Gengraf - Cyclosporine solution prescribing information
WARNING
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 ) .
INDICATIONS AND USAGE
Kidney, Liver, and Heart Transplantation
Gengraf ® Oral Solution (cyclosporine oral solution, 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 ® Oral Solution (cyclosporine oral solution, 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 ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is indicated for the treatment of adult, nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated.
While rebound rarely occurs, most patients will experience relapse with Gengraf ® as with other therapies upon cessation of treatment.
DOSAGE AND ADMINISTRATION
Gengraf ® 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.
Specific Populations
Renal Impairment in Kidney, Liver, and Heart Transplantation
Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (see CLINICAL PHARMACOLOGY ). However, due to its nephrotoxic potential (see WARNINGS ), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated (see WARNINGS and PRECAUTIONS ).
Renal Impairment in Rheumatoid Arthritis and Psoriasis
Patients with impaired renal function should not receive cyclosporine (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ).
Hepatic Impairment
The clearance of cyclosporine may be significantly reduced in severe liver disease patients (see CLINICAL PHARMACOLOGY ). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (see WARNINGS and PRECAUTIONS ).
Newly Transplanted Patients
The initial oral dose of Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Gengraf ® varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Gengraf ® is the same as the initial oral dose of Sandimmune ® . Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune ® in US transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Gengraf ® dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see Blood Concentration Monitoring in Transplant Patients , below). If cyclosporine trough blood concentrations are used, the target range is the same for Gengraf ® as for Sandimmune ® . Using the same trough concentration target range for Gengraf ® as for Sandimmune ® results in greater cyclosporine exposure when Gengraf ® is administered (see Pharmacokinetics, Absorption ). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Gengraf ® doses may be sufficient as maintenance therapy.
Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient's weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.
Conversion from Sandimmune ® Oral Solution (Cyclosporine Oral Solution, USP) to Gengraf ® Oral Solution (Cyclosporine Oral Solution, USP [MODIFIED]) in Transplant Patients
In transplanted patients who are considered for conversion to Gengraf ® from Sandimmune ® , Gengraf ® should be started with the same daily dose as was previously used with Sandimmune ® (1:1 dose conversion). The Gengraf ® dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Gengraf ® as for Sandimmune ® results in greater cyclosporine exposure when Gengraf ® is administered (see Pharmacokinetics, Absorption ). Patients with suspected poor absorption of Sandimmune ® require different dosing strategies (see Transplant Patients with Poor Absorption of Sandimmune ® , below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.
Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Gengraf ® . In addition, clinical safety parameters, such as serum creatinine and blood pressure, should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of Gengraf ® must be adjusted accordingly.
Transplant Patients with Poor Absorption of Sandimmune ®
Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune ® may have poor or inconsistent absorption of cyclosporine from Sandimmune ® . After conversion to Gengraf ® Oral Solution (cyclosporine oral solution, 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 ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]) is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, NSAIDs, 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% to 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 4 weeks after stopping cyclosporine.
Psoriasis
The initial dose of Gengraf ® Oral Solution (cyclosporine oral solution, 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 4.0 mg/kg/day.
Dose decreases by 25% to 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 Special Monitoring for 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 to 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 6 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 lifelong disease.
Gengraf ® Oral Solution (Cyclosporine Oral Solution, USP [MODIFIED])-Recommendations for Administration
To make Gengraf ® Oral Solution (cyclosporine oral solution, USP [MODIFIED] ) more palatable, it should be diluted with orange or apple juice that is at room temperature. Patients should avoid switching diluents frequently. Grapefruit juice affects metabolism of cyclosporine and should be avoided. The combination of Gengraf ® solution with milk can be unpalatable. The effect of milk on the bioavailability of cyclosporine when administered as Gengraf ® Oral Solution (cyclosporine oral solution, USP [MODIFIED] ) has not been evaluated.
Take the prescribed amount of Gengraf ® Oral Solution (cyclosporine oral solution, USP [MODIFIED] ) from the container using the dosing syringe supplied, and transfer the solution to a glass of orange or apple juice. Stir well and drink at once. Do not allow diluted oral solution to stand before drinking. Use a glass container (not plastic). Rinse the glass with more diluent to ensure that the total dose is consumed. After use, dry the outside of the dosing syringe with a clean towel and store in a clean, dry place. Do not rinse the dosing syringe with water or other cleaning agents. If the syringe requires cleaning, it must be completely dry before resuming use.
