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Drug Interactions between colchicine and Sandimmune

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

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Major

cycloSPORINE colchicine

Applies to: Sandimmune (cyclosporine) and colchicine

ADJUST DOSE: Coadministration of cyclosporine and colchicine may significantly increase the plasma concentrations of both drugs. The proposed mechanism is competitive inhibition of P-glycoprotein (P-gp) efflux transporter in the intestine, renal proximal tubule and liver, resulting in increased drug absorption and decreased excretion. Competitive inhibition of CYP450 3A4 metabolism may also be involved. 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 cyclosporine resulted in an approximately 3.5-fold increase in colchicine peak plasma concentration (Cmax) and systemic exposure (AUC). The pharmacokinetics of cyclosporine were not reported in the study, although elevated cyclosporine levels requiring dose reduction have been noted in reports of suspected interaction with colchicine. Clinical manifestations associated with the interaction have included neuromyopathy, rhabdomyolysis, hepato- and nephrotoxicity, cardiotoxicity, bone marrow suppression, multiorgan failure, and fatality. 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.

MANAGEMENT: Due to the risk of life-threatening and fatal toxicity, patients with renal or hepatic impairment should not be given colchicine in combination cyclosporine. In patients with normal renal and hepatic function, the dosage of colchicine should be reduced when used with or within 14 days of cyclosporine therapy. For the treatment of acute 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 dosage of colchicine is 0.6 mg/day when used in the presence of cyclosporine. Patients should be advised to contact their physician if they experience symptoms of toxicity such as abdominal pain, nausea, vomiting, diarrhea, fatigue, myalgia, asthenia, hyporeflexia, paresthesia, and numbness. In addition, cyclosporine blood levels, serum electrolytes, as well as renal and hepatic function should be carefully monitored, and the cyclosporine dosage adjusted as necessary.

References

  1. Arellano F, Krupp P (1991) "Muscular disorders associated with cyclosporin." Lancet, 337, p. 915
  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. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  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. (2009) "Product Information. Colcrys (colchicine)." AR Scientific Inc
  20. 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
  21. 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
  22. Rana SS, Giuliani MJ, Oddis CV, Lacomis D (1997) "Acute onset of colchicine myoneuropathy in cardiac transplant recipients: case study of three patients." Clin Neurol Neurosurg, 99, p. 266-70
  23. Dupont P, Hunt I, Goldberg L, Warrens A (2002) "Colchicine myoneuropathy in a renal transplant patient." Transpl Int, 15, p. 374-6
  24. 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
View all 24 references

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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

  1. Pettinger WA (1975) "Clonidine, a new antihypertensive drug." N Engl J Med, 293, p. 1179-80
  2. Caraco Y, Putterman C, Rahamimov R, Ben-Chetrit E (1992) "Acute colchicine intoxication: possible role of erythromycin administration." J Rheumatol, 19, p. 494-6
  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
View all 19 references

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Moderate

cycloSPORINE food

Applies to: Sandimmune (cyclosporine)

GENERALLY AVOID: Administration with grapefruit juice (compared to water or orange juice) has been shown to increase blood concentrations of cyclosporine with a relatively high degree of interpatient variability. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

GENERALLY AVOID: Administration with red wine or purple grape juice may decrease blood concentrations of cyclosporine. In 12 healthy volunteers, 12 ounces total of a merlot consumed 15 minutes prior to and during cyclosporine administration (single 8 mg/kg dose of Sandimmune) decreased cyclosporine peak blood concentration (Cmax) and systemic exposure (AUC) by 38% and 30%, respectively, compared to water. The time to reach peak concentration (Tmax) doubled, and oral clearance increased 50%. Similarly, one study were 12 healthy patients were administered purple grape juice and a single dose of cyclosporine showed a 30% and a 36% decrease in cyclosporine systemic exposure (AUC) and peak blood concentration (Cmax), respectively. The exact mechanism of interaction is unknown but may involve decreased cyclosporine absorption.

MONITOR: Food has been found to have variable effects on the absorption of cyclosporine. There have been reports of impaired, unchanged, and enhanced absorption during administration with meals relative to the fasting state. The mechanisms are unclear. Some investigators found an association with the fat content of food. In one study, increased fat intake resulted in significantly increased cyclosporine bioavailability and clearance. However, the AUC and pharmacodynamics of cyclosporine were not significantly affected, thus clinical relevance of these findings may be minimal.

MANAGEMENT: Patients receiving cyclosporine therapy should be advised to either refrain from or avoid fluctuations in the consumption of grapefruits and grapefruit juice. Until more data are available, the consumption of red wine or purple grape juice should preferably be avoided or limited. All oral formulations of cyclosporine should be administered on a consistent schedule with regard to time of day and relation to meals so as to avoid large fluctuations in plasma drug levels.

References

  1. Honcharik N, Yatscoff RW, Jeffery JR, Rush DN (1991) "The effect of meal composition on cyclosporine absorption." Transplantation, 52, p. 1087-9
  2. Ducharme MP, Provenzano R, Dehoornesmith M, Edwards DJ (1993) "Trough concentrations of cyclosporine in blood following administration with grapefruit juice." Br J Clin Pharmacol, 36, p. 457-9
  3. Bailey DG, Arnold JMO, Spence JD (1994) "Grapefruit juice and drugs - how significant is the interaction." Clin Pharmacokinet, 26, p. 91-8
  4. Hollander AAMJ, Vanrooij J, Lentjes EGWM, Arbouw F, Vanbree JB, Schoemaker RC, Vanes LA, Vanderwoude FJ, Cohen AF (1995) "The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients." Clin Pharmacol Ther, 57, p. 318-24
  5. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
  6. Tan KKC, Trull AK, Uttridge JA, Metcalfe S, Heyes CS, Facey S, Evans DB (1995) "Effect of dietary fat on the pharmacokinetics and pharmacodynamics of cyclosporine in kidney transplant recipients." Clin Pharmacol Ther, 57, p. 425-33
  7. Yee GC, Stanley DL, Pessa LJ, et al. (1995) "Effect of grrapefruit juice on blood cyclosporin concentration." Lancet, 345, p. 955-6
  8. Ducharme MP, Warbasse LH, Edwards DJ (1995) "Disposition of intravenous and oral cyclosporine after administration with grapefruit juice." Clin Pharmacol Ther, 57, p. 485-91
  9. Ioannidesdemos LL, Christophidis N, Ryan P, Angelis P, Liolios L, Mclean AJ (1997) "Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases." J Rheumatol, 24, p. 49-54
  10. Min DI, Ku YM, Perry PJ, Ukah FO, Ashton K, Martin MF, Hunsicker LG (1996) "Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients." Transplantation, 62, p. 123-5
  11. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
  12. Tsunoda SM, Harris RZ, Christians U, et al. (2001) "Red wine decreases cyclosporine bioavailability." Clin Pharmacol Ther, 70, p. 462-7
  13. Oliveira-Freitas VL, Dalla Costa T, Manfro RC, Cruz LB, Schwartsmann G (2010) "Influence of purple grape juice in cyclosporine availability." J Ren Nutr, 20, p. 309-13
View all 13 references

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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.

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