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Drug Interactions between darifenacin and saquinavir

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

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Interactions between your drugs

Major

saquinavir darifenacin

Applies to: saquinavir and darifenacin

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of darifenacin, which is partially metabolized by the isoenzyme. Darifenacin is also metabolized by CYP450 2D6, but 3A4 is the major pathway of metabolism in so-called poor metabolizers of 2D6 (approximately 7% of Caucasians and 2% of Asians and those of African descent). In a drug interaction study involving 10 extensive metabolizers and 1 poor metabolizer of 2D6, coadministration with the potent 3A4 inhibitor ketoconazole (400 mg) increased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of darifenacin (extended-release 7.5 mg once a day) approximately 5-fold each compared to values previously reported for extensive metabolizers of 2D6. In the poor metabolizer, Cmax and AUC of darifenacin increased approximately 13-fold each compared to values previously reported for poor metabolizers. When a 15 mg daily dose of extended-release darifenacin was given with ketoconazole, mean darifenacin Cmax and AUC in 3 extensive metabolizers increased approximately 12-fold compared to historical values, while Cmax and AUC increased approximately 6-fold in the poor metabolizer compared to historical values.

MANAGEMENT: The dosage of darifenacin should not exceed 7.5 mg/day when used with potent CYP450 3A4 inhibitors. Some authorities recommend avoiding concomitant use of darifenacin during and for 2 weeks after treatment with itraconazole.

References (4)
  1. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  2. (2005) "Product Information. Enablex (darifenacin)." Novartis Pharmaceuticals
  3. Cerner Multum, Inc. "Australian Product Information."
  4. Niwa T, Shiraga T, Takagi A (2005) "Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, CYP3A4 activities in human liver microsomes." Biol Pharm Bull, 28, p. 1805-8

Drug and food interactions

Moderate

saquinavir food

Applies to: saquinavir

ADJUST DOSING INTERVAL: Food significantly increases the absorption of saquinavir.

MONITOR: Coadministration with grapefruit juice may increase the plasma concentrations of saquinavir. The primary mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In eight healthy volunteers, ingestion of 400 mL of grapefruit juice prior to administration of a 600 mg dose of saquinavir mesylate increased the area under the plasma concentration-time curve and oral bioavailability of saquinavir by 50% and 100%, respectively, compared to water; however, the increase is not considered clinically relevant. A high degree of intersubject variability in the grapefruit juice effect was also observed. The extent to which this interaction may occur with the saquinavir free base soft gelatin capsule is unknown. However, the saquinavir soft gelatin capsule formulation is no longer commercially available.

MANAGEMENT: Saquinavir mesylate should be taken with meals or within 2 hours after eating to enhance bioavailability. Patients should be advised to avoid the consumption of large amounts of grapefruit and grapefruit juice during saquinavir therapy unless otherwise directed by their doctor, as the interaction is unreliable and subject to a high degree of interpatient variation.

References (6)
  1. (2001) "Product Information. Invirase (saquinavir)." Roche Laboratories
  2. Kupferschmidt HHT, Fattinger KE, Ha HR, Follath F, Krahenbuhl S (1998) "Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man." Br J Clin Pharmacol, 45, p. 355-9
  3. Bailey DG, Malcolm J, Arnold O, Spence JD (1998) "Grapefruit juice-drug interactions." Br J Clin Pharmacol, 46, p. 101-10
  4. Eagling VA, Profit L, Back DJ (1999) "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components." Br J Clin Pharmacol, 48, p. 543-52
  5. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  6. Cerner Multum, Inc. "Australian Product Information."
Minor

darifenacin food

Applies to: darifenacin

The consumption of grapefruit juice may be associated with increased plasma concentrations of darifenacin. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The clinical significance is unknown.

References (1)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."

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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