cyclosporine

Absorption: Erratically absorbed (range 10–60%) after oral administration, with significant first-pass metabolism by the liver.

Microemulsion (Gengraf or Neoral) has better bioavailability than Sandimmune.

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.

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:

Renal impairment (frequent dose changes may be necessary);
Severe hepatic impairment (↓ dose);
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).

Route/Dosage ⬆ ⬇

Sandimmune cannot be used interchangeably with Gengraf or Neoral because they are not bioequivalent.

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.

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

Assessment ⬆ ⬇

Monitor intake and output, 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 that may be fatal; withhold dose and notify health care provider promptly. PML symptoms may begin gradually (hemiparesis, apathy, confusion, cognitive deficiencies, 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 for signs and symptoms of hypersensitivity (wheezing, dyspnea, flushing of face or neck) continuously during at least the 1st 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 before and during administration.
- Perform a baseline physical exam including BP on two occasions before starting therapy. Monitor BP every 2 wk during initial 3 mo and then monthly if stable. If hypertension occurs, ↓ dose.
Psoriasis: Assess skin lesions prior to and during therapy.

Lab Test Considerations:

Monitor BUN, serum creatinine, CBC, magnesium, potassium, uric acid, and lipids at baseline, every 2 wk during initial therapy, and then monthly if stable. Nephrotoxicity may occur.
- May cause hepatotoxicity; monitor for ↑ AST, ALT, alkaline phosphatase, amylase, and bilirubin.
- May ↑ serum potassium, lipid, and uric acid levels and ↓ serum magnesium levels.

Toxicity and Overdose:

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.
- Only health care providers experienced in immunosuppressive therapy and management of organ transplant patients should prescribe cyclosporine.
- Administer initial dose 4–12 hr 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.
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.

IV Administration:

Due to risk of anaphylaxis, IV dose should be reserved for patients who are unable to take the soft gelatin capsules or oral solution.
Intermittent Infusion: Diluent: Dilute each 1 mL (50 mg) of IV concentrate immediately before use with 20–100 mL of D5W or 0.9% NaCl for injection. Solution is stable for 24 hr in D5W. In 0.9% NaCl, it is stable for 6 hr in a polyvinylchloride container and 12 hr in a glass container at room temperature. Concentration: 2.5 mg/mL.
Rate: Infuse slowly over 2–6 hr via infusion pump.
Continuous Infusion: May be administered over 24 hr.
Y-Site Compatibility:
- alemtuzumab
- amikacin
- aminocaproic acid
- aminophylline
- amiodarone
- amphotericin B lipid complex
- anidulafungin
- argatroban
- arsenic trioxide
- ascorbic acid
- atropine
- azathioprine
- azithromycin
- aztreonam
- benztropine
- bivalirudin
- bleomycin
- bumetanide
- buprenorphine
- butorphanol
- calcium chloride
- calcium gluconate
- carboplatin
- carmustine
- caspofungin
- cefazolin
- cefotaxime
- cefotetan
- cefoxitin
- ceftaroline
- ceftazidime
- ceftriaxone
- cefuroxime
- chloramphenicol
- chlorpromazine
- cisplatin
- clindamycin
- cyclophosphamide
- cytarabine
- dacarbazine
- dactinomycin
- daptomycin
- daunorubicin
- defibrotide
- dexamethasone
- dexmedetomidine
- dexrazoxane
- digoxin
- diltiazem
- dimenhydrinate
- diphenhydramine
- dobutamine
- docetaxel
- dopamine
- doxorubicin hydrochloride
- doxorubicin liposomal
- doxycycline
- enalaprilat
- ephedrine
- epinephrine
- epirubicin
- epoetin alfa
- eptifibatide
- ertapenem
- erythromycin
- esmolol
- etoposide
- etoposide phosphate
- famotidine
- fentanyl
- fluconazole
- fludarabine
- fluorouracil
- folic acid
- foscarnet
- fosphenytoin
- furosemide
- ganciclovir
- gemcitabine
- gentamicin
- glycopyrrolate
- granisetron
- heparin
- hetastarch
- hydrocortisone
- hydromorphone
- ifosfamide
- imipenem/cilastatin
- indomethacin
- irinotecan
- isoproterenol
- ketorolac
- labetalol
- leucovorin
- levofloxacin
- lidocaine
- linezolid
- lorazepam
- mannitol
- meperidine
- meropenem
- methadone
- methotrexate
- methylprednisolone
- metoclopramide
- metoprolol
- metronidazole
- micafungin
- midazolam
- milrinone
- minocycline
- mitomycin
- mitoxantrone
- morphine
- moxifloxacin
- multivitamins
- nafcillin
- nicardipine
- nitroglycerin
- nitroprusside
- norepinephrine
- octreotide
- ondansetron
- oxacillin
- oxaliplatin
- oxytocin
- paclitaxel
- palonosetron
- pamidronate
- papaverine
- pemetrexed
- penicillin G
- pentamidine
- phentolamine
- phenylephrine
- phytonadione
- piperacillin/tazobactam
- potassium acetate
- potassium chloride
- procainamide
- prochlorperazine
- promethazine
- propofol
- propranolol
- protamine
- pyridoxine
- sargramostim
- sodium acetate
- sodium bicarbonate
- succinylcholine
- sufentanil
- tacrolimus
- theophylline
- thiamine
- thiotepa
- tigecycline
- tirofiban
- tobramycin
- topotecan
- vancomycin
- vasopressin
- vecuronium
- verapamil
- vinblastine
- vincristine
- vinorelbine
- zoledronic acid
Y-Site Incompatibility:
- amphotericin B liposomal
- ceftolozane/tazobactam
- cyanocobalamin
- dantrolene
- diazepam
- diazoxide
- gemtuzumab ozogamicin
- idarubicin
- isavuconazonium
- nalbuphine
- pentobarbital
- phenobarbital
- phenytoin
- rituximab
- tedizolid
- trastuzumab
- trimethoprim/sulfamethoxazole
- voriconazole

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 provider. Emphasize the importance of follow-up exams and lab tests.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider 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 provider immediately if they occur.
Instruct patient and/or caregiver to notify health care provider 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 provider 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 provider if pregnancy is planned or suspected and to avoid breastfeeding.

section name header

Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