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GENGRAF® Capsules
(cyclosporine capsules
USP [MODIFIED])
WARNING
Only physicians experienced in the management of systemic immunosuppressive therapy for the indicated disease should prescribe Gengraf (cyclosporine capsules, 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 (cyclosporine capsules, USP [MODIFIED ]) has increased bioavailability in comparison to Sandimmune®* (cyclosporine capsules, 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.
For Psoriasis Patients (see also BOXED WARNINGS 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 (cyclosporine capsules, 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.
DESCRIPTION
Gengraf (cyclosporine capsules, USP [MODIFIED]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment.
Cyclosporine, the active principle in Gengraf, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Aphanocladium album.
Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic-(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl- L-2-amino-6-octenoyl-L-α-amino-butyryl-N-methylglycyl-N -methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).
Gengraf Capsules (cyclosporine capsules, USP [MODIFIED]) are available in 25 mg and 100 mg strengths.
Each 25 mg capsule contains
cyclosporine, 25 mg, alcohol, USP, absolute, 12.8% v/v (10.1% wt/vol.).
Each 100 mg capsule contains
cyclosporine, 100 mg, alcohol, USP, absolute, 12.8% v/v (10.1% wt/vol.).
Inactive Ingredients
FD&C Blue No. 2, gelatin NF, polyethylene glycol NF, polyoxyl 35 castor oil NF, polysorbate 80 NF, propylene glycol USP, sorbitan monooleate NF, titanium dioxide.
The chemical structure for cyclosporine USP is:
CLINICAL PHARMACOLOGY
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 vs. 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 G0- and G1-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.
Pharmacokinetics
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.
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%-21% for cyclosporine (MODIFIED) and 19%-26% for Sandimmune®. In the same studies, intrasubject variability of trough concentrations (% CV) was 17%-30% for cyclosporine (MODIFIED) and 16%-38% for Sandimmune®.
Special Population
CLINICAL TRIALS
Rheumatoid Arthritis
The effectiveness of Sandimmune® and cyclosporine (MODIFIED) in the treatment of severe rheumatoid arthritis was evaluated in five clinical studies involving a total of 728 cyclosporine treated patients and 273 placebo treated patients.
A summary of the results is presented for the "responder" rates per treatment group, with a responder being defined as a patient having completed the trial with a 20% improvement in the tender and the swollen joint count and a 20% improvement in 2 of 4 of investigator global, patient global, disability, and erythrocyte sedimentation rates (ESR) for the Studies 651 and 652 and 3 of 5 of investigator global, patient global, disability, visual analog pain, and ESR for Studies 2008, 654, and 302.
Study 651 enrolled 264 patients with active rheumatoid arthritis with at least 20 involved joints, who had failed at least one major RA drug, using a 3:3:2 randomization to one of the following three groups: (1) cyclosporine dosed at 2.5 to 5 mg/kg/day, (2) methotrexate at 7.5 to 15 mg/week, or (3) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 3.1 mg/kg/day. See Graph below.
Study 652 enrolled 250 patients with active RA with > 6 active painful or tender joints who had failed at least one major RA drug. Patients were randomized using a 3:3:2 randomization to 1 of 3 treatment arms: (1) 1.5 to 5 mg/kg/day of cyclosporine, (2) 2.5 to 5 mg/kg/day of cyclosporine, and (3) placebo. Treatment duration was 16 weeks. The mean cyclosporine dose for group 2 at the last visit was 2.92 mg/kg/day. See Graph below.
Study 2008 enrolled 144 patients with active RA and > 6 active joints who had unsuccessful treatment courses of aspirin and gold or Penicillamine. Patients were randomized to one of two treatment groups: (1) cyclosporine 2.5 to 5 mg/kg/day with adjustments after the first month to achieve a target trough level and (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 3.63 mg/kg/day. See Graph below.
Study 654 enrolled 148 patients who remained with active joint counts of 6 or more despite treatment with maximally tolerated methotrexate doses for at least three months. Patients continued to take their current dose of methotrexate and were randomized to receive, in addition, one of the following medications: (1) cyclosporine 2.5 mg/kg/day with dose increases of 0.5 mg/kg/day at Weeks 2 and 4 if there was no evidence of toxicity and further increases of 0.5 mg/kg/day at Weeks 8 and 16 if a < 30% decrease in active joint count occurred without any significant toxicity; dose decreases could be made at any time for toxicity or (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 2.8 mg/kg/day (range: 1.3 to 4.1). See Graph below.
Study 302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive or intolerant to at least one prior major RA drug. Patients were randomized to 1 of 2 treatment groups (1) cyclosporine (MODIFIED) and (2) Sandimmune® both of which were started at 2.5 mg/kg/day and increased after 4 weeks for inefficacy in increments of 0.5 mg/kg/day to a maximum of 5 mg/kg/day and decreased at any time for toxicity. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 2.91 mg/kg/day (range: 0.72 to 5.17) for cyclosporine (MODIFIED) and 3.27 mg/kg/day (range: 0.73 to 5.68) for Sandimmune®. See Graph below.
