cycloSPORINE† (sye-kloe-spor-een) Gengraf, Neoral, SandIMMUNE

 Indications

PO, IV: Prevention and treatment of rejection in renal,

cardiac, and hepatic transplantation (with corticosteroids).

PO: Treatment of severe active rheumatoid arthritis

(Neoral only). Treatment of severe recalcitrant

psoriasis in adult nonimmunocompromised patients

(Neoral only). Unlabeled Use: Management of recalcitrant ulcerative colitis. Treatment of steroid-resistant

nephrotic syndrome. Treatment of severe steroidresistant

autoimmune disease. Prevention and

treatment of graft vs. host disease in bone marrow

transplant patients.

Action

Inhibits normal immune responses (cellular and humoral)

by inhibiting interleukin-2, a factor necessary

for initiation of T-cell activity. Therapeutic Effects:

Prevention of rejection reactions. Slowed progression

of rheumatoid arthritis or psoriasis.

Pharmacokinetics

Absorption: Erratically absorbed (range 10–60%)

after oral administration, with significant first-pass metabolism

by the liver. Microemulsion (Neoral) has better

bioavailability.

Distribution: Widely distributed, mainly into extracellular

fluid and blood cells. Crosses the placenta; enters

breast milk.

Protein Binding: 90–98%.

Metabolism and Excretion: Extensively metabolized

by the liver by CYP3A4 (first pass); excreted in

bile, small amounts excreted unchanged in urine.

Half-life: Children—7 hr; adults—19 hr.

TIME/ACTION PROFILE (blood levels)

ROUTE ONSET PEAK DURATION

PO unknown† 2–6 hr unknown

IV unknown end of infusion

unknown

†Onset of action in rheumatoid arthritis is 4–8 wk and may

last 4 wk after discontinuation; for psoriasis, onset is2–6wk

and lasts 6 wk following discontinuation.

Contraindications/Precautions

Contraindicated in: Hypersensitivity to cyclosporine

or polyoxyethylated castor oil (vehicle for IV form);

Disulfiram therapy or known alcohol intolerance (IV

and oral liquid dose forms contain alcohol); Patients

with psoriasis receiving immunosuppressants or radiation;

Renal impairment (in patients with rheumatoid arthritis

or psoriasis); Uncontrolled hypertension; OB,

Lactation: Should not be given unless benefits outweigh

risks.

Use Cautiously in: Severe hepatic impairment

(doseprecommended); Renal impairment (frequent

dose changes may be necessary); Active infection; Pedi:

Larger or more frequent doses may be required.

Adverse Reactions/Side Effects

CNS: POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME,

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY,

SEIZURES, tremor, confusion, flushing, headache,

psychiatric problems. CV: hypertension. GI: HEPATOTOXICITY,

diarrhea, nausea, vomiting, abdominal discomfort,

anorexia, pancreatitis. GU: nephrotoxicity.

Derm: hirsutism, acne, psoriasis. F and E: hyperkalemia,

hypomagnesemia. Hemat: anemia, leukopenia,

thrombocytopenia.Metab: hyperlipidemia, hyperuricemia.

Neuro: hyperesthesia, paresthesia. MS: lower

extremity pain. Misc: gingival hyperplasia, hypersensitivity

reactions, infections (including activation of latent

viral infections such as BK virus-associated nephropathy),

malignancy.

Interactions

Drug-Drug: Azithromycin, clarithomycin, allopurinol,

amiodarone, bromocriptine, colchicine,

danazol, digoxin, diltiazem, erythromycin, fluconazole,

fluoroquinolones, imatinib, itraconazole,

ketoconazole, voriconazole, metoclopramide,

methylprednisolone, nefazodone,

nicardipine, protease inhibitors, quinupristin/

dalfopristin, verapamil, or hormonal contraceptives

mayqserum levels and risk of toxicity.qimmunosuppression

with other immunosuppressants (cyclophosphamide,

azathioprine, corticosteroids).

Carbamazepine, nafcillin, octreotide, orlistat, oxcarbazepine,

phenobarbital, phenytoin, rifampin,

rifabutin, or terbinafine mayplevels and effect.

Bosentan may significantlyplevels; avoid concurrent

use.qrisk of hyperkalemia with potassium-sparing

diuretics, potassium supplements, or ACE inhibitors.

Mayqlevels and risk of toxicity of aliskiren,

bosentan, colchicine, digoxin, etoposide, HMGCoA

reductase inhibitors, methotrexate, nifedipine,

repaglinide, and sirolimus. Mayqlevels and

risk of toxicity of ambrisentan; do not titrate dose of

ambrisentan up to maximum daily dose. Mayqlevels of

and risk of bleeding with dabigatran; avoid concurrent

use. Maypantibody response to live-virus vaccines

andqrisk of adverse reactions; avoid concurrent

use. Concurrent use with tacrolimus should be

avoided.qrisk of renal impairment with ciprofloxacin,

aminoglycosides, vancomycin, trimethoprim/

sulfamethoxazole, melphalan, amphotericin B,

ketoconazole, colchicine, NSAIDS, cimetidine,

ranitidine, or fibric acid derivatives.

Drug-Natural Products: Concomitant use with

echinacea and melatonin may interfere with immunosuppression.

Use with St. John’s wort may causep

serum levels and organ rejection for transplant patients.

Drug-Food: Concurrent ingestion of grapefruit or

grapefruit juice mayqserum levels and should be

avoided. Foodpabsorption of microemulsion products

(Neoral).

Route/Dosage

Doses are adjusted on the basis of serum level monitoring.

Prevention of Transplant Rejection

(Sandimmune)

PO (Adults and Children): 14–18 mg/kg/dose 4–

12 hr before transplant then 5–15 mg/kg/day divided

every 12–24 hr postoperatively, taper by 5% weekly to

maintenance dose of 3–10 mg/kg/day.

IV (Adults and Children): 5–6 mg/kg/dose 4–12 hr

before transplant, then 2–10 mg/kg/day in divided

doses every 8–24 hr; change to PO as soon as possible.

Prevention of Transplant Rejection

(Neoral)

PO (Adults and Children): 4–12 mg/kg/day divided

every 12 hr (dose varies depending on organ transplanted).

Rheumatoid Arthritis (Neoral only)

PO (Adults and Children): 2.5 mg/kg/day given in 2

divided doses; mayqby 0.5–0.75 mg/kg/day after 8

and 12 wk, up to 4 mg/kg/day.pdose by 25–50% if

adverse reactions occur.

Severe Psoriasis (Neoral only)

PO (Adults): 2.5 mg/kg/day given in 2 divided doses,

for at least 4 wk; then mayqby 0.5 mg/kg/day every 2

wk, up to 4 mg/kg/day.pdose by 25–50% if adverse

reactions occur.

Autoimmune Diseases (Neoral only)

PO (Adults and Children): 1–3 mg/kg/day.

Availability (generic available)

Microemulsion soft gelatin capsules (Gengraf,

Neoral): 25 mg, 50 mg, 100 mg. Microemulsion

oral solution (Gengraf, Neoral): 100 mg/mL. Soft

gelatin capsules (Sandimmune): 25 mg, 100 mg.

Oral solution (Sandimmune): 100 mg/mL. Injection

(Sandimmune): 50 mg/mL.