Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/877
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Cyclosporine (Solution)
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Cyclosporine Oral Solution, USP has decreased bioavailability in comparison to Neoralsoft gelatin capsules (cyclosporine capsules, USP) MODIFIED and Neoraloral solution (cyclosporine oral solution, USP) MODIFIED. Cyclosporine and Neoral(cyclosporine [MODIFIED]) are not bioequivalent and cannot be used interchangeably without physician supervision. The initial oral dose of cyclosporine should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate. (See Blood Level Monitoring below) In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies children have required and tolerated higher doses than those used in adults. Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A dosage schedule based on the patient's weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation. To make cyclosporine oral solution, USP more palatable, the oral solution may be diluted with milk, chocolate milk, or orange juice preferably at room temperature. Patients should avoid switching diluents frequently. Cyclosporine oral solution should be administered on a consistent schedule with regard to time of day and relation to meals. Take the prescribed amount of cyclosporine from the container using the dosage syringe supplied after removal of the protective cover, and transfer the solution to a glass of milk, chocolate milk, or orange juice. Stir well and drink at once. Do not allow to stand before drinking. It is best to use a glass container and rinse it with more diluent to ensure that the total dose is taken. After use, replace the dosage syringe in the protective cover. Do not rinse the dosage syringe with water or other cleaning agentseither before or after use. If the dosage syringe requires cleaning, it must be completely dry before resuming use. Introduction of water into the product by any means will cause variation in dose.<br/>Blood Level Monitoring: Several study centers have found blood level monitoring of cyclosporine useful in patient management. While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough levels of 100���200 ng/mL as determined by high-pressure liquid chromatography (HPLC). Of major importance to blood level analysis is the type of assay used. The above levels are specific to the parent cyclosporine molecule and correlate directly to the new monoclonal specific radioimmunoassays (mRIA-sp). Nonspecific assays are also available which detect the parent compound molecule and various of its metabolites. Older studies often cited levels using a nonspecific assay which were roughly twice those of specific assays. Assay results are not interchangeable and their use should be guided by their approved labeling. If plasma specimens are employed, levels will vary with the temperature at the time of separation from whole blood. Plasma levels may range from 1/2���1/5 of whole blood levels. Refer to individual assay labeling for complete instructions. In addition, Transplantation Proceedings (June 1990) contains position papers and a broad consensus generated at the Cyclosporine-Therapeutic Drug Monitoring conference that year. Blood level monitoring is not a replacement for renal function monitoring or tissue biopsies.
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Cyclosporine, the active principle in Cyclosporine Oral Solution, USP is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea. 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-��-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl). Cyclosporine Oral Solution, USP is available in 50 mL bottles. Each mL contains:Cyclosporine, USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 mgAlcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5% by volumeDissolved in an olive oil, NF/Labrafil M 1944 CS (polyoxyethylated oleic glycerides) vehicle which must be further diluted with milk, chocolate milk, or orange juice before oral administration. The chemical structure of cyclosporine (also known as cyclosporine A) is:
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Cyclosporine is a potent immunosuppressive agent which in animals prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs. Successful kidney, liver, and heart allogeneic transplants have been performed in man using cyclosporine. The exact mechanism of action of cyclosporine is not known. Experimental evidence suggests that the effectiveness of cyclosporine is due to specific and reversible inhibition of immunocompetent lymphocytes in the G- or G-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 or T-cell growth factor (TCGF). No functional effects on phagocytic (changes in enzyme secretions not altered, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) or tumor cells (growth rate, metastasis) can be detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man. The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Peak concentrations (C) in blood and plasma are achieved at about 3.5 hours. Cand area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood the relationship is curvilinear (parabolic) between 0 and 1400 mg. As determined by a specific assay, Cis approximately 1.0 ng/mL/mg of dose for plasma and 2.7���1.4 ng/mL/mg of dose for blood (for low to high doses). Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The bioavailability of cyclosporine capsules, USP is equivalent to cyclosporine oral solution, USP. Cyclosporine is distributed largely outside the blood volume. In blood the distribution is concentration dependent. Approximately 33%���47% is in plasma, 4%���9% in lymphocytes, 5%���12% in granulocytes, and 41%���58% in erythrocytes. At high concentrations, the uptake by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 hours (range: 10 to 27 hours). Elimination is primarily biliary with only 6% of the dose excreted in the urine. Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only 0.1% of the dose is excreted in the urine as unchanged drug. Of 15 metabolites characterized in human urine, 9 have been assigned structures. The major pathways consist of hydroxylation of the C��-carbon of 2 of the leucine residues, C��-carbon hydroxylation, and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl-N,4-dimethyl-L- 2-amino-6-octenoic acid and N-demethylation of N-methyl leucine residues. Hydrolysis of the cyclic peptide chain or conjugation of the aforementioned metabolites do not appear to be important biotransformation pathways.
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Cyclosporine oral solution is contraindicated in patients with a hypersensitivity to cyclosporine or any of the ingredients in the formulation.
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Cyclosporine Oral Solution, USP 100 mg/mL is a clear, yellow colored solution, for oral administration and is supplied in 50 mL bottles containing 100 mg of cyclosporine per mL. A dosage syringe is provided for dispensing.<br/>Store and Dispense: In the original container. Store at 20��to 25��C (68��to 77��F) [see USP Controlled Room Temperature]. Do not store in the refrigerator. Protect from freezing. Once opened, the contents must be used within 2 months.
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WARNING: Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe cyclosporine. 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. Cyclosporine should be administered with adrenal corticosteroids but not with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Cyclosporine Oral Solution, USP has decreased bioavailability in comparison to Neoral* soft gelatin capsules (cyclosporine capsules, USP) MODIFIED and Neoral* oral solution (cyclosporine oral solution, USP) MODIFIED. Cyclosporine and Neoral* (cyclosporine [MODIFIED]) are not bioequivalent and cannot be used interchangeably without physician supervision. The absorption of cyclosporine during chronic administration of oral solution was found to be erratic. It is recommended that patients taking the oral solution over a period of time be monitored at repeated intervals for cyclosporine blood levels and subsequent dose adjustments be made in order to avoid toxicity due to high levels and possible organ rejection due to low absorption of cyclosporine. This is of special importance in liver transplants. Numerous assays are being developed to measure blood levels of cyclosporine. Comparison of levels in published literature to patient levels using current assays must be done with detailed knowledge of the assay methods employed.
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There is a minimal experience with overdosage. Because of the slow absorption of cyclosporine oral solution, forced emesis would be of value up to 2 hours after administration. Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Cyclosporine is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral LDis 2329 mg/kg in mice, 1480 mg/kg in rats, and>1000 mg/kg in rabbits. The I.V. LDis 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
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Cyclosporine
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Cyclosporine (Solution)
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The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients. Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resemble those seen in the hemolytic-uremic syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathichemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed posttransplantation. 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. The following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants: The following reactions occurred in 2% or less of patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus. The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss. Cyclosporine was discontinued on a temporary basis and then restarted in 18 additional patients. Polyoxyethylated castor oil is known to cause hyperlipemia and electrophoretic abnormalities of lipoproteins. These effects are reversible upon discontinuation of treatment but are usually not a reason to stop treatment.
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Cyclosporine is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. It is always to be used with adrenal corticosteroids. The drug may also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents. Because of the risk of anaphylaxis, cyclosporine injection, USP should be reserved for patients who are unable to take the soft gelatin capsules or oral solution.
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Cyclosporine
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