Get your patient on Gengraf - Cyclosporine capsule (Cyclosporine)

Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine ( MODIFIED ) has been used in combination with azathioprine and corticosteroids.

Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Gengraf ^® can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.

Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is indicated for the treatment of adult, nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated.

While rebound rarely occurs, most patients will experience relapse with Gengraf ^® as with other therapies upon cessation of treatment.

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 ).

The initial oral dose of Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]) can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Gengraf ^® varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of Gengraf ^® is the same as the initial oral dose of Sandimmune ^® . Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune ^® in US transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Gengraf ^® dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see Blood Concentration Monitoring in Transplant Patients , below). If cyclosporine trough blood concentrations are used, the target range is the same for Gengraf ^® as for Sandimmune ^® . Using the same trough concentration target range for Gengraf ^® as for Sandimmune ^® results in greater cyclosporine exposure when Gengraf ^® is administered (see Pharmacokinetics, Absorption ). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Gengraf ^® doses may be sufficient as maintenance therapy.

Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient's weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation.

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.

Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune ^® may have poor or inconsistent absorption of cyclosporine from Sandimmune ^® . After conversion to Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]), patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Gengraf ^® , the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Gengraf ^® at doses greater than 10 mg/kg/day. 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.

The initial dose of Gengraf ^® Capsules (cyclosporine capsules, 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.

The initial dose of Gengraf ^® Capsules (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 4.0 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.

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.

Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]) is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]).

Psoriasis patients who are treated with Gengraf ^® Capsules (cyclosporine capsules, USP [ MODIFIED ]) should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Gengraf ^® .

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.

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 ).

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:

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

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.

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.

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

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

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

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.

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.

FD&C Blue No. 2, gelatin NF, polyethylene glycol USP, polyoxyl 35 castor oil NF, polysorbate 80 NF, propylene glycol USP, sorbitan monooleate NF, titanium dioxide.

The chemical structure for cyclosporine USP is:

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% 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%).

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 Populations

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%).

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.

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.

In the original unit-dose container at controlled room temperature 68°-77°F (20°-25°C). (See USP Controlled Room Temperature).

Gengraf is a trademark of AbbVie Inc.

Sandimmune ^® is a trademark of Novartis AG.

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20085115 R1 August, 2024