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Drug Interactions between colchicine and Pyrukynd

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

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Major

colchicine mitapivat

Applies to: colchicine and Pyrukynd (mitapivat)

CONTRAINDICATED: Coadministration with inhibitors of P-glycoprotein (P-gp) may significantly increase the serum concentrations of colchicine in patients with renal or hepatic impairment. The mechanism involves enhanced absorption as well as reduced excretion of colchicine due to inhibition of the P-gp efflux transporter in the intestine, renal proximal tubule, and liver. Clinical manifestations associated with the interaction have included neuromyopathy, rhabdomyolysis, hepato- and nephrotoxicity, cardiotoxicity, bone marrow suppression, multiorgan failure, and fatality.

ADJUST DOSE: Coadministration with inhibitors of P-glycoprotein (P-gp) may significantly increase the serum concentrations of colchicine in patient with normal hepatic and renal function. In a study of 23 healthy volunteers, administration of a single 0.6 mg dose of colchicine in combination with a single 100 mg dose of the potent P-gp inhibitor cyclosporine resulted in an approximately 3.5-fold increase in colchicine peak plasma concentration (Cmax) and systemic exposure (AUC). In addition, in a retrospective study of renal transplant recipients at a French hospital, investigators reported that five out of ten patients who received cyclosporine in combination with colchicine experienced muscular symptoms, while none did in the control group that received only cyclosporine. Muscular histology, when performed, was consistent with previous reports of colchicine (i.e., vacuolar) myopathy. Mean duration of colchicine therapy was 12.2 months in the patients with muscular symptoms and 6.8 months in the patients without muscular symptoms. All five patients improved after colchicine withdrawal. No significant differences were found for age, gender ratio, transplant duration, serum creatinine levels, or cumulative steroid dose between case patients and controls. A similar interaction is expected with other P-gp inhibitors.

MANAGEMENT: Please consult the product labeling for the specific brand of colchicine being used for complete dosing information.
For the Lodoco brand, the use of colchicine and P-gp inhibitors is considered contraindicated in all patients.
For the Colcrys brand, the use of colchicine and P-gp inhibitors in patients with renal or hepatic impairment is considered contraindicated. In patients with normal renal and hepatic function, the dosage of colchicine should be reduced when used with P-gp inhibitors or within 14 days of using them. For the prophylaxis of gout flares, if the original dose was 0.6 mg twice a day the adjusted dosage recommended is 0.3 mg once a day. If the original dose was 0.6 mg once a day the adjusted dosage recommended is 0.3 mg once every other day. For the treatment of gout flares, the adjusted dosage recommended is 0.6 mg for one dose. Administration should not be repeated for at least three days. For the treatment of familial Mediterranean fever, the maximum recommended daily dosage of colchicine is 0.6 mg/day (may be given as 0.3 mg twice a day).
For the brands Gloperba and Mitigare, the use of colchicine and dual P-gp and CYP450 3A4 inhibitors in patients with renal or hepatic impairment is considered contraindicated. In patients with normal renal and hepatic function, the use of colchicine and P-gp inhibitors should be generally avoided. If coadministration is required, the dose of colchicine should be adjusted by reducing the dose or reducing the dose frequency and the patient should be closely monitored for signs of colchicine toxicity.