INDICATIONS AND USAGE
Kidney, Liver and Heart Transplantation
Gengraf (cyclosporine capsules, USP [MODIFIED ]) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine (MODIFIED ) has been used in combination with azathioprine and corticosteroids.
Rheumatoid Arthritis
Gengraf (cyclosporine capsules, USP [MODIFIED ]) is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Gengraf can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.
Psoriasis
Gengraf (cyclosporine capsules, USP [MODIFIED ]) is indicated for the treatment of adult, nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated.
While rebound rarely occurs, most patients will experience relapse with Gengraf as with other therapies upon cessation of treatment.
CONTRAINDICATIONS
General
Gengraf (cyclosporine capsules, USP [MODIFIED ]) is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.
Rheumatoid Arthritis
Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension or malignancies should not receive Gengraf (cyclosporine capsules, USP [MODIFIED]).
Psoriasis
Psoriasis patients who are treated with Gengraf (cyclosporine capsules, USP [MODIFIED]) should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Gengraf.
WARNINGS
(See also BOXED WARNINGS).
All Patients
Cyclosporine, the active ingredient of Gengraf (cyclosporine capsules, USP [MODIFIED]), can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine. Renal dysfunction including structural kidney damage is a potential consequence of Gengraf and therefore renal function must be monitored during therapy.Care should be taken in using cyclosporine with nephrotoxic drugs (see PRECAUTIONS).
Patients receiving Gengraf require frequent monitoring of serum creatinine (see Special Monitoring under DOSAGE AND ADMINISTRATION). Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction.
An increase in serum creatinine and BUN may occur during Gengraf therapy and reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated. The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.
Because Gengraf (cyclosporine capsules, USP [MODIFIED]) is not bioequivalent to Sandimmune (Cyclosporine Capsules), conversion from Gengraf to Sandimmune using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from Gengraf to Sandimmune should be made with increased monitoring to avoid the potential of underdosing.
Kidney, Liver, and Heart Transplant
Cyclosporine, the active ingredient of Gengraf (cyclosporine capsules, USP [MODIFIED]), can cause nephrotoxicity and hepatotoxicity when used in high doses. It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated.
Based on the historical Sandimmune® experience with oral solution, nephrotoxicity associated with cyclosporine had been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2-3 months after renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35-45 mg/dL and 2.0-2.5 mg/dL respectively. These elevations were often responsive to cyclosporine dosage reduction.
More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to renal rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction.
Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated with one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.
| Nephrotoxicity vs. Rejection | ||
| Parameter | Nephrotoxicity | Rejection |
a p < 0.05, b p < 0.01, c p< 0.001, d p < 0.0001 | ||
| History | Donor > 50 years old or hypotensive Prolonged kidney preservation Prolonged anastomosis time Concomitant nephrotoxic drugs | Anti-donor immune response Retransplant patient |
| Clinical | Often > 6 weeks postopb Prolonged initial nonfunction (acute tubular necrosis) | Often < 4 weeks postopb Fever > 37.5°C Weight gain > 0.5 kg Graft swelling and tenderness Decrease in daily urine volume > 500 mL (or 50%) |
| Laboratory | CyA serum trough level > 200 ng/mL Gradual rise in Cr (< 0.15 mg/dL/day)a Cr plateau < 25% above baseline BUN/Cr ≥ 20 | CyA serum trough level < 150 ng/mL Rapid rise in Cr (> 0.3 mg/dL/day)a Cr > 25% above baseline BUN/Cr < 20 |
| Biopsy | Arteriolopathy (medial hypertrophya, hyalinosis, nodular deposits,
intimal thickening, endothelial vacuolization, progressive scarring) Tubular atrophy, isometric vacuolization, isolated calcifications Minimal edema Mild focal infiltratesc Diffuse interstitial fibrosis, often striped form | Endovasculitisc (proliferationa, intimal arteritisb,
necrosis, sclerosis) Tubulitis with RBCb and WBCb casts, some irregular vacuolization Interstitial edemac and hemorrhageb Diffuse moderate to severe mononuclear infiltratesd Glomerulitis (mononuclear cells)c |
| Aspiration Cytology | CyA deposits in tubular and endothelial cells Fine isometric vacuolization of tubular cells | Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid
cells, and activated T-cells These strongly express HLA-DR antigens |
| Urine Cytology | Tubular cells with vacuolization and granularization | Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment |
| Manometry Ultrasonography | Intracapsular pressure < 40 mm Hgb Unchanged graft cross sectional area | Intracapsular pressure > 40 mm Hgb Increase in graft cross sectional area AP diameter ≥ Transverse diameter |
| Magnetic Resonance Imagery | Normal appearance | Loss of distinct corticomedullary junction, swelling image intensity of parachyma approaching that of psoas, loss of hilar fat |
| Radionuclide Scan | Normal or generally decreased perfusion Decrease in tubular function (131 I-hippuran) > decrease in perfusion (99m Tc DTPA) | Patchy arterial flow Decrease in perfusion > decrease in tubular function Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid |
| Therapy | Responds to decreased cyclosporine | Responds to increased steroids or antilymphocyte globulin |
A form of a cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5% to 15% of transplant recipients who have received cyclosporine will fail to show a reduction in rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate one or several of the following alterations: tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy. Though none of these morphologic changes is entirely specific, a diagnosis of cyclosporine-associated structural nephrotoxicity requires evidence of these findings.
