Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Gengraf ® Oral Solution (cyclosporine oral solution, USP   [ MODIFIED ]).   At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Gengraf ® . 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. Gengraf ® , a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Gengraf ® may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients. Gengraf ® Oral Solution (cyclosporine oral solution, USP   [ MODIFIED ])   has increased bioavailability in comparison to Sandimmune ® Oral Solution (cyclosporine oral solution, USP). Gengraf ® and Sandimmune ® are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Gengraf ® than with Sandimmune ® . If a patient who is receiving exceptionally high doses of Sandimmune ® is converted to Gengraf ® , particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Gengraf ® to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed  ( see   DOSAGE AND ADMINISTRATION ) .

(See also BOXED WARNING )

Gengraf ® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune ® Oral Solution (cyclosporine oral solution, USP). Gengraf ® and Sandimmune ® are not bioequivalent and cannot be used interchangeably without physician supervision. The daily dose of Gengraf ® Oral Solution (cyclosporine oral solution, 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.

Gengraf ® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) A clear, colorless to yellow liquid supplied in 50 mL bottles containing 100 mg/mL with dispensing syringe ( NDC 0074-7269-50).

Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment. Cyclosporine, the active principle in Gengraf ® Oral Solution, 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 ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is available in 50 mL bottles. Each mL contains: cyclosporine 100 mg/mL.

Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

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. 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, 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 C max 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 T max (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and C max 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 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 co-administered 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 99m Tc-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. Interactions Resulting in Decrease of Other Drug Levels Cyclosporine inhibits the enterohepatic circulation of mycophenolic acid (MPA). Concomitant administration of cyclosporine and mycophenolate mofetil or mycophenolate sodium in transplant patients may decrease the mean exposure of MPA by 20% - 50% when compared with other immunosuppressants, which could reduce efficacy of mycophenolate mofetil or mycophenolate sodium. Monitor patients for alterations in efficacy of mycophenolate mofetil or mycophenolate sodium, when they are co-administered with cyclosporine. C. Effect of Cyclosporine on the Efficacy of Live Vaccines   During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided. For additional information on Cyclosporine Drug Interactions please contact AbbVie Inc. Medical Information Department at 1-800-633-9110.

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.

Risk Summary Cyclosporine and its metabolites are present in human milk following oral and intravenous administration. Adverse effects on the breastfed infant have not been reported. There are no data on the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Gengraf ®  and any potential adverse effects on the breastfed infant from Gengraf ® or from the underlying maternal condition. 

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.

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.

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 (0.03 times the maximum recommended human dose (MRHD) based on body surface area (BSA) 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 (0.006 times the MRHD based on BSA). 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 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 a fertility study in rats, increased perinatal mortality and impaired postnatal development of F1 pups were observed at 15 mg/kg/day (0.2 times the MRHD based on BSA). No adverse effects on fertility and reproduction were observed up to 5 mg/kg/day (0.06 times the MRHD based on BSA) 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.

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 ® Oral Solution (cyclosporine oral solution, 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.

Cyclosporine is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft versus host disease in many animal species for a variety of organs. The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G 0 - and G 1 -phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release, including interleukin-2. No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo ) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.

Rheumatoid Arthritis ACR responders graph.

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 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.

For Psoriasis Patients ( s ee also BOXED WARNING above) Psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]). Cyclosporine, the active ingredient in Gengraf ® , in recommended dosages, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.

