Cyclosporine

The principal adverse reactions of Sandimmune (cyclosporine) therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.

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 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 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. (See WARNINGS)

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

Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported. (See WARNINGS, Hepatotoxicity)

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. (See WARNINGS, Polyoma Virus Infection)

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.

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.

Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.

Patients should be informed of the necessity of repeated laboratory tests while they are receiving the drug. They should be given careful dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia.

Patients using cyclosporine oral solution with its accompanying syringe for dosage measurement should be cautioned not to rinse the syringe either before or after use. Introduction of water into the product by any means will cause variation in dose.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Cyclosporine falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

If you take too much cyclosporine, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If cyclosporine is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Sandimmune® (cyclosporine). Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Sandimmune (cyclosporine) should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

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 absorption of cyclosporine during chronic administration of Sandimmune Soft Gelatin Capsules and Oral Solution was found to be erratic. It is recommended that patients taking the soft gelatin capsules or oral solution over a period of time be monitored at repeated intervals for cyclosporine blood concentrations and subsequent dose adjustments be made in order to avoid toxicity due to high concentrations and possible organ rejection due to low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood concentrations of cyclosporine. Comparison of concentrations in published literature to patient concentrations using current assays must be done with detailed knowledge of the assay methods employed.

• Eye Allergy
• Pinkeye (Conjunctivitis)
• Sjogren's Syndrome

Immunosuppressive agent and disease-modifying antirheumatic drug (DMARD);1 2 31 65 cyclic polypeptide.478 479

Storage

Oral

25°C (may be exposed to 15–30°C).479

<30°C.479 Do not refrigerate; protect from freezing.479

Discard 2 months after opening.479

Neoral: 20–25°C.478

Gengraf: 15–30°C.476

Neoral: 20–25°C.478 Do not refrigerate.478

Gengraf: 15–30°C.477 Do not refrigerate.477

Formation of gel, light flocculation, or formation of light sediment may occur at <20°C; warm Neoral oral solution to 25°C and Gengraf oral solution to 15–30°C to reverse these changes.477 478

Discard 2 months after opening.477 478

Parenteral

<30°C; protect from light.479

Polyoxyl 35 castor oil (in cyclosporine injection) can cause leaching of bis(2-ethylhexyl) phthalate (DEHP) from PVC containers.1 Cyclosporine 2 mg/mL is stable for 24 hours in dextrose 5% or sodium chloride 0.9% in glass or PVC containers;94 however, to minimize patient exposure to DEHP, some clinicians suggest that diluted solutions in PVC containers be administered immediately after preparation.95

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

General

Cyclosporine is the active ingredient of Cyclosporine Oral Solution USP MODIFIED. Hypertension is a common side effect of Cyclosporine therapy which may persist (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION for monitoring recommendations). Mild or moderate hypertension is encountered more frequently than severe hypertension and the incidence decreases over time. In recipients of kidney, liver, and heart allografts treated with Cyclosporine, antihypertensive therapy may be required (see Special Monitoring of Rheumatoid Arthritis Patients and Psoriasis Patients). However, since Cyclosporine may cause hyperkalemia, potassium-sparing diuretics should not be used. While calcium antagonists can be effective agents in treating Cyclosporine-associated hypertension, they can interfere with Cyclosporine metabolism (see Drug Interactions).

During treatment with Cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.

Before initiating treatment, a careful physical examination, including blood pressure measurements (on at least two occasions) and two creatinine levels to estimate baseline should be performed. Blood pressure and serum creatinine should be evaluated every 2 weeks during the initial 3 months and then monthly if the patient is stable. It is advisable to monitor serum creatinine and blood pressure always after an increase of the dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and after initiation of new NSAID therapy during Cyclosporine Oral Solution USP MODIFIED treatment. If coadministered with methotrexate, CBC and liver function tests are recommended to be monitored monthly (see also PRECAUTIONS, General, Hypertension).