When considering the development of cyclosporine-associated nephropathy, it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough levels of cyclosporine. This is particularly true during the first 6 post-transplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of cyclosporine. Among other contributing factors to the development of interstitial fibrosis in these patients are prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined. Reversibility of arteriolopathy has been reported after stopping cyclosporine or lowering the dosage.
Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated.
In the event of severe and unremitting rejection, when rescue therapy with pulse steroids and monoclonal antibodies fail to reverse the rejection episode, it may be preferable to switch to alternative immunosuppressive therapy rather than increase the Gengraf dose to excessive levels.
Occasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of cyclosporine and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans (see ADVERSE REACTlONS).
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.
Hepatotoxicity associated with cyclosporine use had been noted in 4% of cases of renal transplantation, 7% of cases of cardiac transplantation, and 4% of cases of liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used and consisted of elevations of hepatic enzymes and bilirubin. The chemistry elevations usually decreased with a reduction in dosage.
As in patients receiving other immunosuppressants, those patients receiving cyclosporine are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Because of the danger of oversuppression of the immune system resulting in increased risk of infection or malignancy, a treatment regimen containing multiple immunosuppressants should be used with caution.
There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high dose methylprednisolone.
Encephalopathy has been described both in postmarketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders and psychiatric disturbances. In many cases, changes in the white matter have been detected using imaging techniques and pathologic specimens. Predisposing factors such as hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus-host disease have been noted in many but not all of the reported cases. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases improvement was noted after reduction of dose. It appears that patients receiving liver transplant are more susceptible to encephalopathy than those receiving kidney transplant. Another rare manifestation of cyclosporine-induced neurotoxicity, occurring in transplant patients more frequently than in other indications, is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension.
Care should be taken in using cyclosporine with nephrotoxic drugs (see PRECAUTIONS).
Rheumatoid Arthritis
Cyclosporine nephropathy was detected in renal biopsies of six out of 60 (10%) rheumatoid arthritis patients after the average treatment duration of 19 months. Only one patient, out of these 6 patients, was treated with a dose ≤ 4 mg/kg/day. Serum creatinine improved in all but one patient after discontinuation of cyclosporine. The "maximal creatinine increase" appears to be a factor in predicting cyclosporine nephropathy.
There is a potential, as with other immunosuppressive agents, for an increase in the occurrence of malignant lymphomas with cyclosporine. It is not clear whether the risk with cyclosporine is greater than that in Rheumatoid Arthritis patients or in Rheumatoid Arthritis patients on cytotoxic treatment for this indication. Five cases of lymphoma were detected: four in a survey of approximately 2,300 patients treated with cyclosporine for rheumatoid arthritis, and another case of lymphoma was reported in a clinical trial. Although other tumors (12 skin cancers, 24 solid tumors of diverse types, and 1 multiple myeloma) were also reported in this survey, epidemiologic analyses did not support a relationship to cyclosporine other than for malignant lymphomas.Patients should be thoroughly evaluated before and during Gengraf (cyclosporine capsules, USP [MODIFIED]) treatment for the development of malignancies. Moreover, use of Gengraf therapy with other immunosuppressive agents may induce an excessive immunosuppression which is known to increase the risk of malignancy.
Psoriasis
(See also BOXED WARNINGS for Psoriasis.)
Since cyclosporine is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using Gengraf (cyclosporine capsules, USP [MODIFIED]) should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in Gengraf, can cause nephrotoxicity and hypertension (see PRECAUTIONS) and the risk increases with increasing dose and duration of therapy. Patients who may be at increased risk such as those with abnormal renal function, uncontrolled hypertension or malignancies, should not receive Gengraf.
Renal dysfunction is a potential consequence of Gengraf, therefore renal function must be monitored during therapy.
Patients receiving Gengraf require frequent monitoring of serum creatinine (see Special Monitoring under DOSAGE AND ADMINISTRATION). Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can cause structural kidney damage and persistent renal dysfunction.