The immunosuppressive activity of cyclosporine is primarily due to parent drug. Following oral administration, absorption of cyclosporine is incomplete. The extent of absorption of cyclosporine is dependent on the individual patient, the patient population, and the formulation. Elimination of cyclosporine is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of cyclosporine from blood is generally biphasic, with a terminal half-life of approximately 8.4 hours (range 5 to 18 hours). Following intravenous administration, the blood clearance of cyclosporine (assay: HPLC) is approximately 5 to 7 mL/min/kg in adult recipients of renal or liver allografts. Blood cyclosporine clearance appears to be slightly slower in cardiac transplant patients. The Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) and Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) are bioequivalent. Gengraf ® Oral Solution diluted with orange juice or with apple juice is bioequivalent to Gengraf ® Oral Solution diluted with water. The effect of milk on the bioavailability of cyclosporine when administered as Gengraf ® Oral Solution has not been evaluated. The relationship between administered dose and exposure (area under the concentration versus time curve, AUC) is linear within the therapeutic dose range. The intersubject variability (total, %CV) of cyclosporine exposure (AUC) when cyclosporine ( MODIFIED ) or Sandimmune ® is administered ranges from approximately 20% to 50% in renal transplant patients. This intersubject variability contributes to the need for individualization of the dosing regimen for optimal therapy (see DOSAGE AND ADMINISTRATION ). Intrasubject variability of AUC in renal transplant recipients (%CV) was 9% to 21% for cyclosporine ( MODIFIED ) and 19% to 26% for Sandimmune ® . In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for cyclosporine ( MODIFIED ) and 16% to 38% for Sandimmune ® . Absorption Cyclosporine ( MODIFIED ) has increased bioavailability compared to Sandimmune ® . The absolute bioavailability of cyclosporine administered as Sandimmune ® is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. The absolute bioavailability of cyclosporine administered as cyclosporine ( MODIFIED ) has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC was approximately 20% to 50% greater and the peak blood cyclosporine concentration (C max ) was approximately 40% to 106% greater following administration of cyclosporine ( MODIFIED ) compared to following administration of Sandimmune ® . The dose normalized AUC in de novo liver transplant patients administered cyclosporine ( MODIFIED ) 28 days after transplantation was 50% greater and C max was 90% greater than in those patients administered Sandimmune ® . AUC and C max are also increased (cyclosporine [ MODIFIED ] relative to Sandimmune ® ) in heart transplant patients, but data are very limited. Although the AUC and C max values are higher on cyclosporine ( MODIFIED ) relative to Sandimmune ® , the predose trough concentrations (dose-normalized) are similar for the two formulations. Following oral administration of cyclosporine ( MODIFIED ), the time to peak blood cyclosporine concentrations (T max ) ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine ( MODIFIED ) decreases the cyclosporine AUC and C max . A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine ( MODIFIED ) administration decreased the AUC by 13% and C max by 33%. The effects of a low-fat meal (667 kcal, 15 grams fat) were similar. The effect of T-tube diversion of bile on the absorption of cyclosporine from cyclosporine ( MODIFIED ) was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine ( MODIFIED ) with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9±41% (range, 55% to 68%). Pharmacokinetic Parameters (mean ± SD) Patient Population Dose/day 1 (mg/d) Dose/ weight (mg/kg/d) AUC 2 (ng·hr/mL) C max (ng/mL) Trough 3 (ng/mL) CL/F (mL/min) CL/F (mL/min/kg) De novo renal transplant 4 Week 4 (N=37) 597±174 7.95±2.81 8772±2089 1802±428 361±129 593±204 7.8±2.9 Stable renal transplant 4 (N=55) 344±122 4.10±1.58 6035±2194 1333±469 251±116 492±140 5.9±2.1 De novo liver transplant 5 Week 4 (N=18) 458±190 6.89±3.68 7187±2816 1555±740 268±101 577±309 8.6±5.7 De novo rheumatoid arthritis 6 (N=23) 182±55.6 2.37±0.36 2641±877 728±263 96.4±37.7 613±196 8.3±2.8 De novo psoriasis 6 Week 4 (N=18) 189±69.8 2.48±0.65 2324±1048 655±186 74.9±46.7 723±186 10.2±3.9 1 Total daily dose was divided into two doses administered every 12 hours. 