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Drug Interactions between lenvatinib and regorafenib

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

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Interactions between your drugs

Moderate

regorafenib lenvatinib

Applies to: regorafenib and lenvatinib

MONITOR: Lenvatinib use in combination with or after recent use of other medications associated with osteonecrosis of the jaw (ONJ) may increase the risk of this rare side effect. Theories as to how ONJ develops include inhibition of bone remodeling, inflammation or infection, angiogenesis inhibition, innate or acquired immune dysfunction, as well as genetic predisposition; however, the pathophysiology is likely related to multiple factors. Medication-related ONJ (MRONJ) is a rare, but severe and debilitating condition whose exact cause remains unknown. Known risk factors for MRONJ include cancer, duration of antiresorptive therapy, dentoalveolar operations (such as tooth extraction), preexisting inflammatory dental disease, and concurrent use of multiple medications associated with a risk of ONJ (such as bisphosphonates, denosumab, romosozumab, angiogenesis inhibitors, and corticosteroids).

MANAGEMENT: Caution is advised when lenvatinib is used with other agents that are also associated with the development of ONJ. A routine oral examination should be performed prior to initiation of either treatment. Patients should be advised regarding good oral hygiene practices and to have regular preventive dentistry performed throughout treatment. For patients requiring invasive dental procedures, discontinuation of lenvatinib may be recommended. Patients should be advised to seek medical attention if they experience signs and symptoms of ONJ, such as: pain in the mouth, teeth, or jaw; swelling or sores inside the mouth; numbness or a feeling of heaviness in the jaw; loosening of a tooth; or exposure of bone in the jaw. Those who are suspected of having or who develop ONJ during lenvatinib therapy should receive care by a dentist or an oral surgeon. In all circumstances involving MRONJ, clinical judgment and a risk-benefit assessment should guide the management plan of each patient based on their specific clinical circumstances.

References (5)
  1. (2015) "Product Information. Lenvima (lenvatinib)." Eisai Inc
  2. Zhang X, Hamadeh IS, Song S Osteonecrosis of the Jaw in the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.2693
  3. Rosella D, Papi P, Giardino R Medication-related osteonecrosis of the jaw: Clinical and practical guidelines. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820581/
  4. AIDhalaan NA, BaQais A, Al-Omar A Medication-related Osteonecrosis of the Jaw: A Review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067354/
  5. Ruggiero SL, Dodson TB, Aghaloo T Medication-Related Osteonecrosis of the Jaw - 2022 Update https://www.aaoms.org/docs/govt_affairs/advocacy_white_papers/mronj_position_paper.pdf

Drug and food interactions

Moderate

regorafenib food

Applies to: regorafenib

ADJUST DOSING INTERVAL: Depending on the amount of fat, food may enhance the oral bioavailability of both regorafenib and its active metabolites, M-2 and M-5. In 24 healthy male subjects, administration of regorafenib with a high-fat meal (945 calories; 54.6 g fat) increased the mean systemic exposure (AUC) of regorafenib by 48% but decreased the mean AUC of M-2 and M-5 by 20% and 51%, respectively, compared to administration under the fasted state. In contrast, administration with a low-fat meal (319 calories; 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively, compared to administration during fasting.

GENERALLY AVOID: Coadministration with grapefruit juice may alter the pharmacokinetics of regorafenib and its active metabolites. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied specifically with grapefruit juice, but has been reported with the potent CYP450 3A4 inhibitor, ketoconazole. In 18 healthy male study subjects, administration of a single 160 mg dose of regorafenib on day 5 of treatment with ketoconazole (400 mg daily for 18 days) resulted in a 33% increase in mean regorafenib systemic exposure (AUC) compared to administration of regorafenib alone. Additionally, there was a 93% decrease each in the mean AUC of the M-2 and M-5 metabolites. Both have been shown to have similar in vitro pharmacological activity and steady-state concentrations as regorafenib, thus the net clinical effect of these pharmacokinetic changes is unknown.

MANAGEMENT: To ensure optimal oral absorption, regorafenib should be administered with a low-fat breakfast that contains less than 30% fat. Examples of a low-fat breakfast include: 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, plus 8 ounces of skim milk (319 calories; 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories; 2 g fat). Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with regorafenib.

References (1)
  1. (2012) "Product Information. Stivarga (regorafenib)." Bayer Pharmaceutical Inc

Therapeutic duplication warnings

Therapeutic duplication is the use of more than one medicine from the same drug category or therapeutic class to treat the same condition. This can be intentional in cases where drugs with similar actions are used together for demonstrated therapeutic benefit. It can also be unintentional in cases where a patient has been treated by more than one doctor, or had prescriptions filled at more than one pharmacy, and can have potentially adverse consequences.

Duplication

Vegf/vegfr inhibitors

Therapeutic duplication

The recommended maximum number of medicines in the 'VEGF/VEGFR inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'VEGF/VEGFR inhibitors' category:

  • lenvatinib
  • regorafenib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

Duplication

Multikinase inhibitors

Therapeutic duplication

The recommended maximum number of medicines in the 'multikinase inhibitors' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'multikinase inhibitors' category:

  • lenvatinib
  • regorafenib

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

See also

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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

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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