CYP3A4 Inhibitor/Inducer Drug-Drug Interactions - All Kinase Inhibitors

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Kinase Inhibitor CYP3A4 Inhibitor Drug(s) CYP3A4 Inducer Drug(s) Recommendations on how DDIs can be managed
Afatinib - Rifampicin

Reduce afatinib dose to 10 mg/day if co-administration with ketoconazole is not tolerated; or administer ketoconazole using staggered dosing, preferably 6 or 12 hours apart from afatinib

For patients requiring chronic therapy with a rifampicin, increase the afitinib daily dose by 10 mg as tolerated

Axitinib Ketoconazole Rifampicin

If use of strong CYP3A4/5 inhibitors is unavoidable, reduce the dose of axitinib by approximately half, as tolerated

If use of strong CYP3A4/5 inducers is unavoidable, a gradual dose increase of axitinib is recommended, with patients carefully monitored for toxicity

Bosutinib Ketoconazole Rifampicin

Consider interruption or dose reduction of bosutinib if co-administration with a potent CYP3A inhibitor is necessary

Avoid concomitant use of bosutinib with potent CYP3A inducers; increasing the dose of bosutinib is unlikely to sufficiently compensate for the loss of exposure

Cabozantinib Ketoconazole Rifampicin Avoid co-administration of cabozantinib with CYP3A4 inhibitors/inducers
Ceritinib Antivirals (e.g. ritonavir), macrolide antibiotics (e.g. telithromycin), antifungals (e.g. ketoconazole) and nefazodone

Rifampicin
 Carbamaze-pine

Phenytoin
 Rifampicin
 St John’s Wort

Avoid concurrent use of strong CYP3A4 inhibitors. If unavoidable, reduce the dose by approximately one third (rounded to the nearest 150 mg dosage strength)

After discontinuation of a strong CYP3A4 inhibitor resume the dose that was taken prior to initiating the strong CYP3A4 inhibitor

Avoid concurrent use of strong CYP3A inducers

Crizotinib Ketoconazole Rifampicin

Extreme caution should be taken if co-administration with a CYP3A4 inhibitor is unavoidable, the crizotinib dose should be lowered, and toxicity must be monitored

If co-administration with a CYP3A4 inducer is unavoidable increase crizotinib dose gradually and monitor toxicity to obtain optimum effectiveness

Dabrafenib Ketoconazole - If co-adminstration of dabrafenib with strong inhibitors/inducers of CYP3A4 is unavoidable, monitor patients closely for adverse reactions (with strong inhibitors) or loss of efficacy (with strong inducers)
Dasatinib - Rifampicin If co-administration is unavoidable, monitor patients closely for toxicity and consider reducing dasatinib dose (from 100 to 20 mg/day, or from 140 to 40 mg/day) with potent CYP3A4 inhibitors, or increasing dasatinib dose with CYP3A4 inducers
Erlotinib Ketoconazole Rifampicin

Reduce erlotinib dose by 50-mg decrements if severe reactions occur with concomitant use of strong CYP3A4 inhibitors

If co-administration with CYP3A4 inducers is unavoidable increase the erlotinib dose by 50-mg increments at 2-week intervals to a maximum of 450 mg

Gefitinib Itraconazole Rifampicin Closely monitor patients for adverse reactions if gefitinib is co-administered with a CYP3A4 inhibitor
Ibrutinib Ketoconazole Rifampicin

Ibrutinib dose should be reduced to 140 mg once daily or withheld for up to 7 days when used concomitantly with strong CYP3A4 inhibitors

If a strong CYP3A4 inducer must be used, patients must be monitored closely for lack of efficacy

Idelalisib Ketoconazole Rifampicin
 Phenytoin
 St. John’s Wort
 Carbamazepine

Avoid coadministration with strong CYP3A4 inducers

If patients are taking strong CYP3A inhibitors monitor for signs of toxicity

Please see the idelasib summary of product characteristics and presecribing information for an extensive of products that are CYP3A4 substrates

Imatinib Ketoconazole Rifampicin

Consider decreasing the dose of imatinib to 300 mg/24 hours if co-administering with strong CYP3A4 inhibitors

