Gengraf
Cyclosporine · Capsule · Oral
Uses
Kidney, Liver, and Heart Transplantation Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine ( MODIFIED ) has been used in combination with azathioprine and corticosteroids. Rheumatoid Arthritis Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Gengraf ® can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone. Psoriasis Gengraf ® Capsules (cyclosporine capsules, USP [ 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 Gengraf ® as with other therapies upon cessation of treatment.
Dosage and administration
Gengraf ® Capsules (cyclosporine capsules, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune ® Soft Gelatin Capsules (cyclosporine capsules, USP). Gengraf ® and Sandimmune ® are not bioequivalent and cannot be used interchangeably without physician supervision. The daily dose of Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) should always be given in two divided doses (BID). It is recommended that Gengraf ® be administered 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. Specific Populations Renal Impairment in Kidney, Liver, and Heart Transplantation 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 (see CLINICAL PHARMACOLOGY ). However, due to its nephrotoxic potential (see WARNINGS ), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated (see WARNINGS and PRECAUTIONS ). Renal Impairment in Rheumatoid Arthritis and Psoriasis Patients with impaired renal function should not receive cyclosporine (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ). Hepatic Impairment The clearance of cyclosporine may be significantly reduced in severe liver disease patients (see CLINICAL PHARMACOLOGY ). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (see WARNINGS and PRECAUTIONS ). Newly Transplanted Patients The initial oral dose of Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Gengraf ® varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Gengraf ® is the same as the initial oral dose of Sandimmune ® . Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune ® in US transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Gengraf ® dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see Blood Concentration Monitoring in Transplant Patients , below). If cyclosporine trough blood concentrations are used, the target range is the same for Gengraf ® as for Sandimmune ® . Using the same trough concentration target range for Gengraf ® as for Sandimmune ® results in greater cyclosporine exposure when Gengraf ® is administered (see Pharmacokinetics, Absorption ). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Gengraf ® doses may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative 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. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation. Conversion from Sandimmune ® Soft Gelatin Capsules (Cyclosporine Capsules, USP) to Gengraf ® Capsules (Cyclosporine Capsules, USP [MODIFIED]) in Transplant Patients In transplanted patients who are considered for conversion to Gengraf ® from Sandimmune ® , Gengraf ® should be started with the same daily dose as was previously used with Sandimmune ® (1:1 dose conversion). The Gengraf ® dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Gengraf ® as for Sandimmune ® results in greater cyclosporine exposure when Gengraf ® is administered (see Pharmacokinetics , Absorption ). Patients with suspected poor absorption of Sandimmune ® require different dosing strategies (see Transplant Patients with Poor Absorption of Sandimmune ® , below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance. Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Gengraf ® . In addition, clinical safety parameters, such as serum creatinine and blood pressure, should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Gengraf ® must be adjusted accordingly. Transplant Patients with Poor Absorption of Sandimmune ® Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune ® may have poor or inconsistent absorption of cyclosporine from Sandimmune ® . After conversion to Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]), patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Gengraf ® , the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Gengraf ® at doses greater than 10 mg/kg/day.
Contraindications
General Gengraf ® Capsules (cyclosporine capsules, USP [ 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 Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]). Psoriasis Psoriasis patients who are treated with Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Gengraf ® .
Warnings
(See also BOXED WARNING ) All Patients Cyclosporine, the active ingredient of Gengraf ® Capsules (cyclosporine capsules, USP [ 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 Gengraf ® and therefore renal function must be monitored during therapy. Care should be taken in using cyclosporine with nephrotoxic drugs ( s ee PRECAUTIONS ) . Patients receiving Gengraf ® 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 Gengraf ® 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 Gengraf ® Capsules (cyclosporine capsules, USP [MODIFIED]) is not bioequivalent to Sandimmune ® Soft Gelatin Capsules (cyclosporine capsules, USP), conversion from Gengraf ® to Sandimmune ® using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from Gengraf ® 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 Gengraf ® Capsules (cyclosporine capsules, USP [ 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 2.0 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 Prolonged kidney preservation Prolonged anastomosis time Concomitant nephrotoxic drugs Anti-donor immune response Retransplant patient Clinical Often > 6 weeks postop b Prolonged initial nonfunction (acute tubular necrosis) Often < 4 weeks postop b Fever > 37.5°C 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 Gradual rise in Cr (< 0.15 mg/dL/day) a Cr plateau < 25% above baseline BUN/Cr ≥ 20 CyA serum trough level < 150 ng/mL Rapid rise in Cr (> 0.3 mg/dL/day) a Cr > 25% above baseline BUN/Cr < 20 Biopsy Arteriolopathy (medial hypertrophy a , hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) Tubular atrophy, isometric vacuolization, isolated calcifications Minimal edema Mild focal infiltrates c Diffuse interstitial fibrosis, often striped form Endovasculitis c (proliferation a , intimal arteritis b , necrosis, sclerosis) Tubulitis with RBC b and WBC b casts, some irregular vacuolization Interstitial edema c and hemorrhage b Diffuse moderate to severe mononuclear infiltrates d Glomerulitis (mononuclear cells) c Aspiration Cytology CyA deposits in tubular and endothelial cells Fine isometric vacuolization of tubular cells Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cells These strongly express HLA-DR antigens Urine Cytology Tubular cells with vacuolization and granularization Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment Manometry Ultrasonography Intracapsular pressure < 40 mm Hg b Unchanged graft cross sectional area Intracapsular pressure > 40 mm Hg b Increase in graft cross sectional area AP diameter ≥ Transverse diameter Magnetic Resonance Imagery Normal appearance Loss of distinct corticomedullary junction, swelling image intensity of parenchyma approaching that of psoas, loss of hilar fat Radionuclide Scan Normal or generally decreased perfusion Decrease in tubular function ( 131 I-hippuran) > decrease in perfusion ( 99m Tc DTPA) Patchy arterial flow Decrease in perfusion > decrease in tubular function Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid Therapy Responds to decreased cyclosporine Responds to increased steroids or antilymphocyte globulin a p <0.05, b p <0.01, c p <0.001, d p <0.0001 A form of a cycl…
Precautions
General Hypertension Cyclosporine is the active ingredient of Gengraf ® Capsules (cyclosporine capsules, 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 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 ). Vaccination During treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided. Special Monitoring of Rheumatoid Arthritis Patients 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 Gengraf ® Capsules (cyclosporine capsules, 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 Gengraf ® should be decreased by 25% to 50% if hypertension occurs. If hypertension persists, the dose of Gengraf ® 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%. Special Monitoring for Psoriasis Patients Before initiating treatment, a careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since Gengraf ® (cyclosporine capsules, 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 Gengraf ® . Skin lesions not typical for psoriasis should be biopsied before starting Gengraf ® . Patients with malignant or premalignant changes of the skin should be treated with Gengraf ® 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 4.0 mg/kg/day, serum creatinine is monitored regularly while cyclosporine is administered, and the dose of Gengraf ® 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 Gengraf ® 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, Gengraf ® 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, Gengraf ® should be reduced by 25% to 50%. Gengraf ® 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 Gengraf ® 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 Gengraf ® , 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 Gengraf ® , then Gengraf ® should be discontinued. For patients with treated hypertension, before the initiation of Gengraf ® therapy, their medication should be adjusted to control hypertension while on Gengraf ® . Gengraf ® 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. Gengraf ® dosage should be reduced by 25% to 50% for any abnormality of clinical concern.
Side effects
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 ( 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 ® ) Body System Adverse Reactions Sandimmune ® (N=227) % Azathioprine (N=228) % Kidney (N=705) % Heart (N=112) % Liver (N=75) % 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 1.0%, 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 (Gengraf ® ), 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 ® Complication Cyclosporine Treatment (N=227) % of Complications Azathioprine with Steroids* (N=228) % 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 10.1 Pneumonia 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, I ncluding 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.
Drug 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 Antineoplastics Anti-inflammatory Drugs Gastrointestinal Agents ciprofloxacin melphalan azapropazon cimetidine gentamicin colchicine ranitidine tobramycin Antifungals diclofenac vancomycin amphotericin B naproxen Immunosuppressives trimethoprim with sulfamethoxazole ketoconazole sulindac tacrolimus Other Drugs 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 Gengraf ® dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (see Blood Concentration Monitoring ). 1. Drugs That Increase Cyclosporine Concentrations Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs diltiazem fluconazole azithromycin methylprednisolone allopurinol nicardipine itraconazole clarithromycin amiodarone verapamil ketoconazole erythromycin bromocriptine voriconazole quinupristin/ dalfopristin colchicine danazol imatinib metoclopramide nefazodone oral contraceptives HIV Protease inhibitors The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly. Grapefruit juice Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided. 2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations Antibiotics Anticonvulsants Other Drugs/Dietary Supplements nafcillin carbamazepine bosentan rifampin oxcarbazepine octreotide phenobarbital orlistat phenytoin sulfinpyrazone St. John's Wort terbinafine ticlopidine Bosentan 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 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.
