Cyclosporin A

From Anvita Health Wiki

Contents 1 Introduction 2 Indications 3 Dosage 4 Pharmacokinetics 5 Monitor 6 Adverse-effects 7 Drug-interactions 8 Laboratory 9 Mechanism-of-action 10 More General Terms 11 Additional Terms 12 Internet Database 13 References

Introduction

• Tradename: Sandimmune, Neoral, Reestasis. Alias CsA.

Indications

• transplantation immunosuppression
• rheumatoid arthritis
• inflammatory bowel disease
• severe asthma
• xerophthalmia (Restasis, ophthalmic) [9]

Dosage

• renal transplant 9 mg/kg/day
• liver transplant 8 mg/kg/day
• heart transplant 7 mg/kg/day
• start: [5]

• 5-6 mg/kg/day IV divided BID ( infused over 12 hours), or
• 14-18 mg/kg/day PO
• begin 4-12 h prior to organ transplantation

• maintenance 5-10 mg/kg/day PO [5]
• liquid form:

• do NOT administer oral liquid form from plastic or styrofoam container
• mixing with milk, orange juice etc improves palatability
• stir well & drink immediately; do NOT allow to stand
• rinse with more diluent to assure total dose is taken
• 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).
• Restasis ( ophthalmic agent): apply BID ($175/month 2003) [9]

Pharmacokinetics

• therapeutic trough concentration ( whole blood): ( HPLC)

• 150-225 ug/L after renal transplant
• 225-325 ug/L after heart & liver transplant
• maintenance 100-175 ug/L (all)

• absorbtion is formulation-dependent
• Sandimmune has poor & erratic bioavailability
• Neoral has 25% greater bioavailability than Sandimmune
• extensively metabolized by cyt P450 3A4 to at least 25 metabolites excreted through the biliary system
• elimination 1/2life is 10-15 hours

• prolonged in elderly & in patients with liver failure
  

• elimination via liver
• 1/2life = 8-24 hours
• protein binding = 96 %
• elimination by hemodialysis = -
• elimination by peritoneal dialysis = -

Monitor

• serum creatinine every 6 months [11]
  
• monitor with immunosuppressive agents

Adverse-effects

• common (> 10%)

• hypertension*, nephrotoxicity, gingival hypertrophy, hypertrichosis, hirsuitism, tremor

• not common (1-10%)

• seizures, headache, leg cramps, nausea/vomiting, acne

• uncommon (< 1%)

• hyperkalemia, anaphylaxis, pancreatitis, hepatotoxicity, tachycardia, warmth, flushing, paresthesias, hypomagnesemia, abdominal discomfort, myositis, hyperuricemia, resipiratory distress, increases susceptibility to infection, temperature sensitivity, sinusitis

• other [3]

• nephrotoxicity, acute & chronic

• RTA type IV
• non oliguric
• generally reversible
• renal interstitial fibrosis (chronic)
• thrombotic microangiopathy (rare)

• BK virus-associated nephropathy in renal transplant patients [10]
• hypertension: isradipine ( Dynacirc is drug of choice)
• hyperkalemia
• lymphoproliferative disorders
• hepatotoxicity - cholestasis
• 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 adverse effects of immunosuppressive agents

Drug-interactions

• erythromycin & other macrolides, imidazoles including ketoconazole, itraconazole, calcium channel blockers (mibefradil, verapamil, nicardipine, diltiazem), allopurinol, cimetidine increase cyclosporin-A levels
• phenytoin & carbamazepine decrease levels of cyclosporin-A
• decreased clearance of corticosteroids & increased levels of cyclosporin-A
• cyclosporine-A reduces clearance of lovastatin, resulting in myositis
• cyclosporin-A increases digoxin levels
• grapefruit juice decreases bioavailability of cyclosporin-A
• anabolic steroids & estrogens increase cyclosporin-A levels
• aminoglycosides, amphotericin B, co-trimoxazole, melphalan, furosemide & NSAIDs may potentiate nephrotoxicity
• barbiturates
• rifampin: decreased levels of cyclosporine
• sulfonamides: decreased levels of cyclosporine & increased nephrotoxicity
• aminoglycosides: increased nephrotoxicity
• amphotericin B: increased nephrotoxicity
• cyclosporin increases levels of sirolimus
• any drug that inhibits cyt P450 3A4 may increase levels of cyclosporine
• any drug that induces cyt P450 3A4 may diminish levels of cyclosporine (including St John's wort)
• cyclosporine inhibits cyt P450 3A4, thus inhibits its own metabolism & metabolism of other cyt P450 3A4 substrates

Laboratory

• specimen: whole blood ( EDTA)
• methods: HPLC, FPIA, EIA
• interferences:

• HPLC is specific for parent compound
• immunoassays are less specific
• monoclonal FPIA more specific than polyclonal assay

Mechanism-of-action

• cyclosporin-A is a cyclic undecapeptide produced by Tolypocladium inflatum
• inhibits cell-mediated immune response, primary & secondary responses to T-cell dependent antigens
• inhibits formation of interleukin-2

More General Terms

• cyclosporin
• immunosuppressive agent
• calcineurin inhibitor

Additional Terms

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

Internet Database

PubChem: 2909
PubChem: 5284373
PubChem: 3033171
PubChem: 171409
PubChem: 5280754
PubChem: 62280

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, American College of Physicians, Philadelphia 1998
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#: [1] (subscription needed) [2]
9. Prescriber's Letter 10(4):23 2003
10. FDA Medwatch [3]
11. Anvita Health guideline :id 1648

cyclosporin A (Sandimmune, Neoral, Restasis, cyclosporin [CsA])