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Indications
Kidney, Liver, and Heart Transplantation Cyclosporine capsules (modified) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine capsules (modified) has been used in combination with azathioprine and corticosteroids. Rheumatoid Arthritis Cyclosporine capsules (modified) is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate.
Cyclosporine capsules (modified) can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone. Psoriasis Cyclosporine capsules (modified) is indicated for the treatment of adult, nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated or cannot be tolerated.
While rebound rarely occurs, most patients will experience relapse with cyclosporine capsules (modified) as with other therapies upon cessation of treatment.
Contraindications
General Cyclosporine capsules (modified) is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation. Rheumatoid Arthritis Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine capsules (modified). Psoriasis Psoriasis patients who are treated with cyclosporine capsules (modified) should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy.
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Psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine capsules (modified).
Warnings and precautions
( See also BOXED WARNING ) All Patients Cyclosporine, the active ingredient of cyclosporine capsules (modified), can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine. Renal dysfunction including structural kidney damage is a potential consequence of cyclosporine capsules (modified) and therefore renal function must be monitored during therapy. Care should be taken in using cyclosporine with nephrotoxic drugs (see PRECAUTIONS ) .
Patients receiving cyclosporine capsules (modified) require frequent monitoring of serum creatinine (see Special Monitoring under DOSAGE AND ADMINISTRATION ) . Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction.
An increase in serum creatinine and BUN may occur during cyclosporine capsules (modified) therapy and reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. 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.
Because cyclosporine capsules (modified) is not bioequivalent to Sandimmune ® , conversion from cyclosporine capsules (modified) to Sandimmune ® using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from cyclosporine capsules (modified) to Sandimmune ® should be made with increased monitoring to avoid the potential of underdosing. Kidney, Liver, and Heart Transplant Nephrotoxicity Cyclosporine, the active ingredient of cyclosporine capsules (modified), can cause nephrotoxicity and hepatotoxicity when used in high doses.
It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated. Based on the historical Sandimmune ® experience with oral solution, nephrotoxicity associated with cyclosporine had been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation.
Mild nephrotoxicity was generally noted 2 to 3 months after renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35 to 45 mg/dL and 2 to 2.5 mg/dL, respectively. These elevations were often responsive to cyclosporine dosage reduction. More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine.
Since these events are similar to renal rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction. Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated with one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.
Nephrotoxicity vs. Rejection Parameter Nephrotoxicity Rejection History Donor > 50 years old or hypotensive Anti-donor immune response Prolonged kidney preservation Retransplant patient Prolonged anastomosis time Concomitant nephrotoxic drugs Clinical Often > 6 weeks postop b Often < 4 weeks postop b Prolonged initial nonfunction Fever > 37.5°C (acute tubular necrosis) Weight gain > 0.5 kg Graft swelling and tenderness Decrease in daily urine volume > 500 mL (or 50%) Laboratory CyA serum trough level > 200 ng/mL CyA serum trough level < 150 ng/mL Gradual rise in Cr (< 0.15 mg/dL/day) a Rapid rise in Cr (> 0.3 mg/dL/day) a Cr plateau < 25% above baseline Cr > 25% above baseline BUN/Cr ≥ 20 BUN/Cr < 20 Biopsy Arteriolopathy (medial hypertrophy a , Endovasculitis c (proliferation a , hyalinosis, nodular deposits, intimal intimal arteritis b , necrosis, sclerosis) thickening, endothelial vacuolization, progressive scarring) Tubular atrophy, isometric vacuolization, Tubulitis with RBC b and WBC b casts, isolated calcifications some irregular vacuolization Minimal edema Interstitial edema c and hemorrhage b Mild focal infiltrates c Diffuse moderate to severe mononuclear infiltrates d Diffuse interstitial fibrosis, Glomerulitis (mononuclear cells) c often striped form Aspiration Cytology CyA deposits in tubular and Inflammatory infiltrate with mononuclear phagocytes, endothelial cells macrophages, lymphoblastoid cells, and Fine isometric vacuolization of tubular activated T-cells cells These strongly express HLA-DR antigens Urine Cytology Tubular cells with vacuolization and Degenerative tubular cells, plasma cells, and granularization lymphocyturia > 20% of sediment Manometry Intracapsular pressure < 40 mm Hg b Intracapsular pressure > 40 mm Hg b Ultrasonography Unchanged graft cross sectional area Increase in graft cross sectional area AP diameter ≥ Transverse diameter Magnetic Resonance Normal appearance Loss of distinct corticomedullary junction, swelling Imagery image intensity of parachyma approaching that of psoas, loss of hilar fat Radionuclide Scan Normal or generally decreased perfusion Patchy arterial flow Decrease in tubular function Decrease in perfusion > decrease in tubular function ( 131 I-hippuran) > decrease in perfusion Increased uptake of Indium 111 labeled platelets or ( 99m Tc DTPA) Tc-99m in colloid Therapy Responds to decreased Responds to increased steroids or cyclosporine antilymphocyte globulin a p < 0.05, b p < 0.01, c p < 0.001, d p < 0.0001 A form of a cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys.