2 AUC was measured over one dosing interval. 3 Trough concentration was measured just prior to the morning cyclosporine ( MODIFIED ) dose, approximately 12 hours after the previous dose. 4 Assay: TDx specific monoclonal fluorescence polarization immunoassay. 5 Assay: Cyclo-trac specific monoclonal radioimmunoassay. 6 Assay: INCSTAR specific monoclonal radioimmunoassay.  Distribution Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 58% in erythrocytes. At high concentrations, the binding capacity of leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk (see PRECAUTIONS, Nursing Mothers ).  Metabolism Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the coadministration of a variety of agents (see   PRECAUTIONS, Drug Interactions ). At least 25 metabolites have been identified from human bile, feces, blood, and urine. The biological activity of the metabolites and their contributions to toxicity are considerably less than those of the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. At steady state following the oral administration of Sandimmune ® , the mean AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5% of the AUC for blood cyclosporine concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered cyclosporine [ MODIFIED ] and Sandimmune ® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered cyclosporine [ MODIFIED ], 3 administered Sandimmune ® ), the percentage of dose present as M1, M9, and M4N metabolites is similar when either cyclosporine ( MODIFIED ) or Sandimmune ® is administered. Excretion Only 0.1% of a cyclosporine dose is excreted unchanged in the urine. Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Neither dialysis nor renal failure alters cyclosporine clearance significantly. Drug Interactions When diclofenac or methotrexate was coadministered with cyclosporine in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased (see PRECAUTIONS, Drug Interactions ). No clinically significant pharmacokinetic interactions occurred between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin. Specific Population s Renal Impairment In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <  5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate. Hepatic Impairment Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients. Pediatric Population Pharmacokinetic data from pediatric patients administered cyclosporine ( MODIFIED ) or Sandimmune ® are very limited. In 15 renal transplant patients aged 3 to 16 years, cyclosporine whole blood clearance after IV administration of Sandimmune ® was 10.6±3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2 to 16, the cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 9 liver transplant patients aged 0.6 to 5.6 years, clearance was 9.3±5.4 mL/min/kg (assay: HPLC). In the pediatric population, cyclosporine ( MODIFIED ) also demonstrates an increased bioavailability as compared to Sandimmune ® . In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of cyclosporine ( MODIFIED ) was 43% (range, 30% to 68%) and for Sandimmune ® in the same individuals absolute bioavailability was 28% (range, 17% to 42%). Pediatric Pharmacokinetic Parameters (mean±SD) Patient Population Dose/day (mg/d) Dose/weight (mg/kg/d) AUC 1 (ng·hr/mL) C max (ng/mL) CL/F (mL/min) CL/F (mL/min/kg) Stable liver transplant 2 Age 2 to 8, Dosed TID (N=9) 101±25 5.95±1.32 2163±801 629±219 285±94 16.6±4.3 Age 8 to 15, Dosed BID (N=8) 188±55 4.96±2.09 4272±1462 975±281 378±80 10.2±4.0 Stable liver transplant 3 Age 3, Dosed BID (N=1) 120 8.33 5832 1050 171 11.9 Age 8 to 15, Dosed BID (N=5) 158±55 5.51±1.91 4452±2475 1013±635 328±121 11.0±1.9 Stable renal transplant 3 Age 7 to 15, Dosed BID (N=5) 328±83 7.37±4.11 6922±1988 1827±487 418±143 8.7±2.9 1 AUC was measured over one dosing interval. 2 Assay: Cyclo-trac specific monoclonal radioimmunoassay. 3 Assay: TDx specific monoclonal fluorescence polarization immunoassay.  Geriatric Population Comparison of single dose data from both normal elderly volunteers (N=18, mean age 69 years) and elderly rheumatoid arthritis patients (N=16, mean age 68 years) to single dose data in young adult volunteers (N=16, mean age 26 years) showed no significant difference in the pharmacokinetic parameters.

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 ).

In the original container at controlled room temperature 68°-77°F (20°-25°C). (See USP Controlled Room Temperature). Do not store in the refrigerator. Once opened, the contents must be used within two months. At temperatures below 68°F (20°C) the solution may gel; light flocculation or the formation of a light sediment may also occur. There is no impact on product performance or dosing using the syringe provided. Allow to warm to room temperature 77°F (25°C) to reverse these changes. 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. 20085116 R1 August, 2024 

Polyoxyl 40 hydrogenated castor oil NF, propylene glycol USP, sorbitan monooleate NF. The chemical structure for cyclosporine USP is:

NDC 0074–7269–50 GENGRAF ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) 100 mg/mL 50 mL WARNING : Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is NOT BIOEQUIVALENT to Sandimmune ® Oral Solution (cyclosporine oral solution, USP). Do NOT use interchangeably without a physician’s supervision. abbvie Rx only

INSTRUCTIONS FOR USE GENGRAF ® (jen-graf) ORAL SOLUTION (cyclosporine oral solution, USP [MODIFIED]) This Instructions for Use contains information on how to prepare and take a dose of Gengraf Oral Solution. Read this Instructions for Use before taking Gengraf Oral Solution for the first time, and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical treatment or condition. Supplies Each carton contains (see Figure A ):                   5 mL syringe 50 mL bottle of Gengraf Oral Solution Bottle adapter The bottle adapter is not child-resistant. You will also need: Glass cup Room-temperature orange or apple juice Clean towel or tissue Figure A Important Information You Need to Know Before Taking Gengraf Oral Solution Do not use if the tamper-evident tape on the carton top or bottom is broken or missing before your first dose. Do not use if the product is expired. Do not rinse the syringe before use. If water gets into the product through the syringe, it will cause variation in dose. Do not rinse the bottle adapter before use. If water gets into the product through the bottle adapter, it will cause variation in dose. Always use the provided syringe for accurate dosing with less waste. Do not dilute with milk or grapefruit juice. Diluting with orange or apple juice improves taste. Do not frequently change the type of juice used. Make sure the juice is at room temperature. Preparing and Taking the Gengraf Oral Solution Dose: 1 To open the Gengraf Oral Solution bottle, push down on the child-resistant cap and turn it. Do not discard the child-resistant cap. 2 Push the bottle adapter into the bottle until it feels tight and secure. Part of the bottle adapter will remain above the bottle rim. D o not rinse  the bottle adapter before use. 3 Open the cover on top of the bottle adapter if it is closed. Insert the tip of the syringe firmly into the opening of the bottle adapter. D o not rinse  the syringe before use. 4 Invert the bottle. Draw up the prescribed amount of Gengraf Oral Solution with the syringe. 5 Remove large bubbles from the syringe . With the syringe attached to the bottle, move the plunger up and down to return air bubbles back into the bottle. 6 After any large air bubbles are removed, hold the syringe at eye level and adjust the plunger until the edge  of the plunger is even with the marking of the dose, as pictured. 7 Turn the bottle upright, then detach the syringe. Transfer the full prescribed dose of Gengraf Oral Solution from the syringe into a glass cup containing at least a few ounces of room temperature orange or apple juice, and stir. Do not  use a plastic cup. Do not use milk or grapefruit juice. If the syringe is not large enough to draw up the full prescribed amount, repeat steps 3 through 6 until the full amount has been measured. 8 Once the full dose is mixed in the glass, drink it right away. Do not allow the diluted oral solution to stand before drinking it. 9 After you finish drinking: There will still be Gengraf Oral S olution left inside the glass, even if you can not see it. To make sure you get your full dose, pour at least a few ounces of additional juice into the glass, stir, and drink. 10 After use, set the bottle on a flat surface, and grasp the body of the bottle adapter. Twist and pull the adapter to remove it from the bottle. The bottle adapter is not child resistant . 11 Reseal the bottle with the child-resistant cap. 12 Wipe the syringe and bottle adapter with clean, dry tissue. Do not rinse them. If water gets into the product, it will cause variation in dose. 13 Store the syringe and bottle adapter in a clean, dry location. Storing Gengraf Oral Solution Store Gengraf Oral Solution in the original bottle at room temperature 68ºF to 77ºF (20ºC to 25ºC). After the bottle is opened for first use, the contents must be used within 2 months. Keep Gengraf Oral Solution and all medicines out of the reach of children. Call your healthcare provider or 1-800-633-9110 if you need help or have any questions about how to take Gengraf Oral Solution. © 2024 AbbVie. All rights reserved. GENGRAF and its design are trademarks of AbbVie Inc. AbbVie Inc., North Chicago, IL 60064, U.S.A. This Instructions for Use has been approved by the U.S. Food and Drug Administration. 20081968 March, 2024

Cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and liver failure, have been reported in patients treated with cyclosporine. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see ADVERSE REACTIONS, Postmarketing Experience , Kidney, Liver and Heart Transplantation ).  Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used. The chemistry elevations usually decreased with a reduction in dosage.

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.

Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Gengraf ® Oral Solution (cyclosporine oral solution, USP   [ MODIFIED ]).   At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Gengraf ® . 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. Gengraf ® , a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Gengraf ® may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients. Gengraf ® Oral Solution (cyclosporine oral solution, USP   [ MODIFIED ])   has increased bioavailability in comparison to Sandimmune ® Oral Solution (cyclosporine oral solution, USP). Gengraf ® and Sandimmune ® are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Gengraf ® than with Sandimmune ® . If a patient who is receiving exceptionally high doses of Sandimmune ® is converted to Gengraf ® , particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Gengraf ® to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed  ( see   DOSAGE AND ADMINISTRATION ) .

Gengraf ® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune ® Oral Solution (cyclosporine oral solution, USP). Gengraf ® and Sandimmune ® are not bioequivalent and cannot be used interchangeably without physician supervision. The daily dose of Gengraf ® Oral Solution (cyclosporine oral solution, 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.

Gengraf ® Oral Solution (cyclosporine oral solution, USP [MODIFIED]) A clear, colorless to yellow liquid supplied in 50 mL bottles containing 100 mg/mL with dispensing syringe ( NDC 0074-7269-50).

(See also BOXED WARNING )

Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

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. 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, 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 C max 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 T max (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and C max 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 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 co-administered 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 99m Tc-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. Interactions Resulting in Decrease of Other Drug Levels Cyclosporine inhibits the enterohepatic circulation of mycophenolic acid (MPA). Concomitant administration of cyclosporine and mycophenolate mofetil or mycophenolate sodium in transplant patients may decrease the mean exposure of MPA by 20% - 50% when compared with other immunosuppressants, which could reduce efficacy of mycophenolate mofetil or mycophenolate sodium. Monitor patients for alterations in efficacy of mycophenolate mofetil or mycophenolate sodium, when they are co-administered with cyclosporine. C. Effect of Cyclosporine on the Efficacy of Live Vaccines   During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided. For additional information on Cyclosporine Drug Interactions please contact AbbVie Inc. Medical Information Department at 1-800-633-9110.

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.

Risk Summary Cyclosporine and its metabolites are present in human milk following oral and intravenous administration. Adverse effects on the breastfed infant have not been reported. There are no data on the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Gengraf ®  and any potential adverse effects on the breastfed infant from Gengraf ® or from the underlying maternal condition. 

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.

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.

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 (0.03 times the maximum recommended human dose (MRHD) based on body surface area (BSA) 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 (0.006 times the MRHD based on BSA). 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 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 a fertility study in rats, increased perinatal mortality and impaired postnatal development of F1 pups were observed at 15 mg/kg/day (0.2 times the MRHD based on BSA). No adverse effects on fertility and reproduction were observed up to 5 mg/kg/day (0.06 times the MRHD based on BSA) 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.

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 ® Oral Solution (cyclosporine oral solution, 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.

Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment. Cyclosporine, the active principle in Gengraf ® Oral Solution, 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 ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is available in 50 mL bottles. Each mL contains: cyclosporine 100 mg/mL.

Cyclosporine is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft versus host disease in many animal species for a variety of organs. The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G 0 - and G 1 -phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release, including interleukin-2. No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo ) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.

Rheumatoid Arthritis ACR responders graph.

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 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.

For Psoriasis Patients ( s ee also BOXED WARNING above) Psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]). Cyclosporine, the active ingredient in Gengraf ® , in recommended dosages, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.

