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Drug Interactions between atazanavir / cobicistat and Onxol

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

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Interactions between your drugs

Major

PACLitaxel atazanavir

Applies to: Onxol (paclitaxel) and atazanavir / cobicistat

MONITOR CLOSELY: Coadministration with certain antiretroviral agents such as protease inhibitors and delavirdine may increase the plasma concentrations and pharmacologic effects of paclitaxel. The proposed mechanism is inhibition of the CYP450 3A4-mediated metabolism of paclitaxel. There have been case reports of life-threatening toxicity and death in patients treated with paclitaxel 100 mg/m2 (a dosage previously found to be safe and effective for AIDS-related Kaposi's sarcoma) who were also receiving highly active antiretroviral therapy (HAART) that included ritonavir, ritonavir/lopinavir, indinavir, saquinavir, and/or delavirdine, all of which are known potent inhibitors of the CYP450 3A4 isoenzyme. Symptoms of toxicity included myalgias, arthralgias, mucositis, febrile neutropenia, leucopenia, thrombocytopenia, infection, alopecia, and ECG abnormalities. A dosage reduction to 60 mg/m2 and concomitant administration with granulocyte colony-stimulating factor (G-CSF) were subsequently required in the patients who recovered.

MANAGEMENT: Caution is advised if paclitaxel is required in patients receiving protease inhibitors and/or delavirdine. A lower initial dosage of paclitaxel may be appropriate. Patients should be closely monitored for the development of dose-related paclitaxel toxicity such as myelosuppression, stomatitis, arthralgia, myalgia, visual disturbances and peripheral neuropathy, and the paclitaxel dosage further adjusted as necessary. Use of repaglinide with the fixed combination of atazanavir-cobicistat is not recommended.

References

  1. (2001) "Product Information. Taxotere (docetaxel)." Rhone Poulenc Rorer
  2. (2001) "Product Information. Taxol (paclitaxel)." Bristol-Myers Squibb
  3. Panday VRN, Hoetelmans RMW, vanHeeswijk RPG, Meenhorst PL, Inghels M, Mulder JW, Beijnen JH (1999) "Paclitaxel in the treatment of human immunodeficiency virus 1-associated Kaposi's sarcoma - drug-drug interactions with protease inhibitors and a nonnucleoside reverse transcriptase inhibitor: a case report study." Cancer Chemother Pharmacol, 43, p. 516-9
  4. Gill PS, Tulpule A, Espina BM, Cabriales S, Bresnahan J, Ilaw M, Louie S, Gustafson NF, Brown MA, Orcutt C, Winograd B, Scad (1999) "Paclitaxel is safe and effective in the treatment of advanced AIDS-related Kaposi's sarcoma." J Clin Oncol, 17, p. 1876-83
  5. Schwartz JD (1999) "Potential interaction of antriretroviral therapy with paclitaxel in patients with AIDS-related Kaposi's sarcoma." AIDS, 13, p. 283-4
  6. Bundow D, Aboulafia DM (2004) "Potential drug interaction with paclitaxel and highly active antiretroviral therapy in two patients with AIDS-associated Kaposi sarcoma." Am J Clin Oncol, 27, p. 81-4
  7. (2015) "Product Information. Evotaz (atazanavir-cobicistat)." Bristol-Myers Squibb
View all 7 references

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Moderate

PACLitaxel cobicistat

Applies to: Onxol (paclitaxel) and atazanavir / cobicistat

MONITOR: Coadministration with inhibitors of CYP450 2C8 and/or 3A4 may increase the plasma concentrations of paclitaxel, which has been found in vitro to be a substrate of these isoenzymes. Formal clinical drug interaction studies have not been conducted. However, in a case report involving a 77-year-old woman with HER2-positive invasive ductal breast cancer on long-term amiodarone therapy, 4 cycles of paclitaxel (80 mg/m2 weekly) and trastuzumab led to development of increasing abdominal discomfort and skin lesions and a diagnosis of paclitaxel-induced skin toxicity. Switching to reduced dose docetaxel (100 mg or 75 mg/m2 weekly) led to the development of severe skin and mucosal toxicity, requiring hospitalization 8 days after the first docetaxel dose was administered. Analysis of two blood samples taken 9 and 10 days after docetaxel administration showed an approximately fivefold increase in its AUC as well as the presence of paclitaxel in unquantifiable levels, 20 and 21 days after it was last administered. The authors of this case study propose that, in addition to CYP450 3A4 inhibition, CYP450 2C8 and P-glycoprotein inhibition due to amiodarone may also contribute to the interaction.