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 nonspecific 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.
Specific Populations
Renal Impairment in Kidney, Liver, and Heart Transplantation
Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (see CLINICAL PHARMACOLOGY ). However, due to its nephrotoxic potential (see WARNINGS ), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated (see WARNINGS and PRECAUTIONS ).
Renal Impairment in Rheumatoid Arthritis and Psoriasis
Patients with impaired renal function should not receive cyclosporine (see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ).
Hepatic Impairment
The clearance of cyclosporine may be significantly reduced in severe liver disease patients (see CLINICAL PHARMACOLOGY ). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (see WARNINGS and PRECAUTIONS ).
CONTRAINDICATIONS
General
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.
Rheumatoid Arthritis
Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Gengraf ® Oral Solution (cyclosporine oral solution, USP [ MODIFIED ]).
Psoriasis
Psoriasis patients who are treated with Gengraf ® Oral Solution (cyclosporine oral solution, 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 ® .
ADVERSE REACTIONS
Kidney, Liver, and Heart Transplantation
The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.
Hypertension
Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.
Glomerular Capillary Thrombosis
Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resembled those seen in the hemolytic-uremic syndrome and included thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed post-transplantation.
Hypomagnesemia
Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity.
Clinical Studies
In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with cyclosporine ( MODIFIED ) were comparable with those observed in 208 transplanted patients who received Sandimmune ® in these same studies when the dosage of the two drugs was adjusted to achieve the same cyclosporine blood trough concentrations.
Based on the historical experience with Sandimmune ® , the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants.
| Randomized Kidney Patients | Cyclosporine Patients (Sandimmune ® ) | |||||
| Body System | Adverse Reactions | Sandimmune ® (N=227) % | Azathioprine (N=228) % | Kidney (N=705) % | Heart (N=112) % | Liver (N=75) % |
| Genitourinary | ||||||
| Renal Dysfunction | 32 | 6 | 25 | 38 | 37 | |
| Cardiovascular | ||||||
| Hypertension | 26 | 18 | 13 | 53 | 27 | |
| Cramps | 4 | <1 | 2 | <1 | 0 | |
| Skin | ||||||
| Hirsutism | 21 | <1 | 21 | 28 | 45 | |
| Acne | 6 | 8 | 2 | 2 | 1 | |
| Central Nervous System | ||||||
| Tremor | 12 | 0 | 21 | 31 | 55 | |
| Convulsions | 3 | 1 | 1 | 4 | 5 | |
| Headache | 2 | <1 | 2 | 15 | 4 | |
| Gastrointestinal | ||||||
| Gum Hyperplasia | 4 | 0 | 9 | 5 | 16 | |
| Diarrhea | 3 | <1 | 3 | 4 | 8 | |
| Nausea/Vomiting | 2 | <1 | 4 | 10 | 4 | |
| Hepatotoxicity | <1 | <1 | 4 | 7 | 4 | |
| Abdominal Discomfort | <1 | 0 | <1 | 7 | 0 | |
| Autonomic Nervous System | ||||||
| Paresthesia | 3 | 0 | 1 | 2 | 1 | |
| Flushing | <1 | 0 | 4 | 0 | 4 | |
| Hematopoietic | ||||||
| Leukopenia | 2 | 19 | <1 | 6 | 0 | |
| Lymphoma | <1 | 0 | 1 | 6 | 1 | |
| Respiratory | ||||||
| Sinusitis | <1 | 0 | 4 | 3 | 7 | |
| Miscellaneous | ||||||
| Gynecomastia | <1 | 0 | <1 | 4 | 3 | |
Among 705 kidney transplant patients treated with cyclosporine oral solution (Sandimmune ® ) in clinical trials, the reason for treatment discontinuation was renal toxicity in 5.4%, infection in 0.9%, lack of efficacy in 1.4%, acute tubular necrosis in 1.0%, lymphoproliferative disorders in 0.3%, hypertension in 0.3%, and other reasons in 0.7% of the patients.
The following reactions occurred in 2% or less of cyclosporine-treated patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, migraine (Gengraf ® ), muscle pain, peptic ulcer, thrombocytopenia, tinnitus.
The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss.
Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and localized infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported (see WARNINGS ).
| Complication | Cyclosporine Treatment (N=227) % of Complications | Azathioprine with Steroids• (N=228) % of Complications |
| Septicemia | 5.3 | 4.8 |
| Abscesses | 4.4 | 5.3 |
| Systemic Fungal Infection | 2.2 | 3.9 |
| Local Fungal Infection | 7.5 | 9.6 |
| Cytomegalovirus | 4.8 | 12.3 |
| Other Viral Infections | 15.9 | 18.4 |
| Urinary Tract Infections | 21.1 | 20.2 |
| Wound and Skin Infections | 7.0 | 10.1 |
| Pneumonia | 6.2 | 9.2 |
| •Some patients also received ALG. | ||
Postmarketing Experience, Kidney, Liver and Heart Transplantation
Hepatotoxicity
Cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported (see WARNINGS, Hepatotoxicity ).
Increased Risk of Infections
Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported (see WARNINGS, Polyoma Virus Infection ).
Headache, I ncluding Migraine
Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.
Pain of lower extremities
Isolated cases of pain of lower extremities have been reported in association with cyclosporine. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.
Rheumatoid Arthritis
The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction (see WARNINGS ), hypertension (see PRECAUTIONS ), headache, gastrointestinal disturbances, and hirsutism/hypertrichosis.
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) | Metho- trexate & Sandimmune ® (N=74) | Metho- trexate & Placebo (N=73) | Cyclosporine (MODIFIED) (N=143) | Placebo (N=201) |
| Autonomic Nervous System Disorders | |||||||
| Flushing | 2% | 2% | 3% | 0% | 5% | 2% | |
| Body As A Whole–General Disorders | |||||||
| Accidental Trauma | 0% | 1% | 10% | 4% | 4% | 0% | |
| Edema NOS• | 5% | 14% | 12% | 4% | 10% | <1% | |
| Fatigue | 6% | 3% | 8% | 12% | 3% | 7% | |
| Fever | 2% | 3% | 0% | 0% | 2% | 4% | |
| Influenza-like symptoms | <1% | 6% | 1% | 0% | 3% | 2% | |
| Pain | 6% | 9% | 10% | 15% | 13% | 4% | |
| Rigors | 1% | 1% | 4% | 0% | 3% | 1% | |
| Cardiovascular 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 Disorder 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% | |
| † Includes patients in 2.5 mg/kg/day dose group only. •NOS=Not Otherwise Specified. | |||||||
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.
Autonomic Nervous System: dry mouth, increased sweating
Body as a Whole: allergy, asthenia, hot flushes, malaise, overdose, procedure NOS•, tumor NOS•, weight decrease, weight increase
Cardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia
Central and Peripheral Nervous System: hypoesthesia, neuropathy, vertigo
Endocrine: goiter
Gastrointestinal: constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder
Infection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection
Hematologic: anemia, epistaxis, leukopenia, lymphadenopathy
Liver and Biliary System: bilirubinemia
Metabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia
Musculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder
Neoplasms: breast fibroadenosis, carcinoma
Psychiatric: anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence
Reproductive (Female): breast pain, uterine hemorrhage
Respiratory System: abnormal chest sounds, bronchospasm
Skin and Appendages: abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria
Special Senses: abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder
Urinary System: abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence
•NOS=Not Otherwise Specified
Psoriasis
The principal adverse reactions associated with the use of cyclosporine in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.
In psoriasis patients treated in US controlled clinical studies within the recommended dose range, cyclosporine therapy was discontinued in 1.0% 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) |
| 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% | |
| •Total percentage of events within the system. ••Newly occurring hypertension = SBP ≥ 160 mm Hg and/or DBP ≥ 90 mm Hg. | |||
The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:
Body as a Whole: fever, flushes, hot flushes
Cardiovascular: chest pain
Central and Peripheral Nervous System: appetite increased, insomnia, dizziness, nervousness, vertigo
Gastrointestinal: abdominal distention, constipation, gingival bleeding
Liver and Biliary System: hyperbilirubinemia
Neoplasms: skin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]
Reticuloendothelial: platelet, bleeding, and clotting disorders, red blood cell disorder
Respiratory: infection, viral and other infection
Skin and Appendages: acne, folliculitis, keratosis, pruritus, rash, dry skin
Urinary System: micturition frequency
Vision: abnormal vision
Mild hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases in uric acid may occur and attacks of gout have been rarely reported. A minor and dose related hyperbilirubinemia has been observed in the absence of hepatocellular damage. Cyclosporine therapy may be associated with a modest increase of serum triglycerides or cholesterol. Elevations of triglycerides (> 750 mg/dL) occur in about 15% of psoriasis patients; elevations of cholesterol (> 300 mg/dL) are observed in less than 3% of psoriasis patients. Generally these laboratory abnormalities are reversible upon dose reduction or discontinuation of cyclosporine.