Use in specific populations
Specific Populations Renal Impairment in Kidney, Liver, and Heart Transplantation 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 (see CLINICAL PHARMACOLOGY ). However, due to its nephrotoxic potential (see WARNINGS ), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated (see WARNINGS and PRECAUTIONS ). Renal Impairment in Rheumatoid Arthritis and Psoriasis Patients with impaired renal function should not receive cyclosporine (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ). Hepatic Impairment The clearance of cyclosporine may be significantly reduced in severe liver disease patients (see CLINICAL PHARMACOLOGY ). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (see WARNINGS and PRECAUTIONS ).
Pregnancy
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cyclosporine, including Gengraf ® Capsules (cyclosporine capsules, USP [MODIFIED] ), during pregnancy. Encourage women who are taking Gengraf ® during pregnancy to enroll in the Transplant Pregnancy Registry International (TPRI) by calling 1-877-955-6877 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 MRHD based on BSA. The alcohol content of Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) should be taken into account when given to pregnant women (see WARNINGS, Special Excipients). 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.
Pediatric use
Pediatric Use Although no adequate and well-controlled studies have been completed in children, transplant recipients as young as one year of age have received cyclosporine ( MODIFIED ) with no unusual adverse effects. The safety and efficacy of cyclosporine ( MODIFIED ) treatment in children with juvenile rheumatoid arthritis or psoriasis below the age of 18 have not been established.
Geriatric use
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 ( 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.
Overdosage
There is a minimal experience with cyclosporine overdosage. Forced emesis and gastric lavage can be of value up to 2 hours after administration of Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]). Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. Oral doses of cyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Cyclosporine is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral dosage at which half of experimental animals are estimated to die is 31 times, 39 times, and > 54 times the human maintenance dose for transplant patients (6mg/kg; corrections based on body surface area) in mice, rats, and rabbits.
Description
Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment. Cyclosporine, the active principle in Gengraf ® Capsules, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Aphanocladium album . Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic-(L-alanyl-D-alanyl- N -methyl-L-leucyl- N -methyl-L-leucyl- N -methyl-L-valyl-3-hydroxy- N ,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyryl- N -methylglycyl- N -methyl-L-leucyl-L-valyl- N -methyl-L-leucyl). Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) are available in 25 mg and 100 mg strengths. Each 25 mg capsule contains cyclosporine, 25 mg, alcohol, USP, absolute, 12.8% v/v (10.1% wt/vol.). Each 100 mg capsule contains cyclosporine, 100 mg, alcohol, USP, absolute, 12.8% v/v (10.1% wt/vol.). The chemical structure for cyclosporine USP is Inactive Ingredients FD&C Blue No. 2, gelatin NF, polyethylene glycol USP, polyoxyl 35 castor oil NF, polysorbate 80 NF, propylene glycol USP, sorbitan monooleate NF, titanium dioxide. The chemical structure for cyclosporine USP is:
How supplied
Gengraf ® Capsules (cyclosporine capsules, USP [MODIFIED]) 25 mg Oval, white imprinted in blue, 25 mg, and the code OR. Packages of 30 unit-dose blisters. ( NDC 0074-3108-32). 100 mg Oval, white, with two blue stripes, imprinted in blue, 100 mg, and the code OT. Packages of 30 unit-dose blisters. ( NDC 0074-3109-32). Store and Dispense In the original unit-dose container at controlled room temperature 68°-77°F (20°-25°C). (See USP Controlled Room Temperature). Gengraf is a trademark of AbbVie Inc. Sandimmune ® is a trademark of Novartis AG. © 2024 AbbVie. All rights reserved. AbbVie Inc., North Chicago, IL 60064, U.S.A. 20085115 R1 August, 2024
Storage
Store and Dispense In the original unit-dose container at controlled room temperature 68°-77°F (20°-25°C). (See USP Controlled Room Temperature). Gengraf is a trademark of AbbVie Inc. Sandimmune ® is a trademark of Novartis AG. © 2024 AbbVie. All rights reserved. AbbVie Inc., North Chicago, IL 60064, U.S.A. 20085115 R1 August, 2024
Label text from the FDA structured product label by AbbVie Inc. (revised Aug 21, 2024). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Cyclosporine in 2 products
Gengraf NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0074-3108 | Cyclosporine 25 mg/1 Capsule | AbbVie Inc. | ANDA |
| 0074-3109 | Cyclosporine 100 mg/1 Capsule | AbbVie Inc. | ANDA |
Frequently asked questions
What is Gengraf used for?
Kidney, Liver, and Heart Transplantation Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine ( MODIFIED ) has been used in combination with azathioprine and corticosteroids. Rheumatoid Arthritis Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is indicated for…
What are the side effects of Gengraf?
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… See the full label for the complete list.
Who makes Gengraf?
Gengraf is listed by 1 labeler in the FDA NDC directory, including AbbVie Inc..