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Drug Interactions between guanfacine and letrozole / ribociclib

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

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Interactions between your drugs

Major

guanFACINE ribociclib

Applies to: guanfacine and letrozole / ribociclib

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of guanfacine, which is primarily metabolized by the isoenzyme. The risk of adverse reactions such as hypotension, bradycardia, and sedation may increase. Ketoconazole, a potent CYP450 3A4 inhibitor, has been reported to increase guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) by 2- and 3-fold, respectively. A computer simulation suggests that fluconazole, a moderate CYP450 3A4 inhibitor, would increase guanfacine Cmax and AUC by about 1.5- and 2-fold, respectively.

MANAGEMENT: Caution and dosage adjustment are advised when guanfacine is administered with potent and moderate CYP450 3A4 inhibitors. For extended-release guanfacine, the manufacturers recommend reducing the dosage to half the recommended level during concomitant use . Further dosage adjustments may be required based on patient tolerance and response. The dosage should be increased to the recommended level following discontinuation of the CYP450 3A4 inhibitor.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. "Product Information. Intuniv (guanfacine)." Shire US Inc (2009):

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Moderate

letrozole ribociclib

Applies to: letrozole / ribociclib and 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

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

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Drug and food interactions

Major

guanFACINE food

Applies to: guanfacine

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of guanfacine. The risk of adverse reactions such as hypotension, bradycardia, and sedation may increase. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Ketoconazole, a potent CYP450 3A4 inhibitor, has been reported to increase guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 2- and 3-fold, respectively. A computer simulation suggests that fluconazole, a moderate CYP450 3A4 inhibitor, would increase guanfacine Cmax and AUC by about 1.5- and 2-fold, respectively. 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.

GENERALLY AVOID: Alcohol may enhance the sedative and hypotensive effects of guanfacine.

GENERALLY AVOID: Administration of extended-release guanfacine with a high-fat meal may increase the bioavailability of guanfacine. When a single 4 mg dose of extended-release guanfacine was administered to adult volunteers with a high-fat breakfast, mean guanfacine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 75% and 40%, respectively, compared to dosing in a fasted state.

MANAGEMENT: Patients treated with guanfacine should avoid consumption of grapefruit and grapefruit juice. In addition, it is preferable to avoid or limit the use of alcohol during treatment. Patients should be advised against driving or operating hazardous machinery until they know how the medication affects them. The extended-release formulation of guanfacine should not be taken together with a high-fat meal.

References

  1. "Product Information. Tenex (guanfacine)." Wyeth-Ayerst Laboratories PROD (2001):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  3. "Product Information. Intuniv (guanfacine)." Shire US Inc (2009):

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Moderate

ribociclib food

Applies to: 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. "Product Information. Kisqali (ribociclib)." Novartis Pharmaceuticals (2017):

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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.

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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