CYCLOSPORINE

(sye'kloe-spor-een)

Gengraf, Neoral, Sandimmune, Restasis
Classifications: immunosuppressant;
Therapeutic: immunosuppressant; antirheumatic; antipsoriatic
Pregnancy Category: C

Availability

Sandimmune: 25 mg, 50 mg, 100 mg capsules; 100 mg/mL oral solution;

Gengraf, Neoral: (microemulsion) 25 mg, 100 mg capsules; 100 mg/mL oral solution; 50 mg/mL injection;

Restasis: 0.05% ophthalmic emulsion

Action

Has immunosuppressant action by reducing transplant rejection due to selective and reversible inhibition of the first phase of T-cell activation with T-lymphocytes (which normally stimulate antibody production).

Therapeutic Effect

It is used to prevent allograft rejection in transplant patients. Additionally, it is a disease-modifying antirheumatic drug (DMARD).

Uses

In conjunction with adrenal corticosteroids to prevent organ rejection after kidney, liver, and heart transplants (allografts). Has had limited use in pancreas, bone marrow, and heart/lung transplantations. Also used for treatment of chronic transplant rejection in patients previously treated with other immunosuppressants; rheumatoid arthritis, severe psoriasis. Ophthalmic emulsion for the treatment of keratoconjunctivitis sicca.

Unlabeled Uses

Sjögren's syndrome, to prevent rejection of heart-lung and pancreatic transplants, ulcerative colitis.

Contraindications

Hypersensitivity to cyclosporine or to ingredients in commercially available formulations [e.g., Cremophor (polyoxyl 35 castor oil)]; recent contact with or bout of chickenpox, herpes zoster; administration of live virus vaccines to patient or family members; RA patients with abnormal renal function, uncontrolled hypertension, or malignancies; ocular infection, pregnancy (category C), lactation.

Cautious Use

Renal, hepatic, pancreatic, or bowel dysfunction; biliary tract disease, jaundice, hyperkalemia; electrolyte imbalance, hyperuricemia, hypertension; infection; radiation therapy, older adults, encephalopathy, females of childbearing age, fungal or viral infection, gout, herpes infection, lymphoma, neoplastic disease, malabsorption problems (e.g., liver transplant patients).

Route & Dosage

Prevention of Organ Rejection
Adult/Child: PO 14–18 mg/kg beginning 4–12 h before transplantation and continued for 1–2 wk after surgery, then gradual reduction by 5%/wk, max dose of microemulsion, 10 mg/kg/d; Maintenance 5–10 mg/kg/d. IV 5–6 mg/kg beginning 4–12 h before transplantation and continued after surgery until patient can take oral

Rheumatoid Arthritis (Neoral)
Adult: PO 2.5 mg/kg/d divided into 2 doses. May increase by 0.5–0.75 mg/kg/d q4wk to a max of 4 mg/kg/d

Severe Psoriasis (Neoral)
Adult: PO 1.25 mg/kg b.i.d. If significant improvement has not occurred after 4 wk, may increase dose by 0.5 mg/kg/d every 2 wk to max of 4 mg/kg/d

Keratoconjunctivitis Sicca
Adult: Ophthalmic 1 drop in affected eye(s) twice daily approximately 12 h apart

Administration

Oral

Do not dilute oral solution with grapefruit juice. Dilute with orange or apple juice, stir well, then administer immediately.
Neoral (microemulsion) and Sandimmune are not bioequivalent and cannot be used interchangeably without physician supervision.

Intravenous

PREPARE: IV Infusion: Dilute each 1 mL immediately before administration in 20–100 mL of D5W or NS.

ADMINISTER: IV Infusion: Give by slow infusion over approximately 2–6 h. Rapid IV can result in nephrotoxicity.

INCOMPATIBILITIES Solution/additive: Magnesium sulfate. Y-site: Amphotericin B cholesteryl complex, TPN.

Store preferably at 15°–30° C (59°–86° F) in well-closed containers. Do not refrigerate. Protect ampules from light.