In patients who are receiving Cyclosporine, the dose of Cyclosporine Oral Solution USP MODIFIED should be decreased by 25% to 50% if hypertension occurs. If hypertension persists, the dose of Cyclosporine Oral Solution USP MODIFIED should be further reduced or blood pressure should be controlled with antihypertensive agents. In most cases, blood pressure has returned to baseline when Cyclosporine was discontinued.

In placebo-controlled trials of rheumatoid arthritis patients, systolic hypertension (defined as an occurrence of two systolic blood pressure readings > 140 mmHg) and diastolic hypertension (defined as two diastolic blood pressure readings > 90 mmHg) occurred in 33% and 19% of patients treated with Cyclosporine, respectively. The corresponding placebo rates were 22% and 8%.

Before initiating treatment, a careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since Cyclosporine Oral Solution USP MODIFIED is an immunosuppressive agent, patients should be evaluated for the presence of occult infection on their first physical examination and for the presence of tumors initially, and throughout treatment with Cyclosporine Oral Solution USP MODIFIED. Skin lesions not typical for psoriasis should be biopsied before starting Cyclosporine Oral Solution USP MODIFIED. Patients with malignant or premalignant changes of the skin should be treated with Cyclosporine Oral Solution USP MODIFIED only after appropriate treatment of such lesions and if no other treatment option exists.

Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium, potassium, uric acid, and lipids.

The risk of Cyclosporine nephropathy is reduced when the starting dose is low (2.5 mg/kg/day), the maximum dose does not exceed 4 mg/kg/day, serum creatinine is monitored regularly while Cyclosporine is administered, and the dose of Cyclosporine Oral Solution USP MODIFIED is decreased when the rise in creatinine is greater than or equal to 25% above the patient's pretreatment level. The increase in creatinine is generally reversible upon timely decrease of the dose of Cyclosporine Oral Solution USP MODIFIED or its discontinuation.

Serum creatinine and BUN should be evaluated every 2 weeks during the initial 3 months of therapy and then monthly if the patient is stable. If the serum creatinine is greater than or equal to 25% above the patient’s pretreatment level, serum creatinine should be repeated within two weeks. If the change in serum creatinine remains greater than or equal to 25% above baseline, Cyclosporine Oral Solution USP MODIFIED should be reduced by 25% to 50%. If at any time the serum creatinine increases by greater than or equal to 50% above pretreatment level, Cyclosporine Oral Solution USP MODIFIED should be reduced by 25% to 50%. Cyclosporine Oral Solution USP MODIFIED should be discontinued if reversibility (within 25% of baseline) of serum creatinine is not achievable after two dosage modifications. It is advisable to monitor serum creatinine after an increase of the dose of nonsteroidal anti-inflammatory drug and after initiation of new nonsteroidal anti-inflammatory therapy during Cyclosporine Oral Solution USP MODIFIED treatment.

Blood pressure should be evaluated every 2 weeks during the initial 3 months of therapy and then monthly if the patient is stable, or more frequently when dosage adjustments are made. Patients without a history of previous hypertension before initiation of treatment with Cyclosporine Oral Solution USP MODIFIED, should have the drug reduced by 25% to 50% if found to have sustained hypertension. If the patient continues to be hypertensive despite multiple reductions of Cyclosporine Oral Solution USP MODIFIED, then Cyclosporine Oral Solution USP MODIFIED should be discontinued. For patients with treated hypertension, before the initiation of Cyclosporine Oral Solution USP MODIFIED therapy, their medication should be adjusted to control hypertension while on Cyclosporine Oral Solution USP MODIFIED. Cyclosporine Oral Solution USP MODIFIED should be discontinued if a change in hypertension management is not effective or tolerable.

CBC, uric acid, potassium, lipids, and magnesium should also be monitored every 2 weeks for the first 3 months of therapy, and then monthly if the patient is stable or more frequently when dosage adjustments are made. Cyclosporine Oral Solution USP MODIFIED dosage should be reduced by 25% to 50% for any abnormality of clinical concern.