If co-administration of imatinib and a strong CYP3A4 inducer is needed, the imatinib dose should be increased to 600−700 mg/24 hours

Lapatinib Ketoconazole Carbamazepine

If co-administration of a strong CYP3A4 inhibitor is unavoidable, lapatinib dose should be reduced to 500 mg/day

If co-administration of a strong CYP3A4 inducer is unavoidable, the dose of lapatinib should be titrated gradually from 1250 mg/day up to 4500 mg/day (HER2-positive metastatic breast cancer indication) or from 1500 mg/day up to 5500 mg/day (hormone Receptor-positive, HER2-positive breast cancer indication) based on tolerability

Lenvatinib Ketoconazole Rifamipicin No dose adjustment needed with coadministered with CYP3A4 inhibitors and inducers
Nilotinib Ketoconazole Rifampicin

If administration of a strong CYP3A4 inhibitor is required, it is recommended that nilotinib therapy be interrupted if possible, otherwise close monitoring for prolongation of the QT interval is indicated

In patients for whom CYP3A4 inducers are indicated, alternative agents with less Enzyme induction potential should be selected

Nintedanib Ketoconazole Rifampicin

In case of concomitant use of CYP3A4 inhibitors, patients should be closely monitored for tolerability, and adverse reactions managed with interruption, dose reduction (to 100 mg twice daily), or discontinuation of nintedanib

Avoid co-administration of nintedanib with CYP3A4 inducers

Pazopanib Ketoconazole -

If co-administration of strong CYP3A4 inhibitors is warranted, reduce the dose of pazopanib to 400 mg

In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be selected

Ponatinib Ketoconazole Rifampicin

If co-administration with a strong CYP3A4 inhibitor is warranted, reduce the starting dose of ponatinib to 30 mg once daily

In patients for whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction potential should be selected

Regorafenib - -

If co-administration with a strong CYP3A4 inhibitor cannot be avoided, monitor regorafenib toxicity; dose adjustments are highly recommended

If co-administration with a strong CYP3A4 inducers cannot be avoided, increase the regorafenib dose gradually and monitor toxicity

Ruxolitinib Ketoconazole Rifampicin

If co-administration with a strong CYP3A4 inhibitor cannot be avoided, ruxolitinib dose should be reduced by approximately 50%, with twice-daily administration; ruxolitinib interruption or discontinuation should also be considered

If co-administration with a strong CYP3A4 inducer cannot be avoided, ruxolitinib dose should be titrated (increase by a maximum of 5 mg twice daily) based on safety and efficacy

Sorafenib - Rifampicin Consider increasing the dose of sorafenib to 1,000 mg/24 hours if co-administering with rifampicin
Sunitinib - -

If co-administration with a strong CYP3A4 inhibitor cannot be avoided, consider reducing the sunitinib dose to a minimum of 37.5 mg daily for GIST and mRCC or 25 mg daily for pNET, based on careful monitoring of tolerability

If co-administration with a CYP3A4 inducer is necessary, consider increasing the sunitinib dose in 12.5-mg increments (up to 87.5 mg/day for GIST and mRCC, or 62.5 mg/day for pNET), based on careful monitoring of tolerability

Trametinib - - Trametinib is not a substrate of CYP enzymes or of P-gp. Trametinib is deacetylated via hydrolytic enzymes which are not generally associated with drug interaction risk
Vandetanib   Rifampicin

Vandetanib can be co-administered with CYP3A4 inhibitors if administered with caution

Co-administration of vandetanib with potent CYP3A4 inducers is not recommended

Vemurafenib - - Caution should be taken when coadministering vemurafenib with CYP3A4 inhibitors/inducers as there are currently no data on this DDI

For more information on the most-commonly used kinase inhibitors, please click on each agent below to find out more on drug-drug interactions associated with CYP3A4 inhibitors/inducers.

References

  1. Food and Drug Administration. 2015. (last accessed July 2015)
  2. European Medicines Agency. 2015. (last accessed July 2015)
Last update: 21 July 2015