From 5% to 15% of transplant recipients who have received cyclosporine will fail to show a reduction in rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate one or several of the following alterations: tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy.
Though none of these morphologic changes is entirely specific, a diagnosis of cyclosporine-associated structural nephrotoxicity requires evidence of these findings. When considering the development of cyclosporine-associated nephropathy, it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough concentrations of cyclosporine.
This is particularly true during the first 6 post-transplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of cyclosporine. Among other contributing factors to the development of interstitial fibrosis in these patients are prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection.
The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined. Reversibility of arteriolopathy has been reported after stopping cyclosporine or lowering the dosage. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. In the event of severe and unremitting rejection, when rescue therapy with pulse steroids and monoclonal antibodies fail to reverse the rejection episode, it may be preferable to switch to alternative immunosupp
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Interactions
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 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 s Antifungals Anti- Inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole melphalan amphotericin B ketoconazole azapropazon colchicine diclofenac naproxen sulindac cimetidine ranitidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate 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 capsules (modified) dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (s ee 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/ colchicine dalfopristin 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/DietarySupplements nafcillin carbamazepine bosentan St. John’s Wort rifampin oxcarbazepine octreotide phenobarbital orlistat phenytoin sulfinpyrazone terbinafine ticlopidine Bosentan Coadministration of bosentan (250 to 1,000 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 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 C max 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 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 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 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 Coadministration 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 in mean increases in ambrisentan AUC and C max of approximately 2-fold and 1.5-fold, respectiv
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Pregnancy and breastfeeding
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cyclosporine, including cyclosporine capsules (modified), during pregnancy. Encourage women who are taking cyclosporine capsules (modified) during pregnancy to enroll in the Transplant Pregnancy Registry International (TPRI) by calling 1-877-955-8677 or visiting https://www.transplantpregnancyregistry.org .
Risk Summary Available data from published literature, including the Transplant Pregnancy Registry International, observational cohort studies, case-controlled studies, meta-analysis, case series, and case reports, over decades of use with cyclosporine in pregnancy have not identified a drug associated risk of major birth defects, or miscarriage. Adverse maternal or fetal outcomes including hypertension, preeclampsia, preterm birth, and low birth weight are increased in patients treated with cyclosporine.
However, patients receiving cyclosporine during pregnancy have underlying medical conditions and may be treated with concomitant medications that limit the interpretability of these findings (see Data). Embryo-fetal developmental (EFD) studies in rats and rabbits with cyclosporine have shown embryo-fetal toxicity at dose levels below the maximum recommended human dose (MRHD) based on body surface area (BSA). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Available data from the National Transplantation Pregnancy Registry (NTPR) including 622 pregnancies in renal, liver, and heart transplant recipients exposed to cyclosporine during pregnancy found that the overall rate of major birth defects, live birth rates, and miscarriage rates were comparable to the general population.
Maternal and fetal adverse outcomes, including the rate of hypertension, preeclampsia, premature births, and low birth weight infants appear to be increased in transplant recipients treated with cyclosporine compared to the general population. However, these patients have underlying medical conditions that confound the above findings. Animal Data Animal studies have shown reproductive toxicity in rats and rabbits. Three EFD studies (two oral and one intravenous) are available in rats.
In two EFD studies, pregnant rats were orally administered with cyclosporine either at doses of 10, 17, 30, 100 and 300 mg/kg/day or 4, 10 and 25 mg/kg/day from gestation day (GD) 6 to 15 or from GD 7 to 17, respectively. Maternal toxicity characterized by mortality, clinical signs of toxicity and impaired body weight gain were observed at 30 mg/kg/day and above. Cyclosporine was embryo- and fetotoxic as indicated by increased embryonic mortality and reduced fetal weight together with skeletal retardations in rats at 25 mg/kg/day and above.
