Cyclosporineinteractions

A. Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function (see WARNINGS, Nephrotoxicity). Drugs That May Potentiate Renal Dysfunction Antibiotics Antineoplastic Antifungals Anti-Inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs ciprofloxacin melphalan amphotericin B azapropazon cimetidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) gentamicin ketoconazole colchicine ranitidine methotrexate tobramycin diclofenac trimethoprim with sulfamethoxazole naproxen vancomycin sulindac During the concomitant use of a drug that may exhibit additive or synergistic renal impairment potential with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, reduction in the dosage of cyclosporine and/or coadministered drug or an alternative treatment should be considered. Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase or decrease plasma or whole blood concentrations of cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption, such as orlistat, should be avoided. Appropriate Sandimmune dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (see DOSAGE AND ADMINISTRATION, Blood Concentration Monitoring). 1. Drugs That Increase Cyclosporine Concentrations Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs diltiazem fluconazole azithromycin methylprednisolone allopurinol nicardipine itraconazole clarithromycin amiodarone verapamil ketoconazole erythromycin bromocriptine voriconazole quinupristin/ dalfopristin colchicine danazol imatinib metoclopramide nefazodone oral contraceptives HIV Protease inhibitors The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however, no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly. Grapefruit Juice Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided. 2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations Antibiotics Anticonvulsants Other Drugs / Dietary Supplements nafcillin carbamazepine bosentan St. John’s Wort rifampin oxcarbazepine octreotide phenobarbital orlistat phenytoin sulfinpyrazone terbinafine ticlopidine Bosentan Concomitant use of bosentan (250 to 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a C min of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, C max, and trough concentration of approximately 50%, 30% and 60%, respectively, compared to when cyclosporine was given alone (see also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents). Concomitant use of cyclosporine with bosentan should be avoided. Boceprevir Concomitant use of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and C max of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone. Telaprevir Concomitant use of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on Day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and C max of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone. St. John’s Wort There have been reports of a serious drug interaction between cyclosporine and the herbal dietary supplement, St. John’s Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss. Rifabutin Rifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome P-450 system. The interaction between rifabutin and cyclosporine has not been studied. Care should be exercised when these two drugs are administered concomitantly. B. Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents Cyclosporine is an inhibitor of CYP3A4 and of multiple drug efflux transporters (e.g., P-glycoprotein) and may increase plasma concentrations of comedications that are substrates of CYP3A4, P-glycoprotein, or organic anion transporter proteins. Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and aliskiren, bosentan, dabigatran, repaglinide, NSAIDs, sirolimus, etoposide, and other drugs. See the full prescribing information of the other drug for further information and specific recommendations. The decision on concomitant use of cyclosporine with other drugs or agents should be made by the healthcare provider following the careful assessment of benefits and risks. Digoxin Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored. Colchicine There are reports on the potential of cyclosporine to enhance the toxic effects of colchicine, such as myopathy and neuropathy, especially in patients with renal dysfunction. Concomitant administration of cyclosporine and colchicine results in significant increases in colchicine plasma concentrations. If colchicine is used concurrently with cyclosporine, a reduction in the dosage of colchicine is recommended. HMG Co-A Reductase Inhibitors (Statins) Literature and postmarketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely, fluvastatin. When concurrently administered with cyclosporine, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis. Repaglinide Cyclosporine may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycemia. In 12 healthy male subjects who received two doses of 100 mg cyclosporine capsule orally 12 hours apart with a single dose of 0.25 mg repaglinide tablet (one half of a 0.5 mg tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide mean C max and AUC were increased 1.8-fold (range, 0.6 to 3.7-fold) and 2.4-fold (range, 1.2 to 5.3-fold), respectively. Close monitoring of blood glucose level is advisable for a patient taking cyclosporine and repaglinide concomitantly. Ambrisentan Concomitant use of ambrisentan (5 mg daily) and cyclosporine (100 