDICATED: Coadministration with inhibitors of CYP450 2D6 may increase the plasma concentrations and adverse effects of thioridazine and its two active metabolites, mesoridazine and sulforidazine, all of which are substrates of the isoenzyme. A study in 19 healthy male patients reviewed thioridazine metabolism in 6 slow and 13 rapid hydroxylators of debrisoquin (the rate of which is believed to be dependent upon the level of CYP450 2D6 activity). A single oral dose of thioridazine (25 mg) produced a 2.4-fold higher peak plasma concentration (Cmax) and a 4.5-fold higher systemic exposure (AUC) for thioridazine in the slow hydroxylators, which is predicted to be similar to what would be seen in patients on CYP450 2D6 inhibitors. Additionally, significant increases (up to severalfold) have been observed during coadministration with fluvoxamine, propranolol, and pindolol in pharmacokinetic studies, although these reductions in clearance may be via other currently unknown mechanisms. The use of thioridazine has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death. Several cases of torsade de pointes have been reported.

MANAGEMENT: The use of thioridazine with fluvoxamine, propranolol, pindolol and/or drugs that inhibit CYP450 2D6 is considered contraindicated. Depending on the elimination half-life of these drugs, a considerable waiting period may be appropriate following their discontinuation before thioridazine is initiated. For example, the manufacturer of fluoxetine recommends that thioridazine not be administered within 5 weeks after discontinuing fluoxetine because of the drug's long half-life. In addition, the prolonged duration of CYP450 2D6 inhibition by the moderate CYP450 2D6 inhibitor rolapitant of at least 28 days after its administration should also be taken into account.

References

  1. Silver JM, Yudofsky SC, Kogan M, Katz BL "Elevation of thioridazine plasma levels by propranolol." Am J Psychiatry 143 (1986): 1290-2
  2. Greendyke RM, Kanter DR "Plasma propranolol levels and their effect on plasma thioridazine and haloperidol concentrations." J Clin Psychopharmacol 7 (1987): 178-82
  3. Greendyke RM, Gulya A "Effect of pindolol administration on serum levels of thioridazine, haloperidol, phenytoin, and phenobarbital." J Clin Psychiatry 49 (1988): 105-7
  4. Abernethy DR, Greenblatt DJ, Steel K, Shader RI "Impairment of hepatic drug oxidation by propoxyphene." Ann Intern Med 97 (1982): 223-4
  5. "Product Information. Prozac (fluoxetine)." Dista Products Company PROD (2001):
  6. Fletcher GF, Kazamias TM "Cardiotoxic effects of Mellaril: conduction disturbances and supraventricular arrhythmias." Am Heart J 78 (1969): 135-8
  7. Markowitz JS, Wells BG, Carson WH "Interactions between antipsychotic and antihypertensive drugs." Ann Pharmacother 29 (1995): 603-9
  8. "Product Information. Mellaril (thioridazine)." Sandoz Pharmaceuticals Corporation PROD (2001):
  9. Thomas M, Maconochie JG, Fletcher E "The dilemma of the prolonged QT interval in early drug studies." Br J Clin Pharmacol 41 (1996): 77-81
  10. Hartigan-Go K, Bateman DN, Nyberg G, Martensson E, Thomas SHL "Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans." Clin Pharmacol Ther 60 (1996): 543-53
  11. Carrillo JA, Ramos SI, Herraiz AG, Llerena A, Agundez JAG, Berecz R, Duran M, Benitez J "Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients." J Clin Psychopharmacol 19 (1999): 494-9
  12. Glassman AH, Bigger JT Jr "Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death." Am J Psychiatry 158 (2001): 1774-82
  13. "Product Information. Varubi (rolapitant)." Tesaro Inc. (2015):
  14. "Product Information. Thioridazine Hydrochloride (thioridazine)." Mylan Institutional (formerly UDL Laboratories) (2019):
View all 14 references

Drug and food interactions

Major

capivasertib food

Applies to: capivasertib

Consumer information for this interaction is not currently available.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of capivasertib, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been studied with other CYP450 3A4 inhibitors. Based on clinical studies and model-informed approaches, concomitant use with the potent CYP450 3A4 inhibitor itraconazole is predicted to increase capivasertib systemic exposure (AUC) by up to 1.7-fold and peak plasma concentration (Cmax) by up to 1.4-fold. Coadministration with the moderate CYP450 3A4 inhibitors erythromycin and verapamil is predicted to increase the AUC and Cmax of capivasertib by up to 1.5-fold 1.3-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to capivasertib may increase the risk of adverse effects such as diarrhea, cutaneous adverse reactions, decreased lymphocytes, decreased hemoglobin, hyperglycemia, nausea, and fatigue.

MANAGEMENT: It may be advisable for patients to avoid the consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with capivasertib.

References

  1. "Product Information. Truqap (capivasertib)." Astra-Zeneca Pharmaceuticals (2023):
Moderate

thioridazine food

Applies to: Mellaril (thioridazine)

Ask your doctor before using thioridazine together with ethanol. This can cause uncontrollable movements, agitation, seizures, severe dizziness or fainting, coma, very deep sleep, irregular heartbeats, and high or low body temperature. Use caution when driving, operating machinery, or performing other hazardous activities, these medicaions may cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

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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.

See also

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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

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

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