In addition, ventricular septal defect was observed at 25 mg/kg/day in fetuses. In the first study, the oral no observed effect level (NOEL) for both dams and fetuses was 17 mg/kg/day (0.2 times the MRHD based on BSA). In the other oral study, the NOEL for dams and fetuses were 10 and 4 mg/kg/day (0.13 and 0.05 times the MRHD based on BSA), respectively. In the IV EFD study, rats were administered with 3, 6 and 12 mg/kg/day of cyclosporine from GD 7 to 17.
An increase in post implantation loss was observed at 12 mg/kg/day; ventricular septal defect was observed at ≥ 6 mg/kg/day in fetuses. The IV NOEL for dams and fetus were 6 and 3 mg/kg/day (0.08 and 0.04 times the MRHD, respectively, based on BSA), respectively, after IV administration. In rabbits, cyclosporine was orally administered at dose levels of 10, 30, 100 or 300 mg/kg/day from GD 6 to 18. At 100 mg/kg/day and above, reduction in body weight gain of dams and at 300 mg/kg/day abortions were observed.
Maternal toxicity, embryo-fetotoxicity as indicated by increased pre- and postnatal mortality, reduced fetal weight together with skeletal retardations were observed at 100 mg/kg/day and above. The NOEL for dams and fetuses was 30 mg/kg/day (1 times the MRHD based on BSA). 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.
These findings have not been demonstrated in other species and their relevance for humans is unknown. In a peri- and postnatal development study in rats, pregnant rats were orally administered with cyclosporine (5, 15 or 45 mg/kg/day) from GD 15 until end of lactation. At 45 mg/kg/day (0.5 times the MRHD based on BSA), increased pre and postnatal mortality of offspring and reduced body weight gain of surviving pups were observed.
Cyclosporine up to 15 mg/kg/day (0.2 times the MRHD based on BSA) had no effect on pregnancy, pre and postnatal development of offspring. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cyclosporine, including cyclosporine capsules (modified), during pregnancy. Encourage women who are taking cyclosporine capsules (modified) during pregnancy to enroll in the Transplant Pregnancy Registry International (TPRI) by calling 1-877-955-8677 or visiting https://www.transplantpregnancyregistry.org .
Risk Summary Available data from published literature, including the Transplant Pregnancy Registry International, observational cohort studies, case-controlled studies, meta-analysis, case series, and case reports, over decades of use with cyclosporine in pregnancy have not identified a drug associated risk of major birth defects, or miscarriage. Adverse maternal or fetal outcomes including hypertension, preeclampsia, preterm birth, and low birth weight are increased in patients treated with cyclosporine.
However, patients receiving cyclosporine during pregnancy have underlying medical conditions and may be treated with concomitant medications that limit the interpretability of these findings (see Data). Embryo-fetal developmental (EFD) studies in rats and rabbits with cyclosporine have shown embryo-fetal toxicity at dose levels below the maximum recommended human dose (MRHD) based on body surface area (BSA). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Available data from the National Transplantation Pregnancy Registry (NTPR) including 622 pregnancies in renal, liver, and heart transplant recipients exposed to cyclosporine during pregnancy found that the overall rate of major birth defects, live birth rates, and miscarriage rates were comparable to the general population.
Maternal and fetal adverse outcomes, including the rate of hypertension, preeclampsia, premature births, and low birth weight infants appear to be increased in transplant recipients treated with cyclosporine compared to the general population. However, these patients have underlying medical conditions that confound the above findings. Animal Data Animal studies have shown reproductive toxicity in rats and rabbits. Three EFD studies (two oral and one intravenous) are available in rats.
