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Drug Interactions between Kisqali Femara Co-Pack and lorlatinib

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

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Interactions between your drugs

Moderate

letrozole ribociclib

Applies to: Kisqali Femara Co-Pack (letrozole / ribociclib) and Kisqali Femara Co-Pack (letrozole / ribociclib)

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

References (9)
  1. Zhou XJ, Zhou-Pan XR, Gauthier T, Placidi M, Maurel P, Rahmani R (1993) "Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions." Biochem Pharmacol, 45, p. 853-61
  2. Trivier JM, Libersa C, Belloc C, Lhermitte M (1993) "Amiodarone N-deethylation in human liver microsomes: involvement of cytochrome P450 3A enzymes (first report)." Life Sci, 52, pl91-6
  3. Rawden HC, Kokwaro GO, Ward SA, Edwards G (2000) "Relative contribution of cytochromes P-450 and flavin-containing monoxygenases to the metabolism of albendazole by human liver microsomes." Br J Clin Pharmacol, 49, p. 313-22
  4. DSouza DL, Levasseur LM, Nezamis J, Robbins DK, Simms L, Koch KM (2001) "Effect of alosetron on the pharmacokinetics of alprazolam." J Clin Pharmacol, 41, p. 452-4
  5. Katoh M, Nakajima M, Yamazaki H, Yokoi T (2001) "Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport." Eur J Pharm Sci, 12, p. 505-13
  6. Kane GC, Lipsky JJ (2000) "Drug-grapefruit juice interactions." Mayo Clin Proc, 75, p. 933-42
  7. Yu DK (1999) "The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions." J Clin Pharmacol, 39, p. 1203-11
  8. Nagy J, Schipper HG, Koopmans RP, Butter JJ, van Boxtel CJ, Kager PA (2002) "Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability." Am J Trop Med Hyg, 66, p. 260-3
  9. (2017) "Product Information. Kisqali (ribociclib)." Novartis Pharmaceuticals
Moderate

letrozole lorlatinib

Applies to: Kisqali Femara Co-Pack (letrozole / ribociclib) and lorlatinib

MONITOR: Coadministration with lorlatinib may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is increased clearance due to lorlatinib-mediated induction of CYP450 3A4 metabolism. The interaction has been studied with midazolam, a sensitive substrate of CYP450 3A4. When a single 2 mg oral dose of midazolam was administered with lorlatinib (150 mg orally once daily for 15 days), midazolam peak plasma concentration (Cmax) decreased by 50% and systemic exposure (AUC) decreased by 64%.

MANAGEMENT: Caution is advised when lorlatinib is used concomitantly with drugs that are substrates of CYP450 3A4. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lorlatinib is added to or withdrawn from therapy. Avoid concomitant use with lorlatinib where minimal decreases in concentration of the CYP450 3A4 substrate may lead to serious therapeutic failure. If coadministration is required, the CYP450 3A4 substrate dosage should be increased in accordance with approved product labeling.

References (2)
  1. (2018) "Product Information. Lorbrena (lorlatinib)." Pfizer U.S. Pharmaceuticals Group
  2. (2024) "Product Information. LORBRENA (lorlatinibe)." Pfizer Ltd
Moderate

ribociclib lorlatinib

Applies to: Kisqali Femara Co-Pack (letrozole / ribociclib) and lorlatinib

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ribociclib, which is a substrate of the isoenzyme. Physiologically-based pharmacokinetic simulations (PBPK) suggest that a moderate CYP450 3A4 inducer, efavirenz, may decrease ribociclib Cmax and AUC by 37% and 60%, respectively. However, data with less potent CYP450 3A4 inducers are limited.

MANAGEMENT: The potential for diminished therapeutic effects of ribociclib should be considered when prescribed with inducers of CYP450 3A4, particularly moderate inducers including efavirenz and nevirapine. Pharmacologic effects of ribociclib should be monitored more closely whenever an inducer is added to or withdrawn from therapy. Alternative treatment may be required if an interaction is suspected.

References (3)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. Cerner Multum, Inc. "Australian Product Information."
  3. (2017) "Product Information. Kisqali (ribociclib)." Novartis Pharmaceuticals

Drug and food interactions

Major

lorlatinib food

Applies to: lorlatinib

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of lorlatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients treated with lorlatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. If coadministration is unavoidable, some authorities recommend reducing the initial dosage of lorlatinib from 100 mg orally once daily to 75 mg orally once daily. In patients who have had a dosage reduction to 75 mg orally once daily due to adverse reactions, the lorlatinib dosage should be further reduced to 50 mg orally once daily upon initiation of a potent CYP450 3A4 inhibitor. After 3 plasma half-lives following discontinuation of the potent CYP450 3A4 inhibitor, the lorlatinib dosage may be increased to that used prior to initiation of the inhibitor.

References (2)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. (2018) "Product Information. Lorbrena (lorlatinib)." Pfizer U.S. Pharmaceuticals Group
Moderate

ribociclib food

Applies to: Kisqali Femara Co-Pack (letrozole / ribociclib)

GENERALLY AVOID: Pomegranates and grapefruit may increase the systemic exposure to ribociclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in these fruits. Increased exposure to ribociclib may increase the risk of adverse effects such as infections, neutropenia, leukopenia, anemia, thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, alopecia, fatigue, headache, and abnormal liver function may be increased.

MANAGEMENT: Patients receiving ribociclib should avoid consumption of pomegranates or pomegranate juice and grapefruit or grapefruit juice during treatment.

References (1)
  1. (2017) "Product Information. Kisqali (ribociclib)." Novartis Pharmaceuticals

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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