to 150 mg twice daily initially, then dosing to achieve C min 150 to 200 ng/mL) for 8 days in healthy subjects resulted mean increases in ambrisentan AUC and C max of approximately 2-fold and 1.5-fold, respectively, compared to ambrisentan alone. When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dosage. Anthracycline Antibiotics High dosage of cyclosporine (e.g., at starting intravenous dosage of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) in cancer patients. Aliskiren Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single doses of cyclosporine (200 mg) and reduced dose aliskiren (75 mg), the mean C max of aliskiren was increased by approximately 2.5-fold (90% CI: 1.96 to 3.17) and the mean AUC by approximately 4.3-fold (90% CI: 3.52 to 5.21), compared to when these subjects received aliskiren alone. The concomitant administration of aliskiren with cyclosporine prolonged the median aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the T max (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and C max of cyclosporine were comparable to reported literature values. Concomitant use of cyclosporine and aliskiren in these subjects also resulted in an increase in the number and/or intensity of adverse events, mainly headache, hot flush, nausea, vomiting, and somnolence. The concomitant use of cyclosporine with aliskiren is not recommended. Bosentan In healthy subjects, concomitant use of bosentan and cyclosporine resulted in time-dependent mean increases in dose-normalized bosentan trough concentrations (i.e., approximately 21-fold on Day 1 and 2-fold on Day 8 (steady state)) compared to when bosentan was given alone as a single dose on Day 1 (see also Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety). Concomitant use of cyclosporine with bosentan should be avoided. Dabigatran The effect of cyclosporine on dabigatran concentrations had not been formally studied. Concomitant administration of dabigatran and cyclosporine may result in increased plasma dabigatran concentrations due to the P-gp inhibitory activity of cyclosporine. Concomitant use of cyclosporine with dabigatran should be avoided. Potassium Sparing Diuretics Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur. Caution is also required when cyclosporine is coadministered with potassium-sparing drugs (e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists), potassium-containing drugs as well as in patients on a potassium-rich diet. Control of potassium levels in these situations is advisable. Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions Clinical status and serum creatinine should be closely monitored when cyclosporine is used with NSAIDs in rheumatoid arthritis patients (see WARNINGS). Pharmacodynamic interactions have been reported to occur between cyclosporine and both naproxen and sulindac, in that concomitant use is associated with additive decreases in renal function, as determined by 99m Tc-diethylenetriaminepenta acetic acid (DTPA) and p -aminohippuric acid (PAH) clearances. Although concomitant administration of diclofenac does not affect blood concentrations of cyclosporine, it has been associated with approximate doubling of diclofenac blood levels and occasional reports of reversible decreases in renal function. Consequently, the dosage of diclofenac should be in the lower end of the therapeutic range. Methotrexate Interaction Preliminary data indicate that when methotrexate and cyclosporine were coadministered to rheumatoid arthritis patients (N = 20), methotrexate concentrations (AUCs) were increased approximately 30% and the concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased by approximately 80%. The clinical significance of this interaction is not known. Cyclosporine concentrations do not appear to have been altered (N = 6). Sirolimus Elevations in serum creatinine were observed in studies using sirolimus in combination with full-dosage cyclosporine. This effect is often reversible with cyclosporine dosage reduction. Simultaneous concomitant use of cyclosporine significantly increases blood levels of sirolimus. To minimize increases in sirolimus blood concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration. Nifedipine Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine. Methylprednisolone Convulsions when high dose methylprednisolone is given concomitantly with cyclosporine have been reported. Other Immunosuppressive Drugs and Agents Psoriasis patients receiving other immunosuppressive agents or radiation therapy (including PUVA and UVB) should not receive concurrent cyclosporine because of the possibility of excessive immunosuppression. Interactions Resulting in Decrease of Other Drug Levels Cyclosporine inhibits the enterohepatic circulation of mycophenolic acid (MPA). Concomitant administration of cyclosporine and mycophenolate mofetil or mycophenolate sodium in transplant patients may decrease the mean exposure of MPA by 20% to 50% when compared with other immunosuppressants, which could reduce efficacy of mycophenolate mofetil or mycophenolate sodium. Monitor patients for alterations in efficacy of mycophenolate mofetil or mycophenolate sodium, when they are coadministered with cyclosporine. C. Effect of Cyclosporine on the Efficacy of Live Vaccines During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided.