Drug Interactions
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 non-steroidal anti-inflammatory drugs 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
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Antineoplastics |
Antifungals
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Anti-inflammatory Drugs |
Gastrointestinal Agents
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Immunosuppressives
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Other Drugs
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ciprofloxacin |
melphalan |
amphotericin B |
azapropazon |
cimetidine |
tacrolimus |
fibric acid derivatives |
gentamicin |
| ketoconazole |
colchicine |
ranitidine |
| (e.g., bezafibrate, fenofibrate) |
tobramycin |
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| diclofenac |
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| methotrexate
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vancomycin |
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| naproxen |
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trimethoprim with sulfamethoxazole |
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| sulindac |
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During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment 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 Neoral® dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly. (See Blood Concentration Monitoring)
1. Drugs That
Increase
Cyclosporine Concentrations
Calcium Channel Blockers |
Antifungals
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Antibiotics
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Glucocorticoids
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Other Drugs
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diltiazem |
fluconazole |
azithromycin |
methylprednisolone |
Allopurinol |
nicardipine |
itraconazole |
clarithromycin |
| Amiodarone |
verapamil |
ketoconazole |
erythromycin |
| Bromocriptine |
| voriconazole |
quinupristin/ dalfopristin |
| colchicine |
|
|
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| danazol |
|
|
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| imatinib |
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| metoclopramide |
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| nefazodone |
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| 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 |
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| phenobarbital |
orlistat |
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| phenytoin |
sulfinpyrazone |
|
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| terbinafine |
|
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| ticlopidine |
|
|
|
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Bosentan
Coadministration of bosentan (250–1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a Cmin of 200–250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, Cmax, 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).
Boceprevir
Coadministration 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 Cmax of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.
Telaprevir
Coadministration 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 Cmax 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 the multidrug efflux transporter P-glycoprotein and may increase plasma concentrations of comedications that are substrates of CYP3A4 or P-glycoprotein or both.
Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), and, aliskiren, 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 coadministration of cyclosporine with other drugs or agents should be made by the physician 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-CoA 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 100mg cyclosporine capsule orally 12 hours apart with a single dose of 0.25mg repaglinide tablet (one half of a 0.5mg tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide mean Cmax and AUC were increased 1.8 fold (range: 0.6-3.7 fold) and 2.4 fold (range 1.2-5.3 fold), respectively. Close monitoring of blood glucose level is advisable for a patient taking cyclosporine and repaglinide concomitantly.
Ambrisentan
Coadministration of ambrisentan (5 mg daily) and cyclosporine (100–150 mg twice daily initially, then dosing to achieve Cmin 150–200 ng/mL) for 8 days in healthy subjects resulted in mean increases in ambrisentan AUC and Cmax of approximately 2-fold and 1.5–fold, respectively, compared to ambrisentan alone.
Anthracycline antibiotics
High doses of cyclosporine (e.g., at starting intravenous dose 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 Cmax of aliskiren was increased by approximately 2.5 fold (90% CI: 1.96-3.17) and the mean AUC by approximately 4.3 fold (90% CI: 3.52-5.21), 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 Tmax (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and Cmax of cyclosporine were comparable to reported literature values. Coadministration 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 coadministration of cyclosporine with aliskiren is not recommended.
Bosentan
In healthy subjects, coadministration of bosentan and cyclosporine resulted in mean increases in dose-normalized bosentan trough concentrations on day 1 and day 8 of approximately 21-fold and 2-fold, respectively, 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)
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 nonsteroidal anti-inflammatory agents 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 99mTc-diethylenetriaminepentaacetic 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 concentrations and occasional reports of reversible decreases in renal function. Consequently, the dose 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-dose cyclosporine. This effect is often reversible with cyclosporine dose reduction. Simultaneous coadministration of cyclosporine significantly increases blood levels of sirolimus. To minimize increases in sirolimus 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 concurrently 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.
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.
For additional information on Cyclosporine Drug Interactions please contact Novartis Medical Affairs Department at 888-NOW-NOVA [888-669-6682].
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