An increase in serum creatinine and BUN may occur during Gengraf therapy and reflects a reduction in the glomerular filtration rate.
Kidney biopsies from 86 psoriasis patients treated for a mean duration of 23 months with 1.2 to 7.6 mg/kg/day of cyclosporine showed evidence of cyclosporine nephropathy in 18/86 (21%) of the patients. The pathology consisted of renal tubular atrophy and interstitial fibrosis. On repeat biopsy of 13 of these patients maintained on various dosages of cyclosporine for a mean of 2 additional years, the number with cyclosporine induced nephropathy rose to 26/86 (30%). The majority of patients (19/26) were on a dose of ≥ 5 mg/kg/day (the highest recommended dose is 4 mg/kg/day). The patients were also on cyclosporine for greater than 15 months (18/26) and/or had a clinically significant increase in serum creatinine for greater than 1 month (21/26). Creatinine levels returned to normal range in 7 of 11 patients in whom cyclosporine therapy was discontinued.
There is an increased risk for the development of skin and lymphoproliferative malignancies in cyclosporine-treated psoriasis patients. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive agents.
Tumors were reported in 32 (2.2%) of 1439 psoriasis patients treated with cyclosporine worldwide from clinical trials. Additional tumors have been reported in 7 patients in cyclosporine postmarketing experience. Skin malignancies were reported in 16 (1.1%) of these patients; all but 2 of them had previously received PUVA therapy. Methotrexate was received by 7 patients. UVB and coal tar had been used by 2 and 3 patients, respectively. Seven patients had either a history of previous skin cancer or a potentially predisposing lesion was present prior to cyclosporine exposure. Of the 16 patients with skin cancer, 11 patients had 18 squamous cell carcinomas and 7 patients had 10 basal cell carcinomas.
There were two lymphoproliferative malignancies; one case of non-Hodgkin's lymphoma which required chemotherapy, and one case of mycosis fungoides which regressed spontaneously upon discontinuation of cyclosporine. There were four cases of benign lymphocytic infiltration: 3 regressed spontaneously upon discontinuation of cyclosporine, while the fourth regressed despite continuation of the drug. The remainder of the malignancies, 13 cases (0.9%), involved various organs.
Patients should not be treated concurrently with cyclosporine and PUVA or UVB, other radiation therapy, or other immunosuppressive agents, because of the possibility of excessive immunosuppression and the subsequent risk of malignancies (see CONTRAINDICATIONS) . Patients should also be warned to protect themselves appropriately when in the sun, and to avoid excessive sun exposure. Patients should be thoroughly evaluated before and during treatment for the presence of malignancies remembering that malignant lesions may be hidden by psoriatic plaques. Skin lesions not typical of psoriasis should be biopsied before starting treatment. Patients should be treated with Gengraf (cyclosporine capsules, USP [MODIFIED]) only after complete resolution of suspicious lesions, and only if there are no other treatment options (see Special Monitoring for Psoriasis Patients).
PRECAUTIONS
General
Information for Patients
Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.
Patients should be informed of the necessity of repeated laboratory tests while they are receiving cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.
Patients should be advised that during treatment with cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.
Patients should be advised to take Gengraf 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.
Laboratory Tests
In all patients treated with cyclosporine, renal and liver functions should be assessed repeatedly by measurement of serum creatinine, BUN, serum bilirubin, and liver enzymes. Serum lipids, magnesium, and potassium should also be monitored. Cyclosporine blood concentrations should be routinely monitored in transplant patients (see DOSAGE AND ADMINISTRATION - Blood Concentration Monitoring in Transplant Patients), and periodically monitored in rheumatoid arthritis patients.
Drug Interactions
All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant non-steroidal anti-inflammatory drugs, particularly in the setting of dehydration, may potentiate renal dysfunction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical maintenance dose (6 mg/kg). The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. Published reports indicate the co-treatment of hairless mice with UV irradiation and cyclosporine or other immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone.
Cyclosporine was not mutagenic in appropriate test systems. Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gaveindication of a positive effect (i.e., induction of SCE), at high concentrations in this system.
No impairment in fertility was demonstrated in studies in male and female rats.
Widely distributed papillomatosis of the skin was observed after chronic treatment of dogs with cyclosporine at 9 times the human initial psoriasis treatment dose of 2.5 mg/kg, where doses are expressed on a body surface area basis. This papillomatosis showed a spontaneous regression upon discontinuation of cyclosporine.
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants and patients with rheumatoid arthritis and psoriasis. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin. The risk of malignancies in cyclosporine recipients is higher than in the normal, healthy population but similar to that in patients receiving other immunosuppressive therapies. Reduction or discontinuance of immunosuppression may cause the lesions to regress.