The immunosuppressive activity of cyclosporine is primarily due to parent drug. Following oral administration, absorption of cyclosporine is incomplete. The extent of absorption of cyclosporine is dependent on the individual patient, the patient population, and the formulation. Elimination of cyclosporine is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of cyclosporine from blood is generally biphasic, with a terminal half-life of approximately 8.4 hours (range 5 to 18 hours). Following intravenous administration, the blood clearance of cyclosporine (assay: HPLC) is approximately 5 to 7 mL/min/kg in adult recipients of renal or liver allografts. Blood cyclosporine clearance appears to be slightly slower in cardiac transplant patients. The Gengraf ® Capsules (cyclosporine capsules, USP [ MODIFIED ]) and Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) are bioequivalent. Gengraf ® Oral Solution diluted with orange juice or with apple juice is bioequivalent to Gengraf ® Oral Solution diluted with water. The effect of milk on the bioavailability of cyclosporine when administered as Gengraf ® Oral Solution has not been evaluated. The relationship between administered dose and exposure (area under the concentration versus time curve, AUC) is linear within the therapeutic dose range. The intersubject variability (total, %CV) of cyclosporine exposure (AUC) when cyclosporine ( MODIFIED ) or Sandimmune ® is administered ranges from approximately 20% to 50% in renal transplant patients. This intersubject variability contributes to the need for individualization of the dosing regimen for optimal therapy (see DOSAGE AND ADMINISTRATION ). Intrasubject variability of AUC in renal transplant recipients (%CV) was 9% to 21% for cyclosporine ( MODIFIED ) and 19% to 26% for Sandimmune ® . In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for cyclosporine ( MODIFIED ) and 16% to 38% for Sandimmune ® . Absorption Cyclosporine ( MODIFIED ) has increased bioavailability compared to Sandimmune ® . The absolute bioavailability of cyclosporine administered as Sandimmune ® is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. The absolute bioavailability of cyclosporine administered as cyclosporine ( MODIFIED ) has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC was approximately 20% to 50% greater and the peak blood cyclosporine concentration (C max ) was approximately 40% to 106% greater following administration of cyclosporine ( MODIFIED ) compared to following administration of Sandimmune ® . The dose normalized AUC in de novo liver transplant patients administered cyclosporine ( MODIFIED ) 28 days after transplantation was 50% greater and C max was 90% greater than in those patients administered Sandimmune ® . AUC and C max are also increased (cyclosporine [ MODIFIED ] relative to Sandimmune ® ) in heart transplant patients, but data are very limited. Although the AUC and C max values are higher on cyclosporine ( MODIFIED ) relative to Sandimmune ® , the predose trough concentrations (dose-normalized) are similar for the two formulations. Following oral administration of cyclosporine ( MODIFIED ), the time to peak blood cyclosporine concentrations (T max ) ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine ( MODIFIED ) decreases the cyclosporine AUC and C max . A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine ( MODIFIED ) administration decreased the AUC by 13% and C max by 33%. The effects of a low-fat meal (667 kcal, 15 grams fat) were similar. The effect of T-tube diversion of bile on the absorption of cyclosporine from cyclosporine ( MODIFIED ) was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine ( MODIFIED ) with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9±41% (range, 55% to 68%). Pharmacokinetic Parameters (mean ± SD) Patient Population Dose/day 1 (mg/d) Dose/ weight (mg/kg/d) AUC 2 (ng·hr/mL) C max (ng/mL) Trough 3 (ng/mL) CL/F (mL/min) CL/F (mL/min/kg) De novo renal transplant 4 Week 4 (N=37) 597±174 7.95±2.81 8772±2089 1802±428 361±129 593±204 7.8±2.9 Stable renal transplant 4 (N=55) 344±122 4.10±1.58 6035±2194 1333±469 251±116 492±140 5.9±2.1 De novo liver transplant 5 Week 4 (N=18) 458±190 6.89±3.68 7187±2816 1555±740 268±101 577±309 8.6±5.7 De novo rheumatoid arthritis 6 (N=23) 182±55.6 2.37±0.36 2641±877 728±263 96.4±37.7 613±196 8.3±2.8 De novo psoriasis 6 Week 4 (N=18) 189±69.8 2.48±0.65 2324±1048 655±186 74.9±46.7 723±186 10.2±3.9 1 Total daily dose was divided into two doses administered every 12 hours. 