Contents

Search

cyclosporin A (Sandimmune, Neoral [CsA])

Tradename: Sandimmune, Neoral, Reestasis. Alias CsA. Indications: - transplantation immunosuppression - graft vs host disease - liver transplantation [12] - renal graft rejection - chronic lymphocytic leukemia [12] - rheumatoid arthritis - psoriasis [6] - inflammatory bowel disease - Sjogren's syndrome [12] - severe asthma - xerophthalmia (Restasis, ophthalmic) [9] - systemic lupus erythematosus [6] - rheumatoid arthritis [6] Dosage: 1) renal transplant 9 mg/kg/day 2) liver transplant 8 mg/kg/day 3) heart transplant 7 mg/kg/day 4) start: [5] a) 5-6 mg/kg/day IV divided BID (infused over 12 hours), or b) 14-18 mg/kg/day PO c) begin 4-12 h prior to organ transplantation 5) maintenance 5-10 mg/kg/day PO [5] 6) liquid form: a) do NOT administer oral liquid form from plastic or styrofoam container b) mixing with milk, orange juice etc improves palatability c) stir well & drink immediately; do NOT allow to stand d) rinse with more diluent to assure total dose is taken e) mix in glass container PO conversion of Sandimmune to Neoral: use same daily dose. Sandimmune: Tabs: 25, 50, 100 mg. Injection: 50 mg/mL (5 mL) Solution: (oral) 100 mg/mL (50 mL) Neoral: - Microemulsion capsule: 25, 100 mg. - Microemulsion oral solution: 100 mg/mL (50 mL). Storage: - oral solution must be used within 2 months once original container is opened [13] Pharmacokinetics: 1) therapeutic trough concentration (whole blood): (HPLC) a) 150-225 ug/L after renal transplant b) 225-325 ug/L after heart & liver transplant c) maintenance 100-175 ug/L (all) 2) absorbtion is formulation-dependent 3) Sandimmune has poor & erratic bioavailability 4) Neoral has 25% greater bioavailability than Sandimmune 5) extensively metabolized by cyt P450 3A4 to at least 25 metabolites excreted through the biliary system 6) elimination 1/2life is 10-15 hours - prolonged in elderly & in patients with liver failure Monitor: - serum creatinine every 6 months [11] Adverse effects: 1) common (> 10%) - hypertension*, nephrotoxicity, gingival hypertrophy (image) [14], hypertrichosis, hirsuitism, tremor, dyslipidemia [6] 2) not common (1-10%) - seizures, headache, leg cramps, nausea/vomiting, acne 3) uncommon (< 1%) - hyperkalemia, anaphylaxis, pancreatitis, hepatotoxicity, tachycardia, warmth, flushing, paresthesias, hypomagnesemia, abdominal discomfort, myositis, hyperuricemia, respiratory distress, increases susceptibility to infection, temperature sensitivity, sinusitis 4) other [3] a) nephrotoxicity, acute & chronic - RTA type IV - non oliguric - generally reversible - renal interstitial fibrosis (chronic) e) thrombotic microangiopathy (rare) b) BK virus-associated nephropathy in renal transplant patients [10] c) hypertension: isradipine (Dynacirc is drug of choice) d) hyperkalemia e) lymphoproliferative disorders f) hepatotoxicity - cholestasis g) paresthesias * calcium channel blockers are initial drugs of choice for cyclosporine-induced hypertension; addition of a diuretic, ACE inhibitor or beta-blocker is often required Drug interactions: 1) erythromycin, clarithromycin & other macrolides, imidazoles including ketoconazole, itraconazole, calcium channel blockers (mibefradil, verapamil, nicardipine, diltiazem), allopurinol, cimetidine increase cyclosporin-A levels by inhibiting CYP3A4 2) phenytoin & carbamazepine decrease levels of cyclosporin-A 3) decreased clearance of corticosteroids & increased levels of cyclosporin-A 4) statins - cyclosporin-A reduces clearance of lovastatin, resulting in myositis - statin dose should be reduced in renal transplant patients taking cyclosporin 5) cyclosporin-A increases digoxin levels 6) grapefruit juice increases bioavailability of cyclosporin-A 7) anabolic steroids & estrogens increase cyclosporin-A levels 8) aminoglycosides, amphotericin B, co-trimoxazole, melphalan, furosemide & NSAIDs may potentiate nephrotoxicity 9) barbiturates 10) rifamycins rifampin & to a lesser extent rifabutin strongly inhibit CYP3A4 & decrease levels of cyclosporine [11] 11) sulfonamides: decreased levels of cyclosporine & increased nephrotoxicity 12) aminoglycosides: increased nephrotoxicity 13) amphotericin B: increased nephrotoxicity 14) cyclosporin increases levels of sirolimus 14) any drug that inhibits cyt P450 3A4 may increase levels of cyclosporine 15) any drug that induces cyt P450 3A4 may diminish levels of cyclosporine (including St John's wort) 16) cyclosporine inhibits cyt P450 3A4, thus inhibits its own metabolism & metabolism of other cyt P450 3A4 substrates Laboratory: 1) specimen: whole blood (EDTA) 2) methods: HPLC, FPIA, EIA 3) interferences: a) HPLC is specific for parent compound b) immunoassays are less specific c) monoclonal FPIA more specific than polyclonal assay Mechanism of action: 1) cyclosporin-A is a cyclic undecapeptide produced by Tolypocladium inflatum 2) inhibits calcineurin [6] 3) inhibits cell-mediated immune response, primary & secondary responses to T-cell dependent antigens 4) inhibits formation of interleukin-2

Interactions

molecular events drug interactions drug adverse effects (more general classes) monitor with immunosuppressive agents

Related

cyclosporin A in blood cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) isradipine (DynaCirc)

Specific

ciclosporin ophthalmic; cyclosporine A ophthalmic (Restasis, Cequa)

General

calcineurin inhibitor disease-modifying antirheumatic agent (DMARD) heterocyclic compound, 1 ring immunosuppressive agent

Properties

MISC-INFO: elimination route LIVER 1/2life 8-24 HOURS therapeutic-range 100-400 NG/ML toxic-range >400 NG/ML protein-binding 96% elimination by hemodialysis - peritoneal dialysis - pregnancy-category C safety in lactation -

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 625, 626
  5. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  6. Medical Knowledge Self Assessment Program (MKSAP) 11, 17. American College of Physicians, Philadelphia 1998, 2015
  7. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  8. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  9. Prescriber's Letter 10(4):23 2003
  10. FDA Medwatch http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171828.htm
  11. Baciewicz AM, Chrisman CR, Finch CK, Self TH Update on rifampin and rifabutin drug interactions. Am J Med Sci. 2008 Feb;335(2):126-36. PMID: 18277121
  12. Deprecated Reference
  13. Prescriber's Letter 21(6): 2014 Oral Meds to Keep in Original Containers Detail-Document#: 300622 (subscription needed) http://www.prescribersletter.com
  14. Menon BS, Teh KH Images in Clinical Medicine: Gum Hypertrophy from Cyclosporine. N Engl J Med 2021; 384:744 PMID: 33626603 https://www.nejm.org/doi/full/10.1056/NEJMicm2026082

Component-of

molecular complex