In psoriasis patients on cyclosporine, development of malignancies, especially those of the skin has been reported (see WARNINGS). Skin lesions not typical for psoriasis should be biopsied before starting cyclosporine treatment. Patients with malignant or premalignant changes of the skin should be treated with cyclosporine only after appropriate treatment of such lesions and if no other treatment option exists.
Pregnancy
Nursing Mothers
Since cyclosporine is excreted in human milk, breast-feeding should be avoided.
Pediatric Use
Although no adequate and well-controlled studies have been completed in children, transplant recipients as young as one year of age have received cyclosporine (MODIFIED) with no unusual adverse effects. The safety and efficacy of cyclosporine (MODIFIED) treatment in pediatric patients with juvenile rheumatoid arthritis or psoriasis below the age of 18 have not been established.
Geriatric Use
In rheumatoid arthritis clinical trials with cyclosporine, 17.5% of patients were age 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥ 50% above the baseline after 3-4 months of therapy.
Clinical studies of cyclosporine oral solution (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.
ADVERSE REACTIONS
Kidney, Liver, and Heart Transplantation
The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.
Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.
Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resembled those seen in the hemolytic-uremic syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed post-transplantation.
Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity.
In controlled studies, the nature, severity and incidence of the adverse events that were observed in 493 transplanted patients treated with cyclosporine (MODIFIED) were comparable with those observed in 208 transplanted patients who received Sandimmune® (cyclosporine capsules) in these same studies when the dosage of the two drugs was adjusted to achieve the same cyclosporine blood trough concentrations.
Based on the historical experience with Sandimmune®, the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants.
| Randomized Kidney Patients | Cyclosporine
Patients (Sandimmune® ) | |||||
| Body System | Adverse Reactions | |||||
| Sandimmune® (N = 227) % | Azathioprine (N = 228) % | Kidney (N = 705) % | Heart (N = 112) % | Liver (N = 75) % | ||
| Genitourinary | ||||||
| Renal Dysfunction | 32 | 6 | 25 | 38 | 37 | |
| Cardiovascular | ||||||
| Hypertension | 26 | 18 | 13 | 53 | 27 | |
| Cramps | 4 | < 1 | 2 | < 1 | 0 | |
| Skin | ||||||
| Hirsutism | 21 | < 1 | 21 | 28 | 45 | |
| Acne | 6 | 8 | 2 | 2 | 1 | |
| Central Nervous System | ||||||
| Tremor | 12 | 0 | 21 | 31 | 55 | |
| Convulsions | 3 | 1 | 1 | 4 | 5 | |
| Headache | 2 | <1 | 2 | 15 | 4 | |
| Gastrointestinal | ||||||
| Gum Hyperplasia | 4 | 0 | 9 | 5 | 16 | |
| Diarrhea | 3 | < 1 | 3 | 4 | 8 | |
| Nausea/Vomiting | 2 | < 1 | 4 | 10 | 4 | |
| Hepatotoxicity | < 1 | < 1 | 4 | 7 | 4 | |
| Abdominal Discomfort | < 1 | 0 | <1 | 7 | 0 | |
| Autonomic Nervous System | ||||||
| Paresthesia | 3 | 0 | 1 | 2 | 1 | |
| Flushing | < 1 | 0 | 4 | 0 | 4 | |
| Hematopoietic | ||||||
| Leukopenia | 2 | 19 | < 1 | 6 | 0 | |
| Lymphoma | < 1 | 0 | 1 | 6 | 1 | |
| Respiratory | ||||||
| Sinusitis | < 1 | 0 | 4 | 3 | 7 | |
| Miscellaneous | ||||||
| Gynecomastia | < 1 | 0 | < 1 | 4 | 3 | |
Among 705 kidney transplant patients treated with cyclosporine oral solution in clinical trials, the reason for treatment discontinuation was renal toxicity in 5.4%, infection in 0.9%, lack of efficacy in 1.4%, acute tubular necrosis in 1.0%, lymphoproliferative disorders in 0.3%, hypertension in 0.3%, and other reasons in 0.7% of the patients.
The following reactions occurred in 2% or less of Sandimmune® -treated patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus.
The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss.
| Complication | Cyclosporine Treatment (N = 227) % of Complications | Azathioprine with
Steroids* (N = 228) % of Complications |
* Some patients also received ALG. | ||
| Septicemia | 5.3 | 4.8 |
| Abscesses | 4.4 | 5.3 |
| Systemic Fungal Infection | 2.2 | 3.9 |
| Local Fungal Infection | 7.5 | 9.6 |
| Cytomegalovirus | 4.8 | 12.3 |
| Other Viral Infections | 15.9 | 18.4 |
| Urinary Tract Infections | 21.1 | 20.2 |
| Wound and Skin Infections | 7.0 | 10.1 |
| Pneumonia | 6.2 | 9.2 |
Rheumatoid Arthritis
The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction (see WARNINGS), hypertension (see PRECAUTIONS), headache, gastrointestinal disturbances and hirsutism/hypertrichosis.
