cyclosporin A (Sandimmune, Neoral [CsA])
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Introduction
Tradename: Sandimmune, Neoral, Reestasis. Alias CsA.
Indications
- transplantation immunosuppression
- 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
- 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.
Solution: (oral) 100 mg/mL (50 mL)
Neoral:
Storage
- oral solution must be used within 2 months once original container is opened[13]
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]
Adverse effects
- common (> 10%)
- not common (1-10%)
- uncommon (< 1%)
- hyperkalemia, anaphylaxis, pancreatitis, hepatotoxicity, tachycardia, warmth, flushing, paresthesias, hypomagnesemia, abdominal discomfort, myositis, hyperuricemia, respiratory 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
- nephrotoxicity, acute & chronic
* 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
- erythromycin, clarithromycin & other macrolides, imidazoles including ketoconazole, itraconazole, calcium channel blockers (mibefradil, verapamil, nicardipine, diltiazem), allopurinol, cimetidine increase cyclosporin-A levels by inhibiting CYP3A4
- phenytoin & carbamazepine decrease levels of cyclosporin-A
- decreased clearance of corticosteroids & increased levels of cyclosporin-A
- statins
- cyclosporin-A reduces clearance of lovastatin, resulting in myositis
- statin dose should be reduced in renal transplant patients taking cyclosporin
- cyclosporin-A increases digoxin levels
- grapefruit juice increases bioavailability of cyclosporin-A
- anabolic steroids & estrogens increase cyclosporin-A levels
- aminoglycosides, amphotericin B, co-trimoxazole, melphalan, furosemide & NSAIDs may potentiate nephrotoxicity
- barbiturates
- rifamycins rifampin & to a lesser extent rifabutin strongly inhibit CYP3A4 & decrease levels of cyclosporine[11]
- 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 calcineurin[6]
- inhibits cell-mediated immune response, primary & secondary responses to T-cell dependent antigens
- inhibits formation of interleukin-2
More general terms
- heterocyclic compound, 1 ring
- immunosuppressive agent
- calcineurin inhibitor
- disease-modifying antirheumatic agent (DMARD)
More specific terms
Additional terms
- cyclosporin A in blood
- cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)
- isradipine (DynaCirc)
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995
- ↑ 3.0 3.1 Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 625, 626
- ↑ 5.0 5.1 5.2 Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Medical Knowledge Self Assessment Program (MKSAP) 11, 17. American College of Physicians, Philadelphia 1998, 2015
- ↑ Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
- ↑ Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=220233&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 9.0 9.1 Prescriber's Letter 10(4):23 2003
- ↑ 10.0 10.1 FDA Medwatch http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171828.htm
- ↑ 11.0 11.1 11.2 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: https://www.ncbi.nlm.nih.gov/pubmed/18277121
- ↑ 12.0 12.1 12.2 12.3 Deprecated Reference
- ↑ 13.0 13.1 Prescriber's Letter 21(6): 2014 Oral Meds to Keep in Original Containers Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=300622&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 14.0 14.1 Menon BS, Teh KH Images in Clinical Medicine: Gum Hypertrophy from Cyclosporine. N Engl J Med 2021; 384:744 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33626603 https://www.nejm.org/doi/full/10.1056/NEJMicm2026082
Database
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2909
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5284373
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3033171
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=171409
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5280754
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=62280