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Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Afatinib

-

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Axitinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Bosutinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Cabozantinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
Avoid co-administration of cabozantinib with CYP3A4 inhibitors/inducers


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

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

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Crizotinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Dabrafenib

Ketoconazole

-

Recommendations on how DDIs can be managed
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)


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Dasatinib

-

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Erlotinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Gefitinib

Itraconazole

Rifampicin

Recommendations on how DDIs can be managed
Closely monitor patients for adverse reactions if gefitinib is co-administered with a CYP3A4 inhibitor


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Ibrutinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Idelalisib

Ketoconazole

Rifampicin, Phenytoin, St. John’s Wort, Carbamazepine

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Imatinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Lapatinib

Ketoconazole

Carbamazepine

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Lenvatinib

Ketoconazole

Rifamipicin

Recommendations on how DDIs can be managed
No dose adjustment needed with coadministered with CYP3A4 inhibitors and inducers


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Nilotinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Nintedanib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Pazopanib

Ketoconazole

-

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Ponatinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Regorafenib

-

-

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Ruxolitinib

Ketoconazole

Rifampicin

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Sorafenib

-

Rifampicin

Recommendations on how DDIs can be managed
Consider increasing the dose of sorafenib to 1,000 mg/24 hours if co-administering with rifampicin


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Sunitinib

-

-

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Trametinib

-

-

Recommendations on how DDIs can be managed
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


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Vandetanib

Rifampicin

Recommendations on how DDIs can be managed
Vandetanib can be co-administered with CYP3A4 inhibitors if administered with caution
Co-administration of vandetanib with potent CYP3A4 inducers is not recommended


Kinase Inhibitor

CYP3A4 Inhibitor Drug(s)

CYP3A4 Inducer Drug(s)

Vemurafenib

-

-

Recommendations on how DDIs can be managed
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)

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