Sandimmune (cyclosporine)

The principal adverse reactions of Sandimmune (cyclosporine) therapy are

• renal dysfunction,
•  tremor,
• hirsutism,
• hypertension, and
• gum hyperplasia.

Hypertension

• Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.

Glomerular Capillary Thrombosis

• Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure.
• The pathologic changes resemble those seen in the hemolytic-uremic syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function.
• Similar findings have been observed when other immunosuppressives have been employed post transplantation.

Hypomagnesemia

• Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy.
• Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high-dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity.

Clinical Studies

The following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants:

The following reactions occurred in 2% or less of patients:

• allergic reactions,
• anemia,
• anorexia,
• confusion,
•  conjunctivitis,
• edema,
• fever,
• brittle fingernails,
• gastritis,
• hearing loss,
• hiccups,
• hyperglycemia,
• muscle pain,
• peptic ulcer,
• thrombocytopenia,
• tinnitus.

The following reactions occurred rarely:

• anxiety,
• chest pain,
• constipation,
• depression,
• hair breaking,
• hematuria,
• joint pain,
• lethargy,
• mouth sores,
• myocardial infarction,
• night sweats,
• pancreatitis,
• pruritus,
• swallowing difficulty,
• tingling,
• upper GI bleeding,
• visual disturbance,
• weakness,
• weight loss.

Renal Transplant Patients in Whom Therapy Was Discontinued

• Sandimmune (cyclosporine) was discontinued on a temporary basis and then restarted in 18 additional patients.
• Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine -containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic).
• Both generalized and localized infections can occur. Pre-existing infections may also be aggravated.
• Fatal outcomes have been reported.

Infectious Complications in the Randomized Renal Transplant Patients

• Cremophor EL (polyoxyethylated castor oil) is known to cause hyperlipemia and electrophoretic abnormalities of lipoproteins.
• These effects are reversible upon discontinuation of treatment but are usually not a reason to stop treatment.

Postmarketing Experience

Hepatotoxicity

• Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported.

Increased Risk of Infections

• Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported.

Headache, including Migraine

• Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.

Pain of Lower Extremities

• Isolated cases of pain of lower extremities have been reported in association with cyclosporine. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.

Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP)

• Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP) have decreased bioavailability in comparison to Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED. Sandimmune and Neoral are not bioequivalent and cannot be used interchangeably without physician supervision.
• The initial oral dose of Sandimmune (cyclosporine) should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg.
• Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale.
• There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day.
• The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day.
• Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate.

(See Blood Concentration Monitoring, below)

Specific Populations

Renal Impairment

• Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments.
• However, due to its nephrotoxic potential, careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated.

Hepatic Impairment

• The clearance of cyclosporine may be significantly reduced in severe liver disease patients.
• Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range.

Pediatrics

• In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults.
• Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results.
  • A dosage schedule based on the patient's weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose.
  • Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day.
  • After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation.
• To make Sandimmune Oral Solution (cyclosporine oral solution, USP) more palatable, the oral solution may be diluted with milk, chocolate milk, or orange juice preferably at room temperature. Patients should avoid switching diluents frequently.
• Sandimmune Soft Gelatin Capsules and Oral Solution should be administered on a consistent schedule with regard to time of day and relation to meals.
• Take the prescribed amount of Sandimmune (cyclosporine) from the container using the dosage syringe supplied after removal of the protective cover, and transfer the solution to a glass of milk, chocolate milk, or orange juice.
  • Stir well and drink at once. Do not allow to stand before drinking.
  • It is best to use a glass container and rinse it with more diluent to ensure that the total dose is taken.
  • After use, replace the dosage syringe in the protective cover.
  • Do not rinse the dosage syringe with water or other cleaning agents either before or after use.
  • If the dosage syringe requires cleaning, it must be completely dry before resuming use. Introduction of water into the product by any means will cause variation in dose.

Sandimmune Injection (cyclosporine injection, USP)

FOR INFUSION ONLY

Note: Anaphylactic reactions have occurred with Sandimmune Injection (cyclosporine injection, USP).

• Patients unable to take Sandimmune Soft Gelatin Capsules or Oral Solution pre-or postoperatively may be treated with the intravenous (IV) concentrate.
• Sandimmune Injection (cyclosporine injection, USP) is administered at 1/3 the oral dose.
• The initial dose of Sandimmune Injection (cyclosporine injection, USP) should be given 4 to 12 hours prior to transplantation as a single intravenous dose of 5 to 6 mg/kg/day. This daily single dose is continued postoperatively until the patient can tolerate the soft gelatin capsules or oral solution.
• Patients should be switched to Sandimmune Soft Gelatin Capsules or Oral Solution as soon as possible after surgery.
• In pediatric usage, the same dose and dosing regimen may be used, although higher doses may be required.
• Adjunct steroid therapy is to be used. (See aforementioned.)
• Immediately before use, the intravenous concentrate should be diluted 1 mL Sandimmune Injection (cyclosporine injection, USP) in 20 mL to 100 mL 0.9% Sodium Chloride Injection or 5% Dextrose Injection and given in a slow intravenous infusion over approximately 2 to 6 hours.
• Diluted infusion solutions should be discarded after 24 hours.
• The Cremophor EL (polyoxyethylated castor oil) contained in the concentrate for intravenous infusion can cause phthalate stripping from PVC.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Blood Concentration Monitoring

• Several study centers have found blood concentration monitoring of cyclosporine useful in patient management.
• While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough concentrations of 100 to 200 ng/mL as determined by high-pressure liquid chromatography (HPLC).
• Of major importance to blood concentration analysis is the type of assay used.
• The above concentrations are specific to the parent cyclosporine molecule and correlate directly to the new monoclonal specific radioimmunoassays (mRIA-sp). Nonspecific assays are also available which detect the parent compound molecule and various of its metabolites.
• Older studies often cited concentrations using a nonspecific assay which were roughly twice those of specific assays. Assay results are not interchangeable and their use should be guided by their approved labeling.
• If plasma specimens are employed, concentrations will vary with the temperature at the time of separation from whole blood. Plasma concentrations may range from ½ to 1/5 of whole blood concentrations. Refer to individual assay labeling for complete instructions.
• In addition, Transplantation Proceedings (June 1990) contains position papers and a broad consensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference that year. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

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.

Drugs That May Potentiate Renal Dysfunction

• 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 (cyclosporine) dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly. (See Blood Concentration Monitoring)

Drugs That Increase Cyclosporine Concentrations

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.

Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

Bosentan

• Co-administration 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 Cmin of 200 to 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) Coadministration of cyclosporine with bosentan should be avoided.

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.

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, P­glycoprotein, 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 coadministration 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 Cmax 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

• Coadministration of ambrisentan (5 mg daily) and cyclosporine (100 to 150 mg twice daily initially, then dosing to achieve Cmin 150 to 200 ng/mL) for 8 days in healthy subjects resulted mean increases in ambrisentan AUC and Cmax 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 dose.

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 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 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 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) Coadministration 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.
• Coadministration 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 ^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 levels 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 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.

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 1-888-NOW-NOVA (1-888-669-6682).

• There are no adequate and well-controlled studies in pregnant women and therefore, Sandimmune (cyclosporine) should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.
• Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Sandimmune, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.