MANAGEMENT: Clinicians should consider the potential for interaction with drugs that inhibit CYP450 2C8 and/or 3A4 and monitor for evidence of dose-related toxicities of paclitaxel during coadministration, including diarrhea, mucositis, myelosuppression, and peripheral neuropathy.

References

  1. Spencer CM, Faulds D (1994) "Paclitaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of cancer." Drugs, 48, p. 794-847
  2. Jamis-Dow CA, Klecker RW, Katki AG, Collins JM (1993) "Metabolism of Taxol by human liver microsomes and effect of inhibitors (Meeting abstract)." Proc Annu Meet Am Assoc Cancer Res, 34, a21981993
  3. (2001) "Product Information. Taxol (paclitaxel)." Bristol-Myers Squibb
  4. Bun SS, Ciccolini J, Bun H, Aubert C, Catalin J (2003) "Drug interactions of paclitaxel metabolism in human liver microsomes." J Chemother, 15, p. 266-74
  5. "Product Information. Abraxane (PACLitaxel protein-bound)." American Pharmaceutical Partners
  6. Cerner Multum, Inc. "Australian Product Information."
  7. Bergmann TK, Filppula AM, Launiainen T, Nielsen F, Backman J, Brosen K (2015) "Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60 year old Caucasian woman with ovarian carcinoma." Br J Clin Pharmacol
  8. Starr SP, Hammann F, Gotta V, et al. (2016) "Pharmacokinetic interaction between taxanes and amiodarone leading to severe toxicity." Br J Clin Pharmacol, 450, p. 22-27
View all 8 references

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Drug and food interactions

Moderate

PACLitaxel food

Applies to: Onxol (paclitaxel)

MONITOR: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may increase the plasma concentrations of paclitaxel, which is a substrate of the isoenzyme. Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit. Specific data for paclitaxel are lacking; however, in a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg/m2) reported that docetaxel systemic exposure (AUC) increased by 65% compared with the AUC target of 1.96 mg*h/L and clearance decreased by 63%, with a 71% reduction in the patient's neutrophil count. In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months. Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%. In addition, in a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel AUC increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2.

MANAGEMENT: Caution is recommended if paclitaxel is to be used in combination with grapefruit and grapefruit juice. Patients should be closely monitored for the development of paclitaxel toxicity, including diarrhea, mucositis, myelosuppression, and peripheral neuropathy and dose adjustment considered per local treatment protocols.

References

  1. (2001) "Product Information. Taxotere (docetaxel)." Rhone Poulenc Rorer
  2. Aronson JK, Grahame-Smith DG (1981) "Clinical pharmacology: adverse drug interactions." Br Med J, 282, p. 288-91
  3. McInnes GT, Brodie MJ (1988) "Drug interactions that matter: a critical reappraisal." Drugs, 36, p. 83-110
  4. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  5. Yong WP, Wang LZ, Tham LS, et al. (2008) "A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers." Cancer Chemother Pharmacol, 62, p. 243-51
  6. Cerner Multum, Inc. "Australian Product Information."
  7. Engels FK, Mathot RA, Loos WJ, van Schaik RH, Verweij J (2006) "Influence of high-dose ketoconazole on the pharmacokinetics of docetaxel." Cancer Biol Ther, 5, p. 833-9
  8. Valenzuela B, Rebollo J, Perez T, Brugarolas A, Perez-Ruixo JJ (2011) "Effect of grapefruit juice on the pharmacokinetics of docetaxel in cancer patients: a case report." Br J Clin Pharmacol
  9. Starr SP, Hammann F, Gotta V, et al. (2016) "Pharmacokinetic interaction between taxanes and amiodarone leading to severe toxicity." Br J Clin Pharmacol, 450, p. 22-27
View all 9 references

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Moderate

atazanavir food

Applies to: atazanavir / cobicistat

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.

References

  1. (2003) "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb

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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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