2 AUC was measured over one dosing interval. 3 Trough concentration was measured just prior to the morning cyclosporine ( MODIFIED ) dose, approximately 12 hours after the previous dose. 4 Assay: TDx specific monoclonal fluorescence polarization immunoassay. 5 Assay: Cyclo-trac specific monoclonal radioimmunoassay. 6 Assay: INCSTAR specific monoclonal radioimmunoassay.  Distribution Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 58% in erythrocytes. At high concentrations, the binding capacity of leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk (see PRECAUTIONS, Nursing Mothers ).  Metabolism Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the coadministration of a variety of agents (see   PRECAUTIONS, Drug Interactions ). At least 25 metabolites have been identified from human bile, feces, blood, and urine. The biological activity of the metabolites and their contributions to toxicity are considerably less than those of the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. At steady state following the oral administration of Sandimmune ® , the mean AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5% of the AUC for blood cyclosporine concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered cyclosporine [ MODIFIED ] and Sandimmune ® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered cyclosporine [ MODIFIED ], 3 administered Sandimmune ® ), the percentage of dose present as M1, M9, and M4N metabolites is similar when either cyclosporine ( MODIFIED ) or Sandimmune ® is administered. Excretion Only 0.1% of a cyclosporine dose is excreted unchanged in the urine. Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Neither dialysis nor renal failure alters cyclosporine clearance significantly. Drug Interactions When diclofenac or methotrexate was coadministered with cyclosporine in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased (see PRECAUTIONS, Drug Interactions ). No clinically significant pharmacokinetic interactions occurred between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin. Specific Population s Renal Impairment In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <  5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate. Hepatic Impairment Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients. Pediatric Population Pharmacokinetic data from pediatric patients administered cyclosporine ( MODIFIED ) or Sandimmune ® are very limited. In 15 renal transplant patients aged 3 to 16 years, cyclosporine whole blood clearance after IV administration of Sandimmune ® was 10.6±3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2 to 16, the cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 9 liver transplant patients aged 0.6 to 5.6 years, clearance was 9.3±5.4 mL/min/kg (assay: HPLC). In the pediatric population, cyclosporine ( MODIFIED ) also demonstrates an increased bioavailability as compared to Sandimmune ® . In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of cyclosporine ( MODIFIED ) was 43% (range, 30% to 68%) and for Sandimmune ® in the same individuals absolute bioavailability was 28% (range, 17% to 42%). Pediatric Pharmacokinetic Parameters (mean±SD) Patient Population Dose/day (mg/d) Dose/weight (mg/kg/d) AUC 1 (ng·hr/mL) C max (ng/mL) CL/F (mL/min) CL/F (mL/min/kg) Stable liver transplant 2 Age 2 to 8, Dosed TID (N=9) 101±25 5.95±1.32 2163±801 629±219 285±94 16.6±4.3 Age 8 to 15, Dosed BID (N=8) 188±55 4.96±2.09 4272±1462 975±281 378±80 10.2±4.0 Stable liver transplant 3 Age 3, Dosed BID (N=1) 120 8.33 5832 1050 171 11.9 Age 8 to 15, Dosed BID (N=5) 158±55 5.51±1.91 4452±2475 1013±635 328±121 11.0±1.9 Stable renal transplant 3 Age 7 to 15, Dosed BID (N=5) 328±83 7.37±4.11 6922±1988 1827±487 418±143 8.7±2.9 1 AUC was measured over one dosing interval. 2 Assay: Cyclo-trac specific monoclonal radioimmunoassay. 3 Assay: TDx specific monoclonal fluorescence polarization immunoassay.  Geriatric Population Comparison of single dose data from both normal elderly volunteers (N=18, mean age 69 years) and elderly rheumatoid arthritis patients (N=16, mean age 68 years) to single dose data in young adult volunteers (N=16, mean age 26 years) showed no significant difference in the pharmacokinetic parameters.