In rheumatoid arthritis patients treated in clinical trials within the recommended dose range, cyclosporine therapy was discontinued in 5.3% of the patients because of hypertension and in 7% of the patients because of increased creatinine. These changes are usually reversible with timely dose decrease or drug discontinuation. The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.
The following adverse events occurred in controlled clinical trials
| Studies 651+652+2008 | Study 302 | Study 654 | Study 654 | Study 302 | Studies 651+652 +2008 | ||
| Body System | Preferred Term | Sandimmune®† (N = 269) | Sandimmune® (N = 155) | Methotrexate & Sandimmune® (N = 74) | Methotrexate & Placebo (N = 73) | Cyclosporine (MODIFIED) (N = 143) | Placebo (N = 201) |
† Includes patients in 2.5 mg/kg/day dose group only. * NOS = Not Otherwise Specified. | |||||||
| Autonomic Nervous System Disorders | |||||||
| Flushing | 2% | 2% | 3% | 0% | 5% | 2% | |
| Body As A Whole - General Disorders | |||||||
| Accidental Trauma | 0% | 1% | 10% | 4% | 4% | 0% | |
| Edema NOS* | 5% | 14% | 12% | 4% | 10% | < 1% | |
| Fatigue | 6% | 3% | 8% | 12% | 3% | 7% | |
| Fever | 2% | 3% | 0% | 0% | 2% | 4% | |
| Influenza-like symptoms | < 1% | 6% | 1% | 0% | 3% | 2% | |
| Pain | 6% | 9% | 10% | 15% | 13% | 4% | |
| Rigors | 1% | 1% | 4% | 0% | 3% | 1% | |
| Cardiovascular Disorders | |||||||
| Arrhythmia | 2% | 5% | 5% | 6% | 2% | 1% | |
| Chest Pain | 4% | 5% | 1% | 1% | 6% | 1% | |
| Hypertension | 8% | 26% | 16% | 12% | 25% | 2% | |
| Central and Peripheral Nervous System Disorders | |||||||
| Dizziness | 8% | 6% | 7% | 3% | 8% | 3% | |
| Headache | 17% | 23% | 22% | 11% | 25% | 9% | |
| Migraine | 2% | 3% | 0% | 0% | 3% | 1% | |
| Paresthesia | 8% | 7% | 8% | 4% | 11% | 1% | |
| Tremor | 8% | 7% | 7% | 3% | 13% | 4% | |
| Gastrointestinal System Disorders | |||||||
| Abdominal Pain | 15% | 15% | 15% | 7% | 15% | 10% | |
| Anorexia | 3% | 3% | 1% | 0% | 3% | 3% | |
| Diarrhea | 12% | 12% | 18% | 15% | 13% | 8% | |
| Dyspepsia | 12% | 12% | 10% | 8% | 8% | 4% | |
| Flatulence | 5% | 5% | 5% | 4% | 4% | 1% | |
| Gastrointestinal Disorder NOS* | 0% | 2% | 1% | 4% | 4% | 0% | |
| Gingivitis | 4% | 3% | 0% | 0% | 0% | 1% | |
| Gum Hyperplasia | 2% | 4% | 1% | 3% | 4% | 1% | |
| Nausea | 23% | 14% | 24% | 15% | 18% | 14% | |
| Rectal Hemorrhage | 0% | 3% | 0% | 0% | 1% | 1% | |
| Stomatitis | 7% | 5% | 16% | 12% | 6% | 8% | |
| Vomiting | 9% | 8% | 14% | 7% | 6% | 5% | |
| Hearing and Vestibular Disorders | |||||||
| Ear Disorders NOS* | 0% | 5% | 0% | 0% | 1% | 0% | |
| Metabolic and Nutritional Disorders | |||||||
| Hypomagnesemia | 0% | 4% | 0% | 0% | 6% | 0% | |
| Musculoskeletal System Disorders | |||||||
| Arthropathy | 0% | 5% | 0% | 1% | 4% | 0% | |
| Leg Cramps/ Involuntary Muscle Contractions | 2% | 11% | 11% | 3% | 12% | 1% | |
| Psychiatric Disorders | |||||||
| Depression | 3% | 6% | 3% | 1% | 1% | 2% | |
| Insomnia | 4% | 1% | 1% | 0% | 3% | 2% | |
| Renal | |||||||
| Creatinine elevations ≥ 30% | 43% | 39% | 55% | 19% | 48% | 13% | |
| Creatinine elevations ≥ 50% | 24% | 18% | 26% | 8% | 18% | 3% | |
| Reproductive Disorders, Female | |||||||
| Leukorrhea | 1% | 0% | 4% | 0% | 1% | 0% | |
| Menstrual Disorder | 3% | 2% | 1% | 0% | 1% | 1% | |
| Respiratory System Disorders | |||||||
| Bronchitis | 1% | 3% | 1% | 0% | 1% | 3% | |
| Coughing | 5% | 3% | 5% | 7% | 4% | 4% | |
| Dyspnea | 5% | 1% | 3% | 3% | 1% | 2% | |
| Infection NOS* | 9% | 5% | 0% | 7% | 3% | 10% | |
| Pharyngitis | 3% | 5% | 5% | 6% | 4% | 4% | |
| Pneumonia | 1% | 0% | 4% | 0% | 1% | 1% | |
| Rhinitis | 0% | 3% | 11% | 10% | 1% | 0% | |