Adverse Effects (≥1%)

Body as a Whole: Lymphoma, gynecomastia, chest pain, leg cramps, edema, fever, chills, weight loss, increased risk of skin malignancies in psoriasis patients previously treated with methotrexate, psoralens, or UV light therapy. CV: Hypertension, MI (rare). GI: Gingival hyperplasia, diarrhea, nausea, vomiting, abdominal discomfort, anorexia, gastritis, constipation. Hematologic: Leukopenia, anemia, thrombocytopenia, hypermagnesemia, hyperkalemia, hyperuricemia, decreased serum bicarbonate, hyperglycemia. CNS: Tremor, convulsions, headache, paresthesias, hyperesthesia, flushing, night sweats, insomnia, visual hallucinations, confusion, anxiety, flat affect, depression, lethargy, weakness, paraparesis, ataxia, amnesia. Skin: Hirsutism, acne, oily skin, flushing. Special Senses: Sinusitis, tinnitus, hearing loss, sore throat. Urogenital: Urinary retention, frequency, nephrotoxicity (oliguria).

Diagnostic Test Interference

Hyperlipidemia and abnormalities in electrophoresis reported; believed to be due to polyoxyl 35 castor oil (Cremophor) in IV cyclosporine.

Interactions

Drug: aminoglycosides, danazol, diltiazem, doxycycline, erythromycin, ketoconazole, methylprednisolone, metoclopramide, nicardipine, nsaids, prednisolone, verapamil may increase cyclosporine levels; carbamazepine, isoniazid, octreotide, phenobarbital, phenytoin, rifampin may decrease cyclosporine levels; acyclovir, aminoglycosides, amphotericin B, cimetidine, erythromycin, ketoconazole, melphalan, ranitidine, cotrimoxazole, trimethoprim may increase risk of nephrotoxicity; potassium-sparing diuretics, ace inhibitors (captopril, enalapril) may potentiate hyperkalemia. Food: Grapefruit juice may increase concentration. Herbal: St. John's wort may decrease cyclosporine levels.

Pharmacokinetics

Absorption: Variably and incompletely absorbed (30%). Microemulsion formulation (Neoral) has less variability in absorption and may produce significantly higher serum levels compared with the standard formulation. Peak: 3–4 h. Distribution: Widely distributed; 33–47% distributed to plasma; 41–50% to RBCs; crosses placenta; distributed into breast milk. Metabolism: In liver by CYP3A4, including significant first pass metabolism; considerable enterohepatic circulation. Elimination: Primarily in bile and feces; 6% in urine. Half-Life: 19–27 h.

Nursing Implications

Assessment & Drug Effects

Observe patients receiving the drug parenterally for at least 30 min continuously after start of IV infusion, and at frequent intervals thereafter to detect allergic or other adverse reactions.
Hypersensitivity reactions have been associated with Cremophor emulsifying agent in the parenteral formulation but not with the PO solution, which does not contain this ingredient.
Monitor I&O ratio and pattern: Nephrotoxicity has been reported in about one third of transplant patients. It has occurred in mild forms as late as 2–3 mo after transplantation. In severe form, it can be irreversible, and therefore early recognition is critical.
Monitor vital signs. Be alert to indicators of local or systemic infection that can be fungal, viral, or bacterial. Also report significant rise in BP.
Lab tests: Baseline and periodic tests are advised for (1) renal function (BUN, serum creatinine), (2) liver function (AST, ALT, serum amylase, bilirubin, and alkaline phosphatase), and (3) serum potassium.
Lab tests: In psoriasis patients, CBC, BUN, uric acid, potassium, lipids, and magnesium should be monitored biweekly during first 3 mo.
Periodic tests should be made of neurologic function. Neurotoxic effects generally occur over 13–195 d after initiation of cyclosporine therapy. Signs and symptoms are reportedly fully reversible with dosage reduction or discontinuation of drug.
Monitor blood or plasma drug concentrations at regular intervals, particularly in patients receiving the drug orally for prolonged periods, as drug absorption is erratic.

Patient & Family Education

Use the specially calibrated pipette provided to measure dose.
Take medication with meals to reduce nausea or GI irritation.
Enhance palatability of oral solution by mixing it with milk, chocolate milk, or orange juice, preferably at room temperature. Mix in a glass rather than a plastic container. Stir well, drink immediately, and rinse glass with small quantity of diluent to assure getting entire dose.
Take medication at same time each day to maintain therapeutic blood levels.
Keep scheduled follow-up appointments.
If possible, see a dentist before start of cyclosporine treatment, and practice good oral hygiene. Inspect mouth daily for white patches, sores, swollen gums.
Hirsutism is reversible with discontinuation of drug.

Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug

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