In controlled trials of Cyclosporine in psoriasis patients, Cyclosporine blood concentrations did not correlate well with either improvement or with side effects such as renal dysfunction.

Patients should be advised that any change of Cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.

Patients should be informed of the necessity of repeated laboratory tests while they are receiving Cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.

Patients should be advised that during treatment with Cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Patients should be given careful dosage instructions. Cyclosporine Oral Solution USP MODIFIED should be diluted, preferably with orange or apple juice that is at room temperature. This solution, when mixed with juice, may appear cloudy. The combination of Cyclosporine Oral Solution USP MODIFIED with milk can be unpalatable.

Patients should be advised to take Cyclosporine Oral Solution USP MODIFIED on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of Cyclosporine, thus should be avoided.

In all patients treated with Cyclosporine, renal and liver functions should be assessed repeatedly by measurement of serum creatinine, BUN, serum bilirubin, and liver enzymes. Serum lipids, magnesium, and potassium should also be monitored. Cyclosporine blood concentrations should be routinely monitored in transplant patients (see DOSAGE AND ADMINISTRATION, Blood Concentration Monitoring in Transplant Patients), and periodically monitored in rheumatoid arthritis patients.

Drug Interactions

All of the individual drugs cited below are well substantiated to interact with Cyclosporine. In addition, concomitant use of 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

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 Cyclosporine Oral Solution USP MODIFIED 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

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 and grapefruit juice affect metabolism, increasing blood concentrations of Cyclosporine, thus should be avoided.

2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

Coadministration 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.

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.

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.

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 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.

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 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-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 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 in 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 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 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.

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 Teva Pharmaceuticals at 1-888-838-2872.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity studies were carried out in male and female rats and mice. In the 78 week mouse study, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24 month rat study, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical maintenance dose (6 mg/kg). The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. Published reports indicate that co-treatment of hairless mice with UV irradiation and Cyclosporine or other immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone.

Cyclosporine was not mutagenic in appropriate test systems. Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by Cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE), at high concentrations in this system. In two published research studies, rabbits exposed to Cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of Cyclosporine intravenously (twice the recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown.

No impairment in fertility was demonstrated in studies in male and female rats.

Widely distributed papillomatosis of the skin was observed after chronic treatment of dogs with Cyclosporine at 9 times the human initial psoriasis treatment dose of 2.5 mg/kg, where doses are expressed on a body surface area basis. This papillomatosis showed a spontaneous regression upon discontinuation of Cyclosporine.

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants and patients with rheumatoid arthritis and psoriasis. The most common forms of neoplasms are non-Hodgkin’s lymphoma and carcinomas of the skin. The risk of malignancies in Cyclosporine recipients is higher than in the normal, healthy population but similar to that in patients receiving other immunosuppressive therapies. Reduction or discontinuance of immunosuppression may cause the lesions to regress.

In psoriasis patients on Cyclosporine, development of malignancies, especially those of the skin has been reported (see WARNINGS). Skin lesions not typical for psoriasis should be biopsied before starting Cyclosporine treatment. Patients with malignant or premalignant changes of the skin should be treated with Cyclosporine only after appropriate treatment of such lesions and if no other treatment option exists.

Pregnancy

Pregnancy Category C

Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally). Only at dose levels toxic to dams, were adverse effects seen in reproduction studies in rats. Cyclosporine has been shown to be embryo- and fetotoxic in rats and rabbits following oral administration at maternally toxic doses. Fetal toxicity was noted in rats at 0.8 and rabbits at 5.4 times the transplant doses in humans of 6 mg/kg, where dose corrections are based on body surface area. Cyclosporine was embryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardation.