| Sinusitis | 4% | 4% | 8% | 4% | 3% | 3% | |
| Upper Respiratory Tract | 0% | 14% | 23% | 15% | 13% | 0% | |
| Skin and Appendages Disorders | |||||||
| Alopecia | 3% | 0% | 1% | 1% | 4% | 4% | |
| Bullous Eruption | 1% | 0% | 4% | 1% | 1% | 1% | |
| Hypertrichosis | 19% | 17% | 12% | 0% | 15% | 3% | |
| Rash | 7% | 12% | 10% | 7% | 8% | 10% | |
| Skin Ulceration | 1% | 1% | 3% | 4% | 0% | 2% | |
| Urinary System Disorders | |||||||
| Dysuria | 0% | 0% | 11% | 3% | 1% | 2% | |
| Micturition Frequency | 2% | 4% | 3% | 1% | 2% | 2% | |
| NPN, Increased | 0% | 19% | 12% | 0% | 18% | 0% | |
| Urinary Tract Infection | 0% | 3% | 5% | 4% | 3% | 0% | |
| Vascular (Extracardiac) Disorders | |||||||
| Purpura | 3% | 4% | 1% | 1% | 2% | 0% | |
In addition, the following adverse events have been reported in 1% to < 3% of the rheumatoid arthritis patients in the cyclosporine treatment group in controlled clinical trials.
Psoriasis
The principal adverse reactions associated with the use of cyclosporine in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.
In psoriasis patients treated in U.S. controlled clinical studies within the recommended dose range, cyclosporine therapy was discontinued in 1.0% of the patients because of hypertension and in 5.4% of the patients because of increased creatinine. In the majority of cases, these changes were reversible after dose reduction or discontinuation of cyclosporine.
There has been one reported death associated with the use of cyclosporine in psoriasis. A 27 year old male developed renal deterioration and was continued on cyclosporine. He had progressive renal failure leading to death.
Frequency and severity of serum creatinine increases with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced and may result in irreversible renal damage without dose reduction or discontinuation.
| Body System* Preferred Term | Cyclosporine (MODIFIED) (N = 182) | Sandimmune® (N = 185) |
* Total percentage of events within the system. ** Newly occurring hypertension = SBP≥160 mm Hg and/or DBP ≥90 mm Hg. | ||
| Infection or Potential Infection | 24.7% | 24.3% |
| Influenza-like Symptoms | 9.9% | 8.1% |
| Upper Respiratory Tract Infections | 7.7% | 11.3% |
| Cardiovascular System | 28.0% | 25.4% |
| Hypertension** | 27.5% | 25.4% |
| Urinary System | 24.2% | 16.2% |
| Increased Creatinine | 19.8% | 15.7% |
| Central and Peripheral Nervous System | 26.4% | 20.5% |
| Headache | 15.9% | 14.0% |
| Paresthesia | 7.1% | 4.8% |
| Musculoskeletal System | 13.2% | 8.7% |
| Arthralgia | 6.0% | 1.1% |
| Body As a Whole – General | 29.1% | 22.2% |
| Pain | 4.4% | 3.2% |
| Metabolic and Nutritional | 9.3% | 9.7% |
| Reproductive, Female | 8.5% (4 of 47 females) | 11.5% (6 of 52 females) |
| Resistance Mechanism | 18.7% | 21.1% |
| Skin and Appendages | 17.6% | 15.1% |
| Hypertrichosis | 6.6% | 5.4% |
| Respiratory System | 5.0% | 6.5% |
| Bronchospasm, Coughing, Dyspnea, Rhinitis | 5.0% | 4.9% |
| Psychiatric | 5.0% | 3.8% |
| Gastrointestinal System | 19.8% | 28.7% |
| Abdominal Pain | 2.7% | 6.0% |
| Diarrhea | 5.0% | 5.9% |
| Dyspepsia | 2.2% | 3.2% |
| Gum Hyperplasia | 3.8% | 6.0% |
| Nausea | 5.5% | 5.9% |
| White cell and RES | 4.4% | 2.7% |
The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:
OVERDOSAGE
There is a minimal experience with cyclosporine overdosage. Forced emesis can be of value up to 2 hours after administration of Gengraf (cyclosporine capsules, USP [MODIFIED]). Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. 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 (6 mg/kg; corrections based on body surface area) in mice, rats, and rabbits.
