General

Pronunciation:
sye-kloe-spor-een

Trade Name(s)

• Gengraf
• Neoral
• SandIMMUNE

Ther. Class.

immunosuppressants

antirheumatics

(DMARD)

Pharm. Class.

polypeptides

(cyclic)

†See ophthalmic medications for ophthalmic use

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(s):

• Management of recalcitrant ulcerative colitis.
• Treatment of steroid-resistant nephrotic syndrome.
• Treatment of severe steroid-resistant 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 Effect(s):

• 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. IV administration results in complete bioavailability.

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

Protein Binding: 90–98%.

Metabolism and 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)

Contraindication/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 ↓ recommended);
• 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.

Adverse 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

Metabolic: 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

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

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 effect.
•  Bosentan  may significantly ↓ levels; 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:

• Concomitant use with  echinacea and  melatonin  may interfere with immunosuppression.
• Use with  St. John's wort  may cause ↓ serum levels and organ rejection for transplant patients.

Drug-Food:

• Concurrent ingestion of grapefruit or grapefruit juice may ↑ serum levels and should be avoided.
• Food ↓ absorption 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; 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 (Neoral only)

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.

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

Solution for injection (Sandimmune): 50 mg/mL

Assessment

• Monitor serum creatinine level, intake and output ratios, daily weight, and BP during therapy. Report significant changes.
• Assess for any new signs or symptoms that may be suggestive of PML, an opportunistic infection of the brain caused by the JC virus, which may be fatal; withhold dose and notify health care professional promptly. PML symptoms may begin gradually (hemiparesis, apathy, confusion, cognitive deficiencies, and ataxia) and may include deteriorating renal function and renal graft loss.
• Monitor for signs and symptoms of PRES (impaired consciousness, convulsions, visual disturbances including blindness, loss of motor function, movement disorders and psychiatric disturbances, papilledema, visual impairment). Usually reversible with discontinuation of cyclosporine. Occurs more often in patients with liver transplant than kidney transplant.
• Prevention of Transplant Rejection: Assess for symptoms of organ rejection during therapy.
• IV Monitor patient for signs and symptoms of hypersensitivity (wheezing, dyspnea, flushing of face or neck) continuously during at least the first 30 min of each treatment and frequently thereafter. Oxygen, epinephrine, and equipment for treatment of anaphylaxis should be available with each IV dose.
• Arthritis:

  Assess pain and limitation of movement prior to and during administration.

  • Prior to initiating therapy, perform a physical exam including BP on 2 occasions to determine baseline. Monitor BP every 2 wk during initial 3 mo, then monthly if stable. If hypertension occurs, dose should be reduced.
• Psoriasis: Assess skin lesions prior to and during therapy.

Lab Test Considerations:

Measure serum creatinine, BUN, CBC, magnesium, potassium, uric acid, and lipids at baseline, every 2 wk during initial therapy, and then monthly if stable. Nephrotoxicity may occur; report significant increases.

• May cause hepatotoxicity; monitor for ↑ AST, ALT, alkaline phosphatase, amylase, and bilirubin.
• May cause ↑ serum potassium and uric acid levels and ↓ serum magnesium levels.
• Serum lipid levels may be ↑.

Evaluate serum cyclosporine levels periodically during therapy. Dose may be adjusted daily, in response to levels, during initiation of therapy. Guidelines for desired serum levels will vary among institutions.

Implementation

• Do not confuse cyclosporine with cyclophosphamide or cycloserine. Do not confuse Sandimmune with Sandostatin.
  • Administer initial dose 4–12 hrs before transplantation.
  • Given with adrenal corticosteroids; avoid other immunosuppressive agents. Protect transplant patients from staff and visitors who may carry infection. Maintain protective isolation as indicated.
  • Microemulsion products (Neoral) and other products (Sandimmune) are not interchangeable.
• PO Draw up oral solution in the syringe provided; do not rinse syringe either before or after use. Introduction of water into the product by any means will cause variation in dose. Mix oral solution with milk, chocolate milk, apple juice, or orange juice, preferably at room temperature. Stir well and drink at once. Use a glass container and rinse with more diluent to ensure that total dose is taken. Administer oral doses with meals.

Patient/Family Teaching

• Instruct patient to take medication 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. Do not discontinue medication without advice of health care professional.
• 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 patients and/or parents to notify health care professional if diarrhea develops; decreases 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, increased facial and body hair, gingival hyperplasia). Advise patients 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, increased frequency, cloudy urine, decreased urine output, fever, sore throat, tiredness, or unusual bruising occurs.
• Instruct patient on proper oral hygiene. Meticulous oral hygiene and dental examinations for teeth cleaning and plaque control every 3 mo will help decrease gingival inflammation and hyperplasia.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking other Rx, OTC, or herbal products or receiving any vaccinations while taking this medication.
• Rep:  Advise patient to notify health care professional if pregnancy is planned or suspected, and to avoid breastfeeding.
• Emphasize the importance of follow-up exams and lab tests.

Evaluation/Desired Outcomes

• Prevention of rejection of transplanted tissues.

• Decrease in severity of pain in patients with rheumatoid arthritis.

  • Increased ease of joint movement in patients with rheumatoid arthritis.
• Decrease in progression of psoriasis.