cyclosporine

REMS

PO: IV: Prevention and treatment of rejection in renal, cardiac, and hepatic transplantation (with corticosteroids).
PO: Severe active rheumatoid arthritis (Gengraf and Neoral only).
Severe recalcitrant psoriasis in nonimmunocompromised patients (Gengraf and Neoral only).

Unlabeled Use:

Recalcitrant ulcerative colitis.
Steroid-resistant nephrotic syndrome.
Severe steroid-resistant autoimmune disease.
Prevention and treatment of graft-versus-host disease in bone marrow transplant patients.

Contraind./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 rheumatoid arthritis or psoriasis);
Uncontrolled hypertension;
Lactation: Lactation.

Use Cautiously in:

Severe hepatic impairment (↓ dose);
Renal impairment (frequent dose changes may be necessary);
Active infection;
OB: An acceptable immunosuppressant when used following a kidney, heart, or liver transplant; not a preferred agent for other indications;
Pedi: Larger or more frequent doses may be required in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypertension

Derm: hirsutism, acne, psoriasis

F and E: hyperkalemia, hypomagnesemia

GI: diarrhea, nausea, vomiting, abdominal discomfort, anorexia, HEPATOTOXICITY, PANCREATITIS

GU: nephrotoxicity

Hemat: anemia, leukopenia, thrombocytopenia

Metab: hyperlipidemia, hyperuricemia

MS: lower extremity pain

Neuro: tremor, confusion, flushing, headache, hyperesthesia, paresthesia, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML), psychiatric problems, SEIZURES

Misc: gingival hyperplasia, hypersensitivity reactions, infection (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, verapamil, or hormonal contraceptives may ↑ levels and risk of toxicity.
↑immunosuppression with other immunosuppressants (cyclophosphamide, azathioprine, corticosteroids).
Carbamazepine, nafcillin, octreotide, orlistat, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifabutin, or terbinafine may ↓ levels and effectiveness.
Bosentan may significantly ↓ levels and effectiveness; avoid concurrent use.
↑risk of hyperkalemia with potassium-sparing diuretics, potassium supplements, or ACE inhibitors.
May ↑ levels and risk of toxicity of aliskiren, bosentan, colchicine, digoxin, etoposide, HMG-CoA reductase inhibitors, methotrexate, nifedipine, repaglinide, and sirolimus.
May ↑ levels and risk of toxicity of ambrisentan; do not titrate dose of ambrisentan up to maximum daily dose.
May ↑ levels of and risk of bleeding with dabigatran; avoid concurrent use.
May ↓ antibody response to live-virus vaccines and ↑ risk of adverse reactions; avoid concurrent use.
Concurrent use with tacrolimus should be avoided.
↑risk of renal impairment with ciprofloxacin, aminoglycosides, vancomycin, trimethoprim/sulfamethoxazole, melphalan, amphotericin B, ketoconazole, colchicine, NSAIDs, cimetidine, or fibric acid derivatives.

Drug-Natural Products:

Echinacea and melatonin may interfere with immunosuppression.
St. John’s wort may ↓ levels and effectiveness.

Drug-Food:

Grapefruit or grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.
Food↓ absorption of microemulsion products (Neoral).

Availability ⬆ ⬇

(Generic available)

Microemulsion soft gelatin capsules (Gengraf, Neoral): 25 mg; 50 mg; 100 mg
Microemulsion oral solution (Neoral): 100 mg/mL
Soft gelatin capsules (Sandimmune): 25 mg; 100 mg
Solution for injection (Sandimmune): 50 mg/mL

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 (Gengraf or Neoral)

PO (Adults and Children ): 4–12 mg/kg/day divided every 12 hr (dose varies depending on organ transplanted).

Rheumatoid Arthritis (Gengraf or Neoral)

PO (Adults and Children ): 2.5 mg/kg/day given in 2 divided doses; may ↑ by 0.5–0.75 mg/kg/day after 8 and 12 wk, up to 4 mg/kg/day. ↓ dose by 25–50% if adverse reactions occur.

Severe Psoriasis (Gengraf or Neoral)

PO (Adults ): 2.5 mg/kg/day given in 2 divided doses, for at least 4 wk; then may ↑ by 0.5 mg/kg/day every 2 wk, up to 4 mg/kg/day. ↓ dose by 25–50% if adverse reactions occur.

Autoimmune Diseases (Neoral only)

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

US Brand Names ⬆ ⬇

Gengraf, Neoral, SandIMMUNE

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.

Classifications ⬆ ⬇

Therapeutic Classification: Immunosuppressant agents, antirheumatics (DMARD)

Pharmacologic Classification: polypeptides (cyclic)

Pharmacokinetics ⬆ ⬇

Absorption: Erratically absorbed (range 10–60%) after oral administration, with significant first-pass metabolism by the liver. Microemulsion (Neoral) has better bioavailability. IV administration results in complete bioavailability.

Distribution: Widely distributed, mainly into extracellular fluid and blood cells.

Protein Binding: 90–98%.

Metabolism/Excretion: Extensively metabolized by the liver by the CYP3A4 isoenzyme (first pass); excreted in bile, small amounts excreted unchanged in urine.

Half-Life: Children: 7 hr; Adults: 19 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

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 is 2–6 wk and lasts 6 wk following discontinuation.

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Instruct patient to take at the same time each day with meals, as directed. Take missed doses as soon as remembered within 12 hr. Do not skip doses or double up on missed doses, and do not discontinue medication without advice of health care professional. Emphasize the importance of follow-up exams and lab tests.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other medications.
Reinforce the need for lifelong therapy to prevent transplant rejection. Review symptoms of rejection for transplanted organ, and stress need to notify health care professional immediately if they occur.
Instruct patient and/or caregiver to notify health care professional if diarrhea develops; ↓ absorption of cyclosporine and can result in rejection.
Instruct patient to avoid grapefruit and grapefruit juice to prevent interaction with cyclosporine.
Advise patient of common side effects (nephrotoxicity, ↑ BP, hand tremors, ↑ facial and body hair, gingival hyperplasia). Advise patient that if hair growth is excessive, depilatories or waxing can be used.
Teach patient the correct method for monitoring BP. Instruct patient to notify health care professional of significant changes in BP or if hematuria, ↑ urinary frequency, cloudy urine, ↓ urine output, fever, sore throat, tiredness, or unusual bruising occur.
Instruct patient on proper oral hygiene. Meticulous oral hygiene and dental examinations for teeth cleaning and plaque control every 3 mo will help ↓ gingival inflammation and hyperplasia.
Rep: Advise patient to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding.

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Indications ⬇