cyclosporine
Neoral, Sandimmune

cyclosporine, modified
Gengraf

Available forms
Available by prescription only
Capsules: 25 mg, 50 mg, 100 mg
Capsules for microemulsion: 25 mg, 100 mg
Emulsion solution: 100 mg
Injection: 50 mg/ml
Oral solution: 100 mg/ml

Indications and dosages
 Prophylaxis of organ rejection in kidney, liver, heart, bone marrow, pancreas ◇, cornea transplants ◇. Adults and children: 15 mg/kg P.O. daily 4 to 12 hours before transplantation. Continue daily dose postoperatively for 1 to 2 weeks. Then, gradually reduce dosage by 5% weekly to maintenance level of 5 to 10 mg/kg daily. Or, administer an I.V. concentrate of 5 to 6 mg/kg 4 to 12 hours before transplantation.
 Postoperatively, administer 5 to 6 mg/kg daily as an I.V. dilute solution infusion (50 mg per 20 to 100 ml infused over 2 to 6 hours) until patient can tolerate oral forms.
 Note: Sandimmune and Neoral aren’t bioequivalent and can’t be used interchangeably without supervision. When converting to Neoral from Sandimmune, start with same daily dose (1:1) and follow serum trough levels frequently.
 Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants.
Gengraf. Adults: Same initial dosage as Sandimmune.
 Treatment of severe, active rheumatoid arthritis that hasn’t adequately responded to methotrexate.
Gengraf. Adults: 2.5 mg/kg P.O. daily taken b.i.d. May be increased by 0.5 to 0.75 mg/kg daily after 8 weeks and again after 12 weeks to maximum of 4 mg/kg daily.
 Nonimmunocompromised patients with severe, recalcitrant plaque psoriasis who have failed to respond to at least one systemic therapy; patients for whom other systemic therapies are contraindicated or can’t be tolerated.
Gengraf. Adults: 2.5 mg/kg P.O. daily given b.i.d. for at least 4 weeks. If no improvement, increase dosage at 2-week intervals by 0.5 mg/kg daily to a maximum of 4 mg/kg daily.
 Conversion from Sandimmune to Gengraf.
Adults: Use same daily dose as previously used on Sandimmune. Monitor blood levels every 4 to 7 days after conversion, and monitor blood pressure and serum creatinine level every 2 weeks during the first 2 months.

Pharmacodynamics
Immunosuppressive action: Exact mechanism is unknown; its action is thought to be related to the inhibition of induction of interleukin-2, which plays a role in both cellular and humoral immune responses.

Pharmacokinetics
Absorption: Absorption after oral administration varies widely among patients and in the same individual. Only 30% of an oral dose reaches systemic circulation. Neoral has a greater bioavailability than Sandimmune. Cyclosporine modified (Gengraf) has an increased bioavailability compared with nonmodified, peaking in 1 1/2 to 2 hours.
Distribution: Distributed widely outside the blood volume. About 33% to 47% is found in plasma; 4% to 9%, in leukocytes; 5% to 12%, in granulocytes; and 41% to 58%, in erythrocytes. In plasma, about 90% is bound to proteins, primarily lipoproteins. Cyclosporine crosses the placental barrier; cord blood levels are about 60% those of maternal blood. Cyclosporine appears in breast milk.
Metabolism: Metabolized extensively in the liver.
Excretion: Primarily excreted in the feces (biliary excretion) with only 6% of drug found in urine.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or to polyoxyethylated castor oil (found in injectable form). Gengraf is contraindicated in patients with rheumatoid arthritis or psoriasis with abnormal renal function, uncontrolled hypertension, or malignancies. Psoriasis patients shouldn’t receive phototherapy with either psoralen and long-wave ultraviolet radiation (PUVA) or short-wave ultraviolet radiation (UVB), methotrexate, other immunosuppressants, coal tar, or radiation.

Interactions
Drug-drug. Allopurinol, bromocriptine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, methylprednisolone, metoclopramide, nicardipine, verapamil: Increases cyclosporine levels. Monitor levels.
Aminoglycosides, amphotericin B: Increases nephrotoxicity and cyclosporine blood levels. Avoid use together.
Amphotericin B, cimetidine, diclofenac, gentamycin, ketoconazole, melphalan, naproxen, ranitidine, sulfamethoxazole/trimethoprim, sulindac, tacrolimus, tobramycin, vancomycin: May potentiate renal dysfunction when used with cyclosporine. Use cautiously.
Carbamazepine, nafcillin, octreotide, phenobarbital, phenytoin, rifampin, ticlopidine: Decreases cyclosporine levels. Monitor levels.
Co-trimoxazole, phenobarbital, phenytoin, rifampin: Lower plasma levels of cyclosporine. Monitor patient closely.
Digoxin, lovastatin, prednisolone: Decreases clearance of these drugs. Use together cautiously.
Diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, possibly corticosteroids, verapamil: Increases plasma cyclosporine levels. Reduced dosage of cyclosporine may be needed.
Immunosuppressants (except corticosteroids): Increases risk of malignancy (lymphoma) and susceptibility to infection. Avoid use together.
Potassium-sparing diuretics: Increases risk of hyperkalemia. Avoid use together.
Vaccines: Decreases effectiveness. Avoid use of live attenuated vaccines.
Drug-herb. Alfalfa sprouts, astragalus, echinacea, licorice: May interfere with immunosuppressive effect of drug. Discourage use together.
St. John’s wort: May reduce cyclosporine levels, decreasing efficacy. Discourage use together.
Drug-food. Grapefruit juice: May increase trough levels. Discourage use together.