DOSAGE AND ADMINISTRATION
Gengraf (cyclosporine capsules, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune® (cyclosporine capsules). Gengraf and Sandimmune are not bioequivalent and cannot be used interchangeably without physician supervision.
The daily dose of Gengraf (cyclosporine capsules, USP [MODIFIED ]) should always be given in two divided doses (BID). It is recommended that Gengraf be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.
Newly Transplanted Patients
The initial oral dose of Gengraf (cyclosporine capsules, USP [MODIFIED]) can be given 4-12 hours prior to transplantation or be given postoperatively. The initial dose of Gengraf varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Gengraf is the same as the initial oral dose of Sandimmune®. Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® in U.S. transplant centers. The mean ± SD initial doses were 9 ± 3 mg/kg/day for renal transplant patients (75 centers), 8 ± 4 mg/kg/day for liver transplant patients (30 centers), and 7 ± 3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Gengraf dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see DOSAGE AND ADMINISTRATION - Blood Concentration Monitoring in Transplant Patients, below). If cyclosporine trough blood concentrations are used, the target range is the same for Gengraf as for Sandimmune® . Using the same trough concentration target range for Gengraf as for Sandimmune® results in greater cyclosporine exposure when Gengraf is administered (see CLINICAL PHARMACOLOGY - Pharmacokinetics,Absorption). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Gengraf doses may be sufficient as maintenance therapy.
Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient's weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.
Conversion from Sandimmune* (Cyclosporine) to Gengraf (Cyclosporine Capsules, USP [MODIFIED]) in Transplant Patients
In transplanted patients who are considered for conversion to Gengraf from Sandimmune* (cyclosporine), Gengraf should be started with the same daily dose as was previously used with Sandimmune* (cyclosporine) (1:1 dose conversion). The Gengraf dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Gengraf as for Sandimmune* (cyclosporine) results in greater cyclosporine exposure when Gengraf is administered (see CLINICAL PHARMACOLOGY - Pharmacokinetics,Absorption). Patients with suspected poor absorption of Sandimmune* (cyclosporine) require different dosing strategies (see DOSAGE AND ADMINISTRATION - Transplant Patients with Poor Absorption of Sandimmune* (cyclosporine), below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.
Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Gengraf.In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Gengraf must be adjusted accordingly.
Transplant Patients with Poor Absorption of Sandimmune* (Cyclosporine)
Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune* (cyclosporine) may have poor or inconsistent absorption of cyclosporine from Sandimmune* (cyclosporine). After conversion to Gengraf (cyclosporine capsules, USP [MODIFIED]), patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Gengraf, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Gengraf at doses greater than 10 mg/kg/day. The dose of Gengraf should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.
Rheumatoid Arthritis
The initial dose of Gengraf (cyclosporine capsules, USP [MODIFIED]) is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, nonsteroidal anti-inflammatory agents, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS - Drug Interactions). Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Gengraf therapy should be discontinued.
Dose decreases by 25%-50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient's pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS). If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, Gengraf should be discontinued. The same initial dose and dosage range should be used if Gengraf is combined with the recommended dose of methotrexate. Most patients can be treated with Gengraf doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week (see CLINICAL PHARMACOLOGY - Clinical Trials).
There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within four weeks after stopping cyclosporine.
Psoriasis
The initial dose of Gengraf (cyclosporine capsules, USP [MODIFIED]) should be 2.5 mg/kg/day. Gengraf should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient's dosage should be increased at 2 week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4 mg/kg/day.
Dose decreases by 25%-50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥ 25% above the patient's pretreatment level), or clinically significant laboratory abnormalities.
If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, Gengraf should be discontinued (see PRECAUTIONS - Special Monitoring of Psoriasis Patients).
Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12-16 weeks to achieve. Results of a dose-titration clinical trial with Gengraf indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient's maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of Gengraf should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.
Upon stopping treatment with cyclosporine, relapse will occur in approximately six weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long term experience with Gengraf in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long term management of patients with this life long disease.
Blood Concentration Monitoring in Transplant Patients
Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.
Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a non-specific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.
HOW SUPPLIED
Gengraf Capsules (Cyclosporine Capsules, USP [MODIFIED])
Store and Dispense
In the original unit-dose container at controlled
room temperature
68°-77°F (20°-25°C). (See USP Controlled
Room Temperature).
*Sandimmune® is a registered trademark of Novartis Pharmaceuticals
Corporation.
© Abbott
Manufactured by: Abbott Laboratories
North Chicago, IL 60064, U.S.A.
Abbott Laboratories
North Chicago, IL 60064, U.S.A.