There are no adequate and well-controlled studies in pregnant women therefore, Cyclosporine Oral Solution USP MODIFIED should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant transplant recipients who are being treated with immunosuppressants the risk of premature birth is increased. The following data represent the reported outcomes of 116 pregnancies in women receiving Cyclosporine during pregnancy, 90% of whom were transplant patients, and most of whom received Cyclosporine throughout the entire gestational period. The only consistent patterns of abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for gestational age. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) were complicated by disorders; including, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility, and fetoplacental dysfunction. Pre-term delivery occurred in 47%. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were small for gestational age. Neonatal complications occurred in 27%. Therefore, the risks and benefits of using Cyclosporine Oral Solution USP MODIFIED during pregnancy should be carefully weighed.

A limited number of observations in children exposed to Cyclosporine in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.

Because of the possible disruption of maternal-fetal interaction, the risk/benefit ratio of using Cyclosporine Oral Solution USP MODIFIED in psoriasis patients during pregnancy should carefully be weighed with serious consideration for discontinuation of Cyclosporine Oral Solution USP MODIFIED.

The alcohol content of Cyclosporine Oral Solution USP MODIFIED should also be taken into account in pregnant women (see WARNINGS, Special Excipients).

Nursing Mothers

Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Cyclosporine Oral Solution USP MODIFIED, 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. Cyclosporine Oral Solution USP MODIFIED contains ethanol. Ethanol will be present in human milk at levels similar to that found in maternal serum and if present in breast milk will be orally absorbed by a nursing infant (see WARNINGS).

Pediatric Use

Although no adequate and well-controlled studies have been completed in pediatric patients, transplant recipients as young as one year of age have received Cyclosporine Oral Solution USP MODIFIED with no unusual adverse effects. The safety and efficacy of Cyclosporine Oral Solution USP MODIFIED treatment in pediatric patients with juvenile rheumatoid arthritis or psoriasis below the age of 18 have not been established.

Geriatric Use

In rheumatoid arthritis clinical trials with Cyclosporine, 17.5% of patients were age 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥ 50% above the baseline after 3 to 4 months of therapy.

Clinical studies of Cyclosporine Oral Solution USP MODIFIED in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Kidney, Liver, and Heart Transplantation

The principal adverse reactions of Cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.

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 has been found in patients treated with Cyclosporine and may progress to graft failure. The pathologic changes resembled those seen in the hemolytic-uremic syndrome and included 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 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.

In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with Cyclosporine Oral Solution USP MODIFIED were comparable with those observed in 208 transplanted patients who received Sandimmune (Cyclosporine Oral Solution USP) in these same studies when the dosage of the two drugs was adjusted to achieve the same Cyclosporine blood trough concentrations.

Based on the historical experience with Sandimmune (Cyclosporine Oral Solution USP), the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants.

Among 705 kidney transplant patients treated with Cyclosporine oral solution (Sandimmune) in clinical trials, the reason for treatment discontinuation was renal toxicity in 5.4%, infection in 0.9%, lack of efficacy in 1.4%, acute tubular necrosis in 1%, lymphoproliferative disorders in 0.3%, hypertension in 0.3%, and other reasons in 0.7% of the patients.

The following reactions occurred in 2% or less of Cyclosporine-treated patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, migraine (Cyclosporine Oral Solution USP MODIFIED), 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.

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 (see WARNINGS).

Postmarketing Experience, Kidney, Liver and Heart Transplantation

Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported (see WARNINGS, Hepatotoxicity).

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 (see WARNINGS, Polyoma Virus Infections).

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.

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.

Rheumatoid Arthritis

The principal adverse reactions associated with the use of Cyclosporine in rheumatoid arthritis are renal dysfunction (see WARNINGS), hypertension (see PRECAUTIONS), headache, gastrointestinal disturbances, and hirsutism/hypertrichosis.

In rheumatoid arthritis patients treated in clinical trials within the recommended dose range, Cyclosporine therapy was discontinued in 5.3% of the patients because of hypertension and in 7% of the patients because of increased creatinine. These changes are usually reversible with timely dose decrease or drug discontinuation. The frequency and severity of serum creatinine elevations increase with dose and duration of Cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.

The following adverse events occurred in controlled clinical trials:

In addition, the following adverse events have been reported in 1% to < 3% of the rheumatoid arthritis patients in the Cyclosporine treatment group in controlled clinical trials.