Adverse reactions
CNS: tremor, headache, seizures, confusion, paresthesia.
CV: hypertension, flushing.
EENT: sinusitis.
GI: gum hyperplasia, oral candidiasis, nausea, vomiting, diarrhea, abdominal discomfort.
GU: nephrotoxicity.
Hematologic: anemia, leukopenia, thrombocytopenia, hemolytic anemia.
Hepatic: hepatotoxicity.
Skin: acne, hirsutism.
Other: anaphylaxis, gynecomastia, increased low-density lipoprotein levels, infections.

Effects on lab test results
• May increase BUN, creatinine, LDL, bilirubin, AST, ALT, and blood glucose levels.
• May decrease hemoglobin, hematocrit, and WBC and platelet counts.

Overdose and treatment
Signs and symptoms of overdose include extensions of common adverse effects. Hepatotoxicity and nephrotoxicity often accompany nausea and vomiting; tremor and seizures may occur.
 Up to 2 hours after ingestion, empty stomach by induced emesis or lavage; thereafter, treat supportively. Monitor vital signs and fluid and electrolyte levels closely. Drug isn’t removed by hemodialysis or charcoal hemoperfusion.

Special considerations
• Cyclosporine can cause nephrotoxicity and hepatotoxicity.
• Cyclosporine usually is prescribed with corticosteroids.
• Consider possible kidney rejection before discontinuation of drug for suspected nephrotoxicity.
• Give dose at the same time each day. Measure oral solution carefully in oral syringe and mix with plain or chocolate milk or fruit juice to improve palatability; serve in a glass to minimize drug adherence to container walls. Drug can be taken with food to minimize nausea.
• Neoral capsules and oral solution are bioequivalent. Sandimmune capsules and oral solution have decreased bioavailability compared with Neoral.
 ALERT Gengraf and Sandimmune aren’t bioequivalent and can’t be interchanged. Conversion from Gengraf to Sandimmune should be done with increased monitoring to prevent underdosing.
• Gengraf is bioequivalent to and interchangeable with Neoral capsules.
• Psoriasis patients previously treated with PUVA, methotrexate, immunosuppressants, UVB, coal tar, or radiation therapy are at increased risk for developing skin malignancies when taking Gengraf.
• For patients with rheumatoid arthritis: Before starting treatment, measure blood pressure and creatinine levels at least twice to obtain baseline. Evaluate blood pressure and serum creatinine every 2 weeks during first 3 months, then monthly if the patient is stable. Monitor blood pressure and serum creatinine after an increase in dosage of NSAIDs or introduction of a new NSAID. Monitor CBC and liver function test results monthly if patient is receiving methotrexate concomitantly. If hypertension occurs, decrease dosage of Gengraf by 25% to 50%. If hypertension persists, decrease dosage further or control blood pressure with antihypertensives.
• For patients with psoriasis: Initially, measure blood pressure at least twice. Evaluate patient for occult infection and tumors initially and throughout treatment. Obtain baseline serum creatinine (on two occasions), CBC, BUN, serum magnesium, uric acid, potassium, and lipids. Evaluate serum creatinine and BUN levels every 2 weeks during first 3 months and then monthly thereafter if patient is stable. If serum creatinine level is greater than or equal to 25% above pretreatment, repeat serum creatinine determination within 2 weeks. If it remains 25% to 50% or more above baseline, reduce dosage by 25% to 50%. If at any time serum creatinine level is 50% or more above baseline, reduce dosage by 25% to 50%. Discontinue if reversibility of serum creatine level isn’t achieved after two dosage modifications. Monitor serum creatinine level after dosage increase of NSAID or after initiation of new NSAID.
• Evaluate blood pressure, CBC, and uric acid, potassium, lipid, and magnesium levels every 2 weeks for the first 3 months, then monthly if patient is stable or more frequently when dosage adjustments are made. Dosage should be reduced by 25% to 50% for an abnormality of clinical concern.
Pregnant patients
• There are potential risks when using drug in pregnant women.
Breast-feeding patients
• Cyclosporine appears in breast milk. Avoid use in breast-feeding women.
Pediatric patients
• Safety and efficacy haven’t been established; however, drug has been used in children as young as age 6 months. Use with caution.

Patient education
• Teach patient about rationale for therapy; explain possible adverse effects and importance of reporting them-especially fever, sore throat, mouth sores, abdominal pain, unusual bleeding or bruising, pale stools, or dark urine.
• Encourage compliance with therapy and follow-up visits.
• Explain to patient importance of frequent laboratory monitoring while receiving therapy.
• Teach patient how and when to take drug for optimal benefit and minimal discomfort; caution against discontinuing drug without medical approval.
• Advise patient to improve palatability of oral solution by diluting with room-temperature milk, chocolate milk, or orange juice. Don’t take Neoral with grapefruit juice or food.
• Tell patient not to rinse syringe with water.
• Warn patient to use sunblock and to avoid excessive sun exposure.
• Advise patient of the potential risk during pregnancy and the increased risk of neoplasia, hypertension, and renal dysfunction.
• Warn patient that, during cyclosporine therapy, vaccination may be less effective.
• Tell patient to take Gengraf on a consistent schedule with regard to time of day and relation to meals.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use