Cyclosporine 25 mg Capsule, Liquid Filled — NDC 75907-047-30 (Billing 75907-0047-30)

WARNINGS (See also Boxed WARNING ) All Patients Cyclosporine, the active ingredient in cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED], can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine. Renal dysfunction including structural kidney damage is a potential consequence of cyclosporine [MODIFIED] and therefore renal function must be monitored during therapy.

Care should be taken in using cyclosporine with nephrotoxic drugs . (See PRECAUTIONS ) Patients receiving cyclosporine [MODIFIED] require frequent monitoring of serum creatinine. (See Special Monitoring under DOSAGE AND ADMINISTRATION ) Elderly patients should be monitored with particular care, since decreases in renal function also occur with age.

If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction. An increase in serum creatinine and BUN may occur during cyclosporine [MODIFIED] therapy and reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated.

The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation. Because cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED] are not bioequivalent to Sandimmune® (cyclosporine), conversion from cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED] to Sandimmune® using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations.

Conversion from cyclosporine [MODIFIED] to Sandimmune® should be made with increased monitoring to avoid the potential of underdosing. Kidney, Liver, and Heart Transplant Nephrotoxicity Cyclosporine, the active ingredient of cyclosporine [MODIFIED], can cause nephrotoxicity and hepatotoxicity when used in high doses. It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy.

These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated. Based on the historical Sandimmune® experience with oral solution, nephrotoxicity associated with cyclosporine had been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2 to 3 months after renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35 to 45 mg/dL and 2 to 2.5 mg/dL respectively.

These elevations were often responsive to cyclosporine dosage reduction. More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to renal rejection episodes, care must be taken to differentiate between them.

This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction. Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated with one or the other. It should be noted, however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.

Nephrotoxicity vs. Rejection Parameter Nephrotoxicity Rejection History Donor >50 years old or hypotensive Prolonged kidney preservation Prolonged anastomosis time Concomitant nephrotoxic drugs Anti-donor immune response Retransplant patient Clinical Often >6 weeks postop p < 0.01, Prolonged initial nonfunction (acute tubular necrosis) Often <4 weeks postop Fever >37.5°C Weight gain >0.5 kg Graft swelling and tenderness Decrease in daily… [Excerpted — this section continues on DailyMed.]

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® (cyclosporine) 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%, 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 (cyclosporine [MODIFIED]) 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 generaliz… [Excerpted — this section continues on DailyMed.]

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 nonsteroidal anti-inflammatory drugs 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 Antifungals Anti-inflammatory Drugs ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole melphalan amphotericin B ketoconazole azapropazon colchicine diclofenac naproxen sulindac Gastrointestinal Agents Immunosuppressives Other Drugs cimetidine ranitidine tacrolimus 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 cyclosporine [MODIFIED]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 Antibiotics Other Drugs diltiazem azithromycin allopurinol nicardipine clarithromycin amiodarone verapamil erythromycin bromocriptine quinupristin/dalfopristin colchicine Antifungals danazol fluconazole Glucocorticoids imatinib itraconazole methylprednisolone metoclopramide ketoconazole nefazodone voriconazole 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 rifampin carbamazepine oxcarbazepine phenobarbital phenytoin bosentan octreotide orlistat sulfinpyrazone St. John's Wort terbinafine ticlopidine Bosentan Coadministration of bosentan (250 - 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 200-250 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 cyclospori… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Hypertension Cyclosporine is the active ingredient of cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED]. Hypertension is a common side effect of cyclosporine therapy which may persist. ( See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION for monitoring recommendations.) Mild or moderate hypertension is encountered more frequently than severe hypertension and the incidence decreases over time.

In recipients of kidney, liver, and heart allografts treated with cyclosporine, antihypertensive therapy may be required. (See Special Monitoring of Rheumatoid Arthritis and Psoriasis Patients .) However, since cyclosporine may cause hyperkalemia, potassium-sparing diuretics should not be used. While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, they can interfere with cyclosporine metabolism.

( See Drug Interactions .) Vaccination During treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided. Special Monitoring of Rheumatoid Arthritis Patients Before initiating treatment, a careful physical examination, including blood pressure measurements (on at least two occasions) and two creatinine levels to estimate baseline should be performed. Blood pressure and serum creatinine should be evaluated every 2 weeks during the initial 3 months and then monthly if the patient is stable.

It is advisable to monitor serum creatinine and blood pressure always after an increase of the dose of nonsteroidal anti-inflammatory drugs and after initiation of new nonsteroidal anti-inflammatory drug therapy during cyclosporine [MODIFIED] treatment. If coadministered with methotrexate, CBC and liver function tests are recommended to be monitored monthly. ( See also PRECAUTIONS, General, Hypertension ) In patients who are receiving cyclosporine, the dose of cyclosporine [MODIFIED] should be decreased by 25% to 50% if hypertension occurs.

If hypertension persists, the dose of cyclosporine [MODIFIED] should be further reduced or blood pressure should be controlled with anti-hypertensive agents. In most cases, blood pressure has returned to baseline when cyclosporine was discontinued. In placebo-controlled trials of rheumatoid arthritis patients, systolic hypertension (defined as an occurrence of two systolic blood pressure readings >140 mm Hg) and diastolic hypertension (defined as two diastolic blood pressure readings >90 mm Hg) occurred in 33% and 19% of patients treated with cyclosporine, respectively.

The corresponding placebo rates were 22% and 8%. Special Monitoring of Psoriasis Patients Before initiating treatment, a careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since cyclosporine [MODIFIED] is an immunosuppressive agent, patients should be evaluated for the presence of occult infection on their first physical examination and for the presence of tumors initially, and throughout treatment with cyclosporine [MODIFIED].

Skin lesions not typical for psoriasis should be biopsied before starting cyclosporine [MODIFIED]. Patients with malignant or premalignant changes of the skin should be treated with cyclosporine [MODIFIED] only after appropriate treatment of such lesions and if no other treatment option exists. Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium, potassium, uric acid, and lipids.

The risk of cyclosporine nephropathy is reduced when the starting dose is low (2.5 mg/kg/day), the maximum dose does not exceed 4 mg/kg/day, serum creatinine is monitored regularly while cyclosporine is administered, and the dose of cyclosporine [MODIFIED] is decreased when the rise in creatinine is greater than or equal to 25% above the patient's pretreatment level. The increase in creatinine is generally reversible upon timely decrease of the dose of cyclosporine [MODIFIED] or… [Excerpted — this section continues on DailyMed.]