References (30)
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  2. Kuncl RW, Duncan G, Watson D, et al. (1987) "Colchicine myopathy and neuropathy." N Engl J Med, 316, p. 1562-8
  3. Rieger EH, Halasz NA, Wahlstrom HE (1990) "Colchicine neuromyopathy after renal transplantation." Transplantation, 49, p. 1196-8
  4. Speeg KV, Maldonado AL, Liaci J, Muirhead D (1992) "Effect of cyclosporine on colchicine secretion by the kidney multidrug transporter studied in vivo." J Pharmacol Exp Ther, 261, p. 50-5
  5. Yussim A, Barnathan N, Lustig S, Shaharabani E, Geier E, Shmuely D, Nakache R, Shapira Z (1994) "Gastrointestinal, hepatorenal, and neuromuscular toxicity caused by cyclosporine-colchicine interaction in renal transplantation." Transplant Proc, 26, p. 2825-6
  6. Rumpf KW, Henning HV (1990) "Is myopathy in renal transplant patients induced by cyclosporin or colchicine?." Lancet, 335, p. 800-1
  7. Menta R, Rossi E, Guariglia A, David S, Cambi V (1987) "Reversible acute cyclosporin nephrotoxicity induced by colchicine administration." Nephrol Dial Transplant, 2, p. 380-1
  8. Jonsson J, Gelpi JR, Light JA, Aquino A, Maszaros S (1992) "Colchicine-induced myoneuropathy in a renal transplant patient." Transplantation, 53, p. 1369-71
  9. Gruberg L, Har-Zahav Y, Agranat O, Freimark D (1999) "Acute myopathy induced by colchicine in a cyclosporine treated heart transplant recipient: possible role of the multidrug resistance transporter." Transplant Proc, 31, p. 2157-8
  10. Caglar K, Safali M, Yavuz I, Odabasi Z, Yenicesu M, Vural A (2002) "Colchicine-induced myopathy with normal creatine phosphokinase level in a renal transplant patient." Nephron, 92, p. 922-924
  11. Fujii Y, Arimura Y, Takahashi N, et al. (2003) "[A case of Behcet's disease associated with neuromyopathy induced by combination therapy with colchicine and cyclosporin]" Ryumachi, 43, p. 44-50
  12. Minetti EE, Minetti L (2003) "Multiple organ failure in a kidney transplant patient receiving both colchicine and cyclosporine." J Nephrol, 16, p. 421-5
  13. Vasudevan AR, Uthamalingam S, Kumar S, Tamarin F, Brensilver JM (2003) "Colchicine-induced rhabdomyolysis: the whole is greater than the sum of its parts!" Am J Med, 115, p. 249
  14. Wilbur K, Makowsky M (2004) "Colchicine myotoxicity: case reports and literature review." Pharmacotherapy, 24, p. 1784-92
  15. Englund G, Hallberg P, Artursson P, Michaelsson K, Melhus H (2004) "Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring." BMC Med, 2, p. 8
  16. Francis L, Bonilla E, Soforo E, et al. (2008) "Fatal toxic myopathy attributed to propofol, methylprednisolone, and cyclosporine after prior exposure to colchicine and simvastatin." Clin Rheumatol, 27, p. 129-31
  17. Eleftheriou G, Bacis G, Fiocchi R, Sebastiano R (2008) "Colchicine-induced toxicity in a heart transplant patient with chronic renal failure." Clin Toxicol (Phila), 46, p. 827-30
  18. (2008) "Colchicine: serious interactions." Prescrire Int, 17, p. 151-3
  19. Lee BI, Shin SJ, Yoon SN, Choi YJ, Yang CW, Bang BK (1997) "Acute myopathy induced by colchicine in a cyclosporine-treated renal transplant recipient--a case report and review of the literature." J Korean Med Sci, 12, p. 160-1
  20. Ducloux D, Schuller V, Bresson-Vautrin C, Chalopin JM (1997) "Colchicine myopathy in renal transplant recipients on cyclosporin." Nephrol Dial Transplant, 12, p. 2389-92
  21. Garrouste C, Philipponnet C, Kaysi S, Enache I, Tiple A, Heng AE (2012) "Severe colchicine intoxication in a renal transplant recipient on cyclosporine." Transplant Proc, 44, p. 2851-2
  22. Volpe DA, Hamed SS, Zhang LK (2014) "Use of different parameters and equations for calculation of IC50 values in efflux assays: potential sources of variability in IC 50 determination." AAPS J, 16, p. 172-80
  23. Nakamura T, Kakumoto M, Yamashita K, et al. (2001) "Factors influencing the prediction of steady state concentrations of digoxin." Biol Pharm Bull, 24, p. 403-8
  24. Mounier G, Guy C, Beyens MN, Ratrema M, Massol A, Ollagnier M (2006) "Colchicine-induced pancytopenia during therapeutic dose administratioin. French parmacovigilance database survey and literature review." Drug Saf, 29, p. 911-1010
  25. FDA. U.S. Food and Drug Administration (2015) Postmarket drug safty information for patients and providers. Drugs. Colchicine (marketed as Colcrys) information. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm174382.htm
  26. FDA. U.S. Food and Drug Administration (2015) Information for Healthcare Professionals: New safety information for Colchicine (marketed as Colcrys). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174315.htm
  27. (2023) "Product Information. Gloperba (colchicine)." Scilex Holding Company
  28. (2024) "Product Information. Mitigare (colchicine)." Hikma Americas, Inc
  29. (2024) "Product Information. Lodoco (colchicine)." AGEPHA Pharma USA, LLC
  30. (2023) "Product Information. Colcrys (colchicine)." Takeda Pharmaceuticals America

Drug and food interactions

Major

colchicine food

Applies to: colchicine

GENERALLY AVOID: Coadministration with grapefruit juice may increase the serum concentrations of colchicine. Clinical toxicity including myopathy, neuropathy, multiorgan failure, and pancytopenia may occur. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism and P-glycoprotein efflux in the gut wall by certain compounds present in grapefruits. A published case report describes an eight-year-old patient with familial Mediterranean fever who developed acute clinical colchicine intoxication after ingesting approximately one liter of grapefruit juice per day for two months prior to hospital admission while being treated with colchicine 2 mg/day. Her condition progressed to circulatory shock and multiorgan failure, but she recovered with supportive therapy after 24 days in the hospital. In a study of 21 healthy volunteers, administration of 240 mL grapefruit juice twice a day for 4 days was found to have no significant effect on the pharmacokinetics of a single 0.6 mg dose of colchicine. However, significant interactions have been reported with other CYP450 3A4 inhibitors such as clarithromycin, diltiazem, erythromycin, ketoconazole, ritonavir, and verapamil.

MANAGEMENT: Patients treated with colchicine should be advised to avoid the consumption of grapefruit and grapefruit juice, and to contact their physician if they experience symptoms of colchicine toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paresthesia, and numbness.

