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Drug Interactions between Kaletra and tretinoin

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

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Interactions between your drugs

Moderate

tretinoin ritonavir

Applies to: tretinoin and Kaletra (lopinavir / ritonavir)

MONITOR: Coadministration with potent inhibitors of CYP450 2C8, 2C9, and/or 3A4 may increase the plasma concentrations and toxicities of tretinoin, which is a substrate of these isoenzymes. There have been isolated reports of pseudotumour cerebri, hypercalcemia, and acute renal failure in patients receiving tretinoin with fluconazole, itraconazole or voriconazole, all of which are considered potent inhibitors of at least one CYP450 isoenzyme involved in the metabolism of tretinoin. The conditions resolved following interruption of tretinoin therapy and/or discontinuation of the azole antifungal agent. As tretinoin is thought to undergo autoinduction of its own metabolism, CYP450 inhibitors have been investigated for use to boost plasma tretinoin concentrations and to overcome treatment resistance that often occurs with continued tretinoin therapy. In a study of two patients with acute promyelocytic leukemia, tretinoin systemic exposure (AUC) was found to be reduced significantly from baseline after one week of treatment. Following two daily doses of fluconazole administered 1 hour before tretinoin, the AUC of tretinoin increased by about 2- to 4-fold compared to day eight of tretinoin treatment alone, but similar to AUCs reported at baseline. In 13 patients who had received tretinoin daily for 4 consecutive weeks, administration of ketoconazole (400 to 1200 mg oral dose) 1 hour before the tretinoin dose on day 29 led to a 72% increase in tretinoin mean plasma AUC. Likewise, in 6 patients with lung cancer, a single 400 mg dose of ketoconazole (but not a 200 mg dose) one hour before tretinoin on day 29 increased tretinoin AUC by 115% compared to day 28 when tretinoin was given alone. No effect was observed when ketoconazole was given on day 2 relative to tretinoin alone on day one. By contrast, one study showed that prolonged ketoconazole administration (400 mg initially, then 200 mg daily for 14 days) in patients receiving tretinoin (45 mg/m2 twice daily for 14 days) had no effect on tretinoin auto-induction, but was associated with more vomiting.

MANAGEMENT: Caution is advised when tretinoin is prescribed in combination with potent inhibitors of CYP450 2C8, 2C9, and/or 3A4. Patients should be closely monitored and advised to seek medical attention immediately if they develop early symptoms of pseudotumour cerebri such as headache, nausea, vomiting, visual disturbances, photosensitivity, and tinnitus.

References

  1. Rigas JR, Francis PA, Muindi JR, Kris MG, Huselton C, DeGrazia F, Orazem JP, Young CW, Warrell RP Jr (1993) "Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole." J Natl Cancer Inst, 85, p. 1921-6
  2. Adamson PC (1994) "Pharmacokinetics of all-trans-retinoic acid: clinical implications in acute promyelocytic leukemia." Semin Hematol, 31, p. 14-7
  3. Muindi JRF, Young CW, Warrell RP (1994) "Clinical pharmacology of all-trans retinoic acid." Leukemia, 8, p. 1807-12
  4. (2001) "Product Information. Vesanoid (tretinoin)." Roche Laboratories
  5. Cordoba R, Ramirez E, Lei SH, et al. (2008) "Hypercalcemia due to an interaction of all-trans retinoic acid (ATRA) and itraconazole therapy for acute promyelocytic leukemia successfully treated with zoledronic acid." Eur J Clin Pharmacol, 64, p. 1031-2
  6. Dixon KS, Hassoun A (2010) "Pseudotumor cerebri due to the potentiation of all-trans retinoic acid by voriconazole." J Am Pharm Assoc (2003), 50, p. 742-4
  7. Marill J, Cresteil T, Lanotte M, Chabot GG (2000) "Identification of human cytochrome P450s involved in the formation of all-trans-retinoic acid principal metabolites." Mol Pharmacol, 58, p. 1341-8
  8. Lotan Y, Lotan R (2008) "Prevention of bladder cancer recurrence by retinoic acid-ketoconazole: a promising strategy?" Cancer Biol Ther, 7, p. 101-2
  9. Hameed DA, el-Metwally TH (2008) "The effectiveness of retinoic acid treatment in bladder cancer: impact on recurrence, survival and TGFalpha and VEGF as end-point biomarkers." Cancer Biol Ther, 7, p. 92-100
  10. Moresco G, Martinello F, Souza LC (2011) "[Acute renal failure in patient treated with ATRA and amphotericin B: case report]." J Bras Nefrol, 33, p. 276-81
  11. Kizaki M, Ueno H, Yamazoe Y, et al. (1996) "Mechanisms of retinoid resistance in leukemic cells: possible role of cytochrome P450 and P-glycoprotein." Blood, 87, p. 725-33
View all 11 references

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Drug and food interactions

Moderate

ritonavir food

Applies to: Kaletra (lopinavir / ritonavir)

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

References

  1. (2001) "Product Information. Norvir (ritonavir)." Abbott Pharmaceutical

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Moderate

lopinavir food

Applies to: Kaletra (lopinavir / ritonavir)

ADJUST DOSING INTERVAL: Food significantly increases the bioavailability of lopinavir from the oral solution formulation of lopinavir-ritonavir. Relative to fasting, administration of lopinavir-ritonavir oral solution with a moderate-fat meal (500 to 682 Kcal; 23% to 25% calories from fat) increased lopinavir peak plasma concentration (Cmax) and systemic exposure (AUC) by 54% and 80%, respectively, whereas administration with a high-fat meal (872 Kcal; 56% from fat) increased lopinavir Cmax and AUC by 56% and 130%, respectively. No clinically significant changes in Cmax and AUC were observed following administration of lopinavir-ritonavir tablets under fed conditions versus fasted conditions. Relative to fasting, administration of a single 400 mg-100 mg dose (two 200 mg-50 mg tablets) with a moderate-fat meal (558 Kcal; 24.1% calories from fat) increased lopinavir Cmax and AUC by 17.6% and 26.9%, respectively, while administration with a high-fat meal (998 Kcal; 51.3% from fat) increased lopinavir AUC by 18.9% but not Cmax. Relative to fasting, ritonavir Cmax and AUC also increased by 4.9% and 14.9%, respectively, with the moderate-fat meal and 10.3% and 23.9%, respectively, with the high-fat meal.

MANAGEMENT: Lopinavir-ritonavir oral solution should be taken with meals to enhance bioavailability and minimize pharmacokinetic variability. Lopinavir-ritonavir tablets may be taken without regard to meals.

References

  1. (2001) "Product Information. Kaletra (lopinavir-ritonavir)." Abbott Pharmaceutical

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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.

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