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Drug Interactions between clomipramine and dabrafenib

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

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Interactions between your drugs

Moderate

clomiPRAMINE dabrafenib

Applies to: clomipramine and dabrafenib

MONITOR: Coadministration with dabrafenib may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4 and/or 2C9. Dabrafenib has been found in vitro to be an inducer of these isoenzymes. Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib; however, transient inhibition of CYP450 isoenzymes may be observed during the first few days of treatment. In 12 study subjects, administration of the CYP450 3A4 probe substrate midazolam following repeat doses of dabrafenib 150 mg twice daily for 15 days reduced midazolam peak plasma concentration (Cmax) by 61% and systemic exposure (AUC) by 74%. When a single 15 mg dose of warfarin was coadministered similarly with dabrafenib, the AUC of S(-) warfarin decreased by 37% and that of R(+) decreased by 33%. S(-) warfarin, the biologically more active enantiomer, is primarily metabolized by CYP450 2C9, while R(+) warfarin is a substrate of CYP450 3A4 and 1A2.

MANAGEMENT: Caution is advised when dabrafenib is prescribed with drugs that undergo metabolism by CYP450 3A4 and/or 2C9. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever dabrafenib is added to or withdrawn from therapy. Significantly reduced plasma concentrations and loss of efficacy may occur with sensitive substrates of CYP450 3A4 or 2C9 such as hormonal contraceptives, immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus), ivacaftor, and warfarin-type anticoagulants. Alternatives to these medications should be considered if possible.

References (2)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. (2013) "Product Information. Tafinlar (dabrafenib)." GlaxoSmithKline

Drug and food interactions

Moderate

clomiPRAMINE food

Applies to: clomipramine

MONITOR: Limited data suggest that the administration of clomipramine with grapefruit juice or cranberry juice may significantly increase plasma drug concentrations of clomipramine. Clomipramine is initially demethylated by CYP450 1A2, 3A3 and 3A4 before undergoing further metabolism to 8-hydroxyclomipramine. The increase in clomipramine bioavailability may stem from inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The precise mechanism by which cranberry juice exerts its effects is unknown, but may involve inhibition of CYP450 isoenzymes. This interaction has occasionally been exploited in attempts to improve symptomatic control of obsessive compulsive disorder.

MANAGEMENT: Patients receiving clomipramine therapy who ingest cranberry juice, grapefruits, or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

References (4)
  1. Oesterheld J, Kallepalli BR (1997) "Grapefruit juice and clomipramine: shifting metabolitic ratios." J Clin Psychopharmacol, 17, p. 62-3
  2. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  4. Cerner Multum, Inc. "Australian Product Information."
Moderate

dabrafenib food

Applies to: dabrafenib

ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of dabrafenib. In study subjects, administration of dabrafenib with a high-fat meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 51% and 31%, respectively, and delayed median Tmax by approximately 3.6 hours compared to administration in the fasted state.

MANAGEMENT: Dabrafenib should be taken at least 1 hour before or 2 hours after a meal.

References (1)
  1. (2013) "Product Information. Tafinlar (dabrafenib)." GlaxoSmithKline
Moderate

clomiPRAMINE food

Applies to: clomipramine

GENERALLY AVOID: The combination of ethanol and a tricyclic antidepressant may result in additive impairment of motor skills, especially driving skills. Also, one study has suggested that clomipramine metabolism is significantly impaired for several weeks or more following discontinuation of chronic alcohol consumption.

MANAGEMENT: Patients should be warned of this interaction and advised to limit their ethanol intake while taking tricyclic antidepressants. Monitoring for TCA toxicity (CNS depression, excessive anticholinergic effects, hypotension, arrhythmias) is recommended during alcohol withdrawal.

References (3)
  1. 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
  2. Berlin I, Cournot A, Zimmer R, et al. (1990) "Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects." Psychopharmacology (Berl), 100, p. 40-5
  3. Balant-Gorgia AE, Gay M, Gex-Fabry M, Balant LP (1992) "Persistent impairment of clomipramine demethylation in recently detoxified alcoholic patients." Ther Drug Monit, 14, p. 119-24

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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