Dry mouth, increased sweating

Allergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor NOS*, weight decrease, weight increase

Abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia

Hypoesthesia, neuropathy, vertigo

Goiter

Constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder

Abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection

Anemia, epistaxis, leukopenia, lymphadenopathy

Bilirubinemia

Diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia

Arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder

Breast fibroadenosis, carcinoma

Anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence

Breast pain, uterine hemorrhage

Abnormal chest sounds, bronchospasm

Abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria

Abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder

Abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence

*NOS = Not Otherwise Specified

Psoriasis

The principal adverse reactions associated with the use of Cyclosporine in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.

In psoriasis patients treated in US controlled clinical studies within the recommended dose range, Cyclosporine therapy was discontinued in 1% of the patients because of hypertension and in 5.4% of the patients because of increased creatinine. In the majority of cases, these changes were reversible after dose reduction or discontinuation of Cyclosporine.

There has been one reported death associated with the use of Cyclosporine in psoriasis. A 27 year-old male developed renal deterioration and was continued on Cyclosporine. He had progressive renal failure leading to death.

Frequency and severity of serum creatinine increases with dose and duration of Cyclosporine therapy. These elevations are likely to become more pronounced and may result in irreversible renal damage without dose reduction or discontinuation.

The following events occurred in 1% to less than 3% of psoriasis patients treated with Cyclosporine:

Fever, flushes, hot flushes

Chest pain

Appetite increased, insomnia, dizziness, nervousness, vertigo

Abdominal distention, constipation, gingival bleeding

Hyperbilirubinemia

Skin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]

Platelet, bleeding, and clotting disorders, red blood cell disorder

Infection, viral and other infection

Acne, folliculitis, keratosis, pruritus, rash, dry skin

Micturition frequency

Abnormal vision

Mild hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases in uric acid may occur and attacks of gout have been rarely reported. A minor and dose related hyperbilirubinemia has been observed in the absence of hepatocellular damage. Cyclosporine therapy may be associated with a modest increase of serum triglycerides or cholesterol. Elevations of triglycerides (> 750 mg/dL) occur in about 15% of psoriasis patients; elevations of cholesterol (> 300 mg/dL) are observed in less than 3% of psoriasis patients. Generally these laboratory abnormalities are reversible upon dose reduction or discontinuation of Cyclosporine.

Cases of transformation to erythrodermic psoriasis or generalized pustular psoriasis upon either withdrawal or reduction of Cyclosporine in patients with chronic plaque psoriasis have been reported.

Cyclosporine Oral Solution USP MODIFIED is available as a yellowish to yellow-brown oily liquid containing 100 mg/mL Cyclosporine, USP in a 50 mL bottle (NDC 0172-7313-20).

Store and Dispense

PHARMACIST: Store and dispense in the original container at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Do not store in the refrigerator. Once opened, the contents must be used within two months. At temperatures below 20°C (68°F) the solution may gel; light flocculation or the formation of a light sediment may also occur. This solution, when mixed with juice, may appear cloudy. There is no impact on product performance or dosing using the syringe provided. Allow to warm to room temperature 25°C (77°F) to reverse these changes.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Manufactured In Czech Republic By:

TEVA CZECH INDUSTRIES s.r.o.

Opava-Komarov, Czech Republic

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. F 4/2015

Cyclosporine Oral Solution USP Modified 100 mg/mL 50 mL Carton Text

NDC 0172-7313-20

Cyclosporine Oral
Solution USP MODIFIED
100 mg/mL

Each mL Contains:
Cyclosporine, USP 100 mg
dehydrated alcohol, USP 15.3% v/v (12.18% wt/vol)

WARNING: Cyclosporine Oral Solution USP
MODIFIED is NOT BIOEQUIVALENT to
Sandimmune® (Cyclosporine Oral Solution USP).
DO NOT use interchangeably without a
physician's supervision.

Rx only

50 mL size

TEVA