Postmarketing Experience, Psoriasis
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.
Drug Interactions
A. Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety
All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of NSAIDs with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function (see WARNINGS, Nephrotoxicity ).
Drugs That May Potentiate Renal Dysfunction
| Antibiotics | Antineoplastics | Anti-inflammatory Drugs | Gastrointestinal Agents |
| Ciprofloxacin | melphalan | azapropazon | cimetidine |
| Gentamicin | colchicine | ranitidine | |
| Tobramycin | Antifungals | diclofenac | |
| vancomycin | amphotericin B | naproxen | Immunosuppressives |
| trimethoprim with sulfamethoxazole | ketoconazole | sulindac | tacrolimus |
| Other Drugs | |||
| fibric acid derivatives (e.g., bezafibrate, fenofibrate) | |||
| methotrexate |
During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.
Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase or decrease plasma or whole blood concentrations of cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption, such as orlistat, should be avoided. Appropriate Gengraf ® dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (see Blood Concentration Monitoring ).
1. Drugs That Increase Cyclosporine Concentrations
| Calcium Channel Blockers | Antifungals | Antibiotics | Glucocorticoids | Other Drugs |
| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/ dalfopristin | colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
HIV Protease inhibitors
The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly.
Grapefruit juice
Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided.
2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
| Antibiotics | Anticonvulsants | Other Drugs/Dietary Supplements |
| nafcillin | carbamazepine | Bosentan |
| rifampin | oxcarbazepine | Octreotide |
| phenobarbital | Orlistat | |
| phenytoin | sulfinpyrazone | |
| St. John's Wort | ||
| Terbinafine | ||
| Ticlopidine |
Bosentan
Coadministration of bosentan (250 to 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a C min of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, C max , and trough concentration of approximately 50%, 30%, and 60%, respectively, compared to when cyclosporine was given alone (see Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents ). Coadministration of cyclosporine with bosentan should be avoided.
Boceprevir
Coadministration of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and C max of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.
Telaprevir
Coadministration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and C max of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone.
St. John's Wort
There have been reports of a serious drug interaction between cyclosporine and the herbal dietary supplement St. John's Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.
Rifabutin
Rifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome P-450 system. The interaction between rifabutin and cyclosporine has not been studied. Care should be exercised when these two drugs are administered concomitantly.
B. Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents
Cyclosporine is an inhibitor of CYP3A4 and of multiple drug efflux transporters (e.g., P-glycoprotein) and may increase plasma concentrations of comedications that are substrates of CYP3A4, P-glycoprotein or organic anion transporter proteins.
Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), and, aliskiren, bosentan, dabigatran, repaglinide, NSAIDs, sirolimus, etoposide, and other drugs.
See the full prescribing information of the other drug for further information and specific recommendations. The decision on coadministration of cyclosporine with other drugs or agents should be made by the healthcare provider following the careful assessment of benefits and risks.
Digoxin
Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored.
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.
DESCRIPTION
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.
Inactive Ingredients
Polyoxyl 40 hydrogenated castor oil NF, propylene glycol USP, sorbitan monooleate NF.
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 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.
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. 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.
CLINICAL TRIALS
Rheumatoid Arthritis
The effectiveness of Sandimmune ® and cyclosporine ( MODIFIED ) in the treatment of severe rheumatoid arthritis was evaluated in 5 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 1 of 2 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.
HOW SUPPLIED
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).
Store and Dispense
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
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 ):
|  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.
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| 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.
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| 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.
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| 4 |  | Invert the bottle. Draw up the prescribed amount of Gengraf Oral Solution with the syringe. |
| 5 |  | Remove large bubbles from the syringe .
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| 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.
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| 8 |  | Once the full dose is mixed in the glass, drink it right away.
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| 9 |  | After you finish drinking:
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| 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.
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| 11 |  | Reseal the bottle with the child-resistant cap. |
| 12 |
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| 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