In two EFD studies, pregnant rats were orally administered with cyclosporine either at doses of 10, 17, 30, 100 and 300 mg/kg/day or 4, 10 and 25 mg/kg/day from gestation day (GD) 6 to 15 or from GD 7 to 17, respectively. Maternal toxicity charac
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Adverse reactions
Kidney, Liver, and Heart Transplantation The principal adverse reactions of 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 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 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 In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with cyclosporine capsules (modified) were comparable with those observed in 208 transplanted patients who received Sandimmune ® 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 ® , the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants. Randomized Kidney Patients Cyclosporine Patients (Sandimmune ® ) Sandimmune ® Azathioprine Kidney Heart Liver Body System/ (N=227) (N=228) (N=705) (N=112) (N=75) Adverse Reactions % % % % % Genitourinary Renal Dysfunction 32 6 25 38 37 Cardiovascular Hypertension 26 18 13 53 27 Cramps 4 < 1 2 < 1 0 Skin Hirsutism 21 < 1 21 28 45 Acne 6 8 2 2 1 Central Nervous System Tremor 12 0 21 31 55 Convulsions 3 1 1 4 5 Headache 2 < 1 2 15 4 Gastrointestinal Gum Hyperplasia 4 0 9 5 16 Diarrhea 3 < 1 3 4 8 Nausea/Vomiting 2 < 1 4 10 4 Hepatotoxicity < 1 < 1 4 7 4 Abdominal Discomfort < 1 0 < 1 7 0 Autonomic Nervous System Paresthesia 3 0 1 2 1 Flushing < 1 0 4 0 4 Hematopoietic Leukopenia 2 19 < 1 6 0 Lymphoma < 1 0 1 6 1 Respiratory Sinusitis < 1 0 4 3 7 Miscellaneous Gynecomastia < 1 0 < 1 4 3 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 capsules (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 ). Infectious Complications in Historical Randomized Studies in Renal Transplant Patients Using Sandimmune ® Cyclosporine Treatment Azathioprine with Steroids* (N=227) (N=228) Complication % of Complications % of Complications Septicemia 5.3
4.8 Abscesses 4.4
5.3 Systemic Fungal Infection 2.2
3.9 Local Fungal Infection 7.5
9.6 Cytomegalovirus 4.8
12.3 Other Viral Infections 15.9
18.4 Urinary Tract Infections 21.1
20.2 Wound and Skin Infections 7.0
10.1Pneumonia 6.2
9.2 *Some patients also received ALG. Postmarketing Experience, Kidney, Liver and Heart Transplantation Hepatotoxicity Cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported (see WARNINGS , Hepatotoxicity ) . 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 (see WARNINGS , Polyoma Virus Infection ) .
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.
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: Cyclosporine capsules (modified)/Sandimmune ® Rheumatoid Arthritis Percentage of Patients with Adverse Events ≥3% in any Cyclosporine Treated Group Studies 651+652+2008 Study 302 Study 654 Study 654 Study 302 Studies 651+652+2008 Body System Preferred Term Sandimmune ® † (N=269) Sandimmune ® (N=155) Methotrexate & Sandimmune ® (N=74) Methotrexate & Placebo (N=73) cyclosporine capsules, (modified) (N=143) Placebo (N=201) Autonomic Nervous System Disorders Flushing 2% 2% 3% 0% 5% 2% Body As A Whole–General Disorders Accidental Trauma 0% 1% 10% 4% 4% 0% Edema NOS* 5% 14% 12% 4% 10% <1% Fatigue 6% 3% 8% 12% 3% 7% Fever 2% 3% 0% 0% 2% 4% Influenza-like symptoms <1% 6% 1% 0% 3% 2% Pain 6% 9% 10% 15% 13% 4% Rigors 1% 1% 4% 0% 3% 1% Cardiovascular Disorder Arrhythmia 2% 5% 5% 6% 2% 1% Chest Pain 4% 5% 1% 1% 6% 1% Hypertension 8% 26% 16% 12% 25% 2% Central and Peripheral Nervous System Disorders Dizziness 8% 6% 7% 3% 8% 3% Headache 17% 23% 22% 11% 25% 9% Migraine 2% 3% 0% 0% 3% 1% Paresthesia 8% 7% 8% 4% 11% 1% Tremor 8% 7% 7% 3% 13% 4% Gastrointestinal System Disorder Abdominal Pain 15% 15% 15% 7% 15% 10% Anorexia 3% 3% 1% 0% 3% 3% Diarrhea 12% 12% 18% 15% 13% 8% Dyspepsia 12% 12% 10% 8% 8% 4% Flatulence Gastrointestinal 5% 5% 5% 4% 4% 1% Disorder NOS* 0% 2% 1% 4% 4% 0% Gingivitis 4% 3% 0% 0% 0% 1% Gum Hyperplasia 2% 4% 1% 3% 4% 1%
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Composition
Active ingredients
CYCLOSPORINE 50MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
