Source: FDA, National Drug Code (US) Revision Year: 2020
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 G0- or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release, including interleukin-2 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 (Cmax) in blood and plasma are achieved at about 3.5 hours. Cmax and 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, Cmax is approximately 1.0 ng/mL/mg of dose for plasma and 2.7 to 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 Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) is equivalent to Sandimmune Oral Solution, (cyclosporine oral solution, USP).
Cyclosporine is distributed largely outside the blood volume. 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 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 CĪ³-carbon of 2 of the leucine residues, CĪ·-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.
In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5mL/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.
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.
Cyclosporine gave no evidence of mutagenic or teratogenic effects in appropriate test systems. Only at dose levels toxic to dams, were adverse effects seen in reproduction studies in rats (See Pregnancy).
Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate in the low-dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.
No impairment in fertility was demonstrated in studies in male and female rats.
Cyclosporine has not been found mutagenic/genotoxic in the Ames test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE), at high concentrations in this system. In two published research studies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown.
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin’s lymphoma and carcinomas of the skin. The risk of malignancies in cyclosporine recipients is higher than in the normal, healthy population, but similar to that in patients receiving other immunosuppressive therapies. It has been reported that reduction or discontinuance of immunosuppression may cause the lesions to regress.
The following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants:
| Body System | Randomized Kidney Patients | All Sandimmune (cyclosporine) Patients | |||
|---|---|---|---|---|---|
| Sandimmune | Azathioprine | Kidney | Heart | Liver | |
| (N=227) | (N=228) | (N=705) | (N=112) | (N=75) | |
| Adverse Reactions | % | % | % | % | % |
| 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 |
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.
Renal Transplant Patients in Whom Therapy Was Discontinued:
| Randomized Patients | All Sandimmune Patients | ||
|---|---|---|---|
| Sandimmune | Azathioprine | ||
| (N=227) | (N=228) | (N=705) | |
| Reason for Discontinuation | % | % | % |
| Renal Toxicity | 5.7 | 0 | 5.4 |
| Infection | 0 | 0.4 | 0.9 |
| Lack of Efficacy | 2.6 | 0.9 | 1.4 |
| Acute Tubular Necrosis | 2.6 | 0 | 1.0 |
| Lymphoma/Lymphoproliferative Disease | 0.4 | 0 | 0.3 |
| Hypertension | 0 | 0 | 0.3 |
| Hematological Abnormalities | 0 | 0.4 | 0 |
| Other | 0 | 0 | 0.7 |
| Sandimmune (cyclosporine) was discontinued on a temporary basis and then restarted in 18 additional patients. | |||
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. Preexisting infections may also be aggravated. Fatal outcomes have been reported (See WARNINGS).
Infectious Complications in the Randomized Renal Transplant Patients:
| Sandimmune Treatment | Standard Treatment* | |
|---|---|---|
| (N=227) | (N=228) | |
| Complication | % of Complications | % 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.
Cremophor EL (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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