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Drug Interactions between cilostazol and selumetinib

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

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Interactions between your drugs

Moderate

cilostazol selumetinib

Applies to: cilostazol and selumetinib

MONITOR: Selumetinib capsules contain vitamin E and may potentiate the effects of anticoagulants and platelet inhibitors. Vitamin E is thought to inhibit the oxidation of reduced vitamin K and interfere with the functions of vitamin K-dependent clotting factors. These effects appear to be dose-dependent and greater in individuals with preexisting vitamin K deficiency. In one study, administration of vitamin E 42 units/day for one month increased the hypoprothrombinemic effect of a single dose of dicumarol in 3 healthy volunteers, as demonstrated by a decrease in prothrombin activity from 52% to 33% thirty-six hours postdose. The interaction was also suspected in a patient who developed ecchymoses and hematuria following two months of vitamin E supplementation at a dosage of 800 to 1200 units/day while taking warfarin. In contrast, two studies found no significant effect of vitamin E on the hypoprothrombinemic effect of chronic warfarin therapy when administered at relatively high dosages (800 or 1200 units/day) to 21 subjects for one month or at low dosages (100 or 400 units/day) to 12 subjects for four weeks. With respect to antiplatelet activities, data from in vitro and ex vivo human studies suggest that vitamin E can inhibit collagen-induced platelet activation and protein kinase C-dependent platelet aggregation. Clinically significant antiplatelet effects have not been consistently observed in published studies, particularly at dosages below 400 units/day. However, there have been isolated reports of excessive bleeding in surgical patients who had taken vitamin E regularly prior to surgery, and one controlled clinical trial found that supplementation with only 50 mg/day of vitamin E resulted in an increase in subarachnoid hemorrhage in male smokers aged 55 to 74 years (n=409). In a random sampling of that same population of male smokers, gingival bleeding was also more common in subjects who received vitamin E with aspirin compared to those who received either agent alone or neither. Selumetinib 10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), while 25 mg capsules contain 36 mg vitamin E as TPGS.

MANAGEMENT: Close clinical and laboratory observation for hematologic complications may be appropriate when selumetinib is initiated in patients stabilized on anticoagulant or antiplatelet therapy. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

References

  1. Corrigan JJ (1982) "The effect of vitamin E on warfarin-induced vitamin K deficiency." Ann N Y Acad Sci, 393, p. 361-8
  2. Corrigan JJ, Ulfers LL (1981) "Effect of vitamin E on prothrombin levels in warfarin-induced vitamin K deficiency." Am J Clin Nutr, 34, p. 1701-5
  3. Schrogie JJ (1975) "Coagulopathy and fat-soluble vitamins." JAMA, 232, p. 19
  4. (1982) "Vitamin K, vitamin E and the coumarin drugs." Nutr Rev, 40, p. 180-2
  5. (1983) "Megavitamin E supplementation and vitamin K-dependent carboxylation." Nutr Rev, 41, p. 268-70
  6. Kim JM, White RH (1996) "Effect of vitamin E on the anticoagulant response to warfarin." Am J Cardiol, 77, p. 545-6
  7. Helson L (1984) "The effect of intravenous vitamin E and menadiol sodium diphosphate on vitamin K dependent clotting factors." Thromb Res, 35, p. 11-8
  8. Heck AM, DeWitt BA, Lukes AL (2000) "Potential interactions between alternative therapies and warfarin." Am J Health Syst Pharm, 57, 1221-7; quiz 1228-30
  9. Celestini A, Pulcinelli FM, Pignatelli P, et al. (2002) "Vitamin E potentiates the antiplatelet activity of aspirin in collagen-stimulated platelets." Haematologica, 87, p. 420-6
  10. Kakishita E, Suehiro A, Oura Y, Nagai K (1990) "Inhibitory effect of vitamin E (alpha-tocopherol) on spontaneous platelet aggregation in whole blood." Thromb Res, 60, p. 489-99
  11. Mardla V, Kobzar G, Samel N (2004) "Potentiation of antiaggregating effect of prostaglandins by alpha-tocopherol and quercetin." Platelets, 15, p. 319-24
  12. Gonzalez-Correa JA, Arrebola MM, Guerrero A, et al. (2005) "Influence of vitamin E on the antiplatelet effect of acetylsalicylic acid in human blood." Platelets, 16(3-4), p. 171-9
  13. Shalansky S, Lynd L, Richardson K, Ingaszewski A, Kerr C (2007) "Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis." Pharmacotherapy, 27, p. 1237-47
  14. Booth SL, Golly I, Sacheck JM, Roubenoff R, Dallal GE, et al. (2004) "Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status." Am J Clin Nutr, 80, p. 143-8
  15. Freedman JE, Farhat JH, Loscalzo J, Keaney JF (1996) "Alpha-tocopherol inhibits aggregation of human platelets by a protein kinase C--dependent mechanism." Circulation, 94, p. 2434-40
  16. Stampfer MJ, Jakubowski JA, Faigel D, Vaillancourt R, Deykin D (1988) "Vitamin E supplementation effect on human platelet function, arachidonic acid metabolism, and plasma prostacyclin levels." Am J Clin Nutr, 47, p. 700-6
  17. Murohara T, Ikeda H, Otsuka Y, Aoki M, Takajo Y, et al. (2004) "Inhibition of platelet adherence to Mononuclear cells by alpha-tocopherol: role of P-selection." Circulation, 110, p. 141-8
  18. Jandak J, Steiner M, Richardson PD (1989) "Alpha-tocopherol, an effective inhibitor of platelet adhesion." Blood, 73, p. 141-9
  19. Liu M, Wallmon A, Olsson-Mortlock C, Wallin R, Saldeen T (2003) "Mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms." Am J Clin Nutr, 77, p. 700-6
  20. (2020) "Product Information. Koselugo (selumetinib)." Astra-Zeneca Pharmaceuticals
View all 20 references