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 ).

In the original container at controlled room temperature 68°-77°F (20°-25°C). (See USP Controlled Room Temperature). Do not store in the refrigerator. Once opened, the contents must be used within two months. At temperatures below 68°F (20°C) the solution may gel; light flocculation or the formation of a light sediment may also occur. There is no impact on product performance or dosing using the syringe provided. Allow to warm to room temperature 77°F (25°C) to reverse these changes. 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. 20085116 R1 August, 2024 

Polyoxyl 40 hydrogenated castor oil NF, propylene glycol USP, sorbitan monooleate NF. The chemical structure for cyclosporine USP is:

NDC 0074–7269–50 GENGRAF ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) 100 mg/mL 50 mL WARNING : Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is NOT BIOEQUIVALENT to Sandimmune ® Oral Solution (cyclosporine oral solution, USP). Do NOT use interchangeably without a physician’s supervision. abbvie Rx only

INSTRUCTIONS FOR USE GENGRAF ® (jen-graf) ORAL SOLUTION (cyclosporine oral solution, USP [MODIFIED]) This Instructions for Use contains information on how to prepare and take a dose of Gengraf Oral Solution. Read this Instructions for Use before taking Gengraf Oral Solution for the first time, and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical treatment or condition. Supplies Each carton contains (see Figure A ):                   5 mL syringe 50 mL bottle of Gengraf Oral Solution Bottle adapter The bottle adapter is not child-resistant. You will also need: Glass cup Room-temperature orange or apple juice Clean towel or tissue Figure A Important Information You Need to Know Before Taking Gengraf Oral Solution Do not use if the tamper-evident tape on the carton top or bottom is broken or missing before your first dose. Do not use if the product is expired. Do not rinse the syringe before use. If water gets into the product through the syringe, it will cause variation in dose. Do not rinse the bottle adapter before use. If water gets into the product through the bottle adapter, it will cause variation in dose. Always use the provided syringe for accurate dosing with less waste. Do not dilute with milk or grapefruit juice. Diluting with orange or apple juice improves taste. Do not frequently change the type of juice used. Make sure the juice is at room temperature. Preparing and Taking the Gengraf Oral Solution Dose: 1 To open the Gengraf Oral Solution bottle, push down on the child-resistant cap and turn it. Do not discard the child-resistant cap. 2 Push the bottle adapter into the bottle until it feels tight and secure. Part of the bottle adapter will remain above the bottle rim. D o not rinse  the bottle adapter before use. 3 Open the cover on top of the bottle adapter if it is closed. Insert the tip of the syringe firmly into the opening of the bottle adapter. D o not rinse  the syringe before use. 4 Invert the bottle. Draw up the prescribed amount of Gengraf Oral Solution with the syringe. 5 Remove large bubbles from the syringe . With the syringe attached to the bottle, move the plunger up and down to return air bubbles back into the bottle. 6 After any large air bubbles are removed, hold the syringe at eye level and adjust the plunger until the edge  of the plunger is even with the marking of the dose, as pictured. 7 Turn the bottle upright, then detach the syringe. Transfer the full prescribed dose of Gengraf Oral Solution from the syringe into a glass cup containing at least a few ounces of room temperature orange or apple juice, and stir. Do not  use a plastic cup. Do not use milk or grapefruit juice. If the syringe is not large enough to draw up the full prescribed amount, repeat steps 3 through 6 until the full amount has been measured. 8 Once the full dose is mixed in the glass, drink it right away. Do not allow the diluted oral solution to stand before drinking it. 9 After you finish drinking: There will still be Gengraf Oral S olution left inside the glass, even if you can not see it. To make sure you get your full dose, pour at least a few ounces of additional juice into the glass, stir, and drink. 10 After use, set the bottle on a flat surface, and grasp the body of the bottle adapter. Twist and pull the adapter to remove it from the bottle. The bottle adapter is not child resistant . 11 Reseal the bottle with the child-resistant cap. 12 Wipe the syringe and bottle adapter with clean, dry tissue. Do not rinse them. If water gets into the product, it will cause variation in dose. 13 Store the syringe and bottle adapter in a clean, dry location. Storing Gengraf Oral Solution Store Gengraf Oral Solution in the original bottle at room temperature 68ºF to 77ºF (20ºC to 25ºC). After the bottle is opened for first use, the contents must be used within 2 months. Keep Gengraf Oral Solution and all medicines out of the reach of children. Call your healthcare provider or 1-800-633-9110 if you need help or have any questions about how to take Gengraf Oral Solution. © 2024 AbbVie. All rights reserved. GENGRAF and its design are trademarks of AbbVie Inc. AbbVie Inc., North Chicago, IL 60064, U.S.A. This Instructions for Use has been approved by the U.S. Food and Drug Administration. 20081968 March, 2024

Cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and liver failure, have been reported in patients treated with cyclosporine. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see ADVERSE REACTIONS, Postmarketing Experience , Kidney, Liver and Heart Transplantation ).  Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used. The chemistry elevations usually decreased with a reduction in dosage.

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.