References (19)
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  3. Schiff D, Drislane FW (1992) "Rapid-onset colchicine myoneuropathy." Arthritis Rheum, 35, p. 1535-6
  4. Putterman C, Ben-Chetrit E, Caraco Y, Levy M (1991) "Colchicine intoxication: clinical pharmacology, risk factors, features, and management." Semin Arthritis Rheum, 21, p. 143-55
  5. Boomershine KH (2002) "Colchicine-induced rhabdomyolysis." Ann Pharmacother, 36, p. 824-6
  6. (2003) "Severe colchicine-macrolide interactions." Prescrire Int, 12, p. 18-9
  7. Tateishi T, Soucek P, Caraco Y, Guengerich FP, Wood AJ (1996) "Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation." Biochem Pharmacol, 53, p. 111-6
  8. Dogukan A, Oymak FS, Taskapan H, Guven M, Tokgoz B, Utas C (2001) "Acute fatal colchicine intoxication in a patient on continuous ambulatory peritoneal dialysis (CAPD). Possible role of clarithromycin administration." Clin Nephrol, 55, p. 181-2
  9. Rollot F, Pajot O, Chauvelot-Moachon L, Nazal EM, Kelaidi C, Blanche P (2004) "Acute colchicine intoxication during clarithromycin administration." Ann Pharmacother, 38, p. 2074-7
  10. Wilbur K, Makowsky M (2004) "Colchicine myotoxicity: case reports and literature review." Pharmacotherapy, 24, p. 1784-92
  11. Hung IF, Wu AK, Cheng VC, et al. (2005) "Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study." Clin Infect Dis, 41, p. 291-300
  12. Cheng VC, Ho PL, Yuen KY (2005) "Two probable cases of serious drug interaction between clarithromycin and colchicine." South Med J, 98, p. 811-3
  13. Akdag I, Ersoy A, Kahvecioglu S, Gullulu M, Dilek K (2006) "Acute colchicine intoxication during clarithromycin administration in patients with chronic renal failure." J Nephrol, 19, p. 515-7
  14. van der Velden W, Huussen J, Ter Laak H, de Sevaux R (2008) "Colchicine-induced neuromyopathy in a patient with chronic renal failure: the role of clarithromycin." Neth J Med, 66, p. 204-6
  15. Goldbart A, Press J, Sofer S, Kapelushnik J (2000) "Near fatal acute colchicine intoxication in a child. A case report." Eur J Pediatr, 159, p. 895-7
  16. (2008) "Colchicine: serious interactions." Prescrire Int, 17, p. 151-3
  17. (2009) "Product Information. Colcrys (colchicine)." AR Scientific Inc
  18. Dahan A, Amidon GL (2009) "Grapefruit juice and its constitueants augment colchicine intestinal absorption: potential hazardous interaction and the role of p-glycoprotein." Pharm Res, 26, p. 883-92
  19. McKinnell J, Tayek JA (2009) "Short term treatment with clarithromycin resulting in colchicine-induced rhabdomyolysis." J Clin Rheumatol, 15, p. 303-5
Major

mitapivat food

Applies to: Pyrukynd (mitapivat)

GENERALLY AVOID: Theoretically, the coadministration with grapefruit juice may increase the plasma concentrations of mitapivat. 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. 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. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid or limit consumption of grapefruit or grapefruit juice during therapy with mitapivat if possible. If concomitant use is unavoidable, close monitoring of hemoglobin levels and for the development of adverse effects such as atrial fibrillation, gastroenteritis, rib fracture, musculoskeletal pain, arthralgia, increased urate levels, and in males, for decreased estrone and estradiol levels, is recommended. The product labeling should be consulted for dose adjustments of mitapivat in the event of the development of adverse reaction or hemoglobin levels above normal.

References (33)
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  3. Bailey DG, Arnold JM, Munoz C, Spence JD (1993) "Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin." Clin Pharmacol Ther, 53, p. 637-42
  4. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  5. Sigusch H, Hippius M, Henschel L, Kaufmann K, Hoffmann A (1994) "Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation." Pharmazie, 49, p. 522-4
  6. Bailey DG, Arnold JM, Strong HA, Munoz C, Spence JD (1993) "Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics." Clin Pharmacol Ther, 54, p. 589-94
  7. Yamreudeewong W, Henann NE, Fazio A, Lower DL, Cassidy TG (1995) "Drug-food interactions in clinical practice." J Fam Pract, 40, p. 376-84
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  17. Bailey DG, Kreeft JH, Munoz C, Freeman DJ, Bend JR (1998) "Grapefruit juice felodipine interaction: Effect of naringin and 6',7'-dihydroxybergamottin in humans." Clin Pharmacol Ther, 64, p. 248-56
  18. Garg SK, Kumar N, Bhargava VK, Prabhakar SK (1998) "Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy." Clin Pharmacol Ther, 64, p. 286-8
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  22. Eagling VA, Profit L, Back DJ (1999) "Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components." Br J Clin Pharmacol, 48, p. 543-52
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Therapeutic duplication warnings

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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.

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