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Drug and food interactions

Major

selumetinib food

Applies to: selumetinib

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selumetinib, which undergoes metabolism primarily by CYP450 3A4 and to a lesser extent by CYP450 2C19, 1A2, 2C9, 2E1 and 3A5, as well as glucuronidation by UGT1A1 and UGT1A3. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When coadministered with itraconazole, a potent CYP450 3A4 inhibitor, selumetinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 19% and 49%, respectively. When coadministered with fluconazole, a potent CYP450 2C19 and moderate CYP450 3A4 inhibitor, selumetinib Cmax and AUC increased by 26% and 53%, respectively. Concomitant use of erythromycin, a moderate CYP450 3A4 inhibitor, is predicted to increase selumetinib Cmax and AUC by 23% and 41%, 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. Increased exposure to selumetinib may increase the risk and/or severity of serious adverse effects such as cardiomyopathy (decrease in left ventricular ejection fraction by 10% or more below baseline), ocular toxicity (blurred vision, photophobia, cataracts, ocular hypertension, retinal pigment epithelial detachment, retinal vein occlusion), gastrointestinal toxicity (diarrhea, colitis), skin toxicity (dermatitis acneiform, maculopapular rash, eczema), and musculoskeletal toxicity (creatine phosphokinase elevations, myalgia, rhabdomyolysis).

ADJUST DOSING INTERVAL: Food may decrease the rate and extent of the oral absorption of selumetinib. When a single 75 mg dose of selumetinib (1.5 times the approved maximum recommended dose) was administered with a high-fat meal (1000 calories; 50% fat) in healthy adults, mean Cmax and AUC of selumetinib decreased by 50% and 16%, respectively, and time to reach peak concentration (Tmax) was delayed by approximately 1.5 hours compared to administration in the fasted state. When a single 50 mg dose of selumetinib was administered with a low-fat meal (400 calories; 25% fat) in healthy adults, selumetinib Cmax and AUC decreased by 60% and 38%, respectively, and Tmax was delayed by approximately 0.9 hours.

MANAGEMENT: Selumetinib should be administered on an empty stomach at least 1 hour before or 2 hours after a meal. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with selumetinib.

References

  1. (2020) "Product Information. Koselugo (selumetinib)." Astra-Zeneca Pharmaceuticals

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Moderate

cilostazol food

Applies to: cilostazol

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of cilostazol. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Until more information is available, the manufacturer recommends avoiding consumption of grapefruit juice during cilostazol therapy. Orange juice is not expected to interact with cilostazol.

References

  1. (2001) "Product Information. Pletal (cilostazol)." Otsuka American Pharmaceuticals Inc

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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.

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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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