• The benefits of AUC monitoring of CsA (ciclosporin) are offset by three challenges:

1. Multiple blood sampling is impractical for both the patient and the transplant team, especially in the outpatient setting
2. Multiple blood samples per day may compromise the patient's haemodynamic status, especially in paediatric patients
3. Multiple sample analyses will increase monitoring costs

• Single-point concentrations, other than C_ohr , may offer a more sensitive predictor of clinical outcomes with Neoral

• A significant correlation between acute relection incidence and CsA maximum concentrations post-dose (C_max) in liver transplant patients was identified⁵

• When all treatment groups were pooled and differern tiated into quartiles defined by range of C_max , there was a strong relationship between upper C_max quar-tiles and low acute relection incidence irrespective of the formulation used⁶

• In liver transplant patients, the C_2hr , point appears to be most consistent with C_max⁷

• However; as yet there is no consensus that the C_2hr ,sampling point is the best choice for therapeutic drug monitoring of CsA⁷

• The sparse-sampling algorithm is a practical way of predicting full AUCs without the need for extensive blood sampling points^8'9

• Examples of two-point combinations tested are: 0 and 2 hours post-dose; 1.5 and 4 hours; 1 and 4 hours; 1.5 and 6 hours; 2 and 5 hours⁷

• Many sparse-sampling algorithms for estimations of AUC are accurate and practical in the clinical setting

• A specific algorithm that is applicable for all transplant groups or age ranges has not yet been fully accepted⁷

• Although two-point samplings have been used, a three-point sampling algorithm may be beneficial in the first weeks post-tra nsplant⁷

• It has documented a high level of correlation (r²=0.92 1) between the sparsesample estimated AUC and full AUC¹⁰

• Target AUC ranges have been determined for various phases post-transplant for the adult renal transplant recipient in order to titrate Neoral® dosing for optimi-sation of immunosuppression¹¹

• Estimated or abbreviated AUCs have not only demon-strated their practicality and accuracy in day-to-day CsA dosing management, but patients with CsA absorption problems have been more clearly identified than with traditional C_ohr  monitoring practices

• By use of abbreviated AUC monitoring (0 to 4 hours post-dosel,12 clinicians were able to differentiate between poor and good CsA absorbers receiving Sandimmun® prior to conversion

• Of note, however, was the normalisation of absorption of CsA when poor absorbers were converted to Neoral®

SANDIMMUN NEORAL®

Immunosuppressive agent

Presentation
Ciclosporin

SANDIMNIUN NEORAL solution: 100 mg/mL
SANDIMMUN NEORAL capsules: 25, 50 and 100 mg
SANDIMMUN concentrate for i.v. infusion: 50 ni~mL (contains polyoxyethylated castor oil)

Indications

Solid organ transplantation (kidney, liver; heart, combined heart-lung, lung, pancreas); bone marmw transplantation; endogenous uveitis; nephrotic syndrome; severe, active rheumatoid arthritis; severe psoriasis; seve!;e atopic dermatitis

Dosage

Depends upon indication and route of administration. See full  product information. Conversion from SANDIMMUN to SANDIMMUN NEORAL The recommended dose ratio is 1:1. For specific safety measures  in transplantation and autoimmune diseases see full product information.

Contraindleations

Flypersensitivity to ciclosporin. For SANDIMMUN concentrate, in  addition: hypersensitivity to polyoxyethylated castor oil (e.g. Cremophor EL)

Precautions

SANDIMMUN NEORAL should be used only by physicians experienced in immunosuppressive therapy, after they have consulted the full product information. Monitor closely kidney and liver function, blood pressure, and ciclosporin blood levels in transplanted patients. Avoid excessive immunosuppression. Do not use potassium-containing medication  or potassium-sparing diuretics, avoid high dietary potassium intake. Moiiitoring of serum   potassium is recommended. Caution is required in treating patients with hyperuricaemia, when vaccinating (avoid live-attenuated vac-cines), during pregnancy and when using the concentrate fori.v. infusion. Mothers treated with SANDIMMUN NEORAL should not breast ~ See full product information.

Interactions

Aminoglycosides, amphotericin B, ciprofloxacin, meiphalan, trimethoprim; NSAIDs; lovastatine,colchicine; ketoconazole, erythromycin, josamycin, doxycycline,oral contraceptives,propafenone, calcium-channel blockers; barbiturates, carbamazepine, phenytoin, metamizole,rifampicin, nafeillin, sulphadimidine and trimethoprim i.v.; prednisolone, methylprednisolone.See full product information.

Side effects

The following side effects observed with SANDIMMUN are also likely to occur with SANDIMMUN NEORAL: impaired renal function, hepatic dysfunction, hypertension, hyper-trichosis, gingival hypertrophy, tremol; paraesthesia, convulsions, fatigue, anorexia, nausea, vomit-ing, abdominal pain, diarrhoea; hyperkalaemia, hypcruricaemia, hypomagnesaemia, weight increase, oedema, pancreatitis, headache, rash, dysmenorrhoea, amenorrhoea, muscle cramps,muscle weakness, myopathy, mild anaemia, thrombocytopenia associated with micro-angiopathic haemolytic anaemia and renal failure; increased susceptibility  to infections, development of malignancies and lymphoproliferative disorders.

Packs

Country specific FULL PRODUCT INFORM~flON AVAILABLE FROM NOVARTIS PI-IARMAAG

References:

1. Lindholm A, Kahan BD. Influence of cyclosporine pharmacokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Cirn Pliarniacol The,: 1993;54:205.

2. Schroeder TJ, Hariharin S, First MR. Relationship between cyclosporine bioavailability and clinical outcome in renal transplant recipients. Transplant Proc. 1994;26:2787.

3. Kahan BD, Welsh M, Schoenberg L, et al. Variable oral absorption of cyclosporine. A biophar-maceutical risk factor for chronic renal allograft rejection. Transplantation. 1996;62:599.

4. Halloran P, Johnston A, Kahan BD, et al. New strategies for therapeutic drug monitonng of Neoral. Focus on Medicine No 13. Oxford, UK: Blackwell Science Ltd; 1998.

5. Hemming AW, Greig PD, Cattral MS, et al. A microemulsion of  cyclosporine without intravenous cyclosporine in liver transplantation. Transplantation.1996;62:1798.

6. Levy G for the Canadian Liver Transplantation Study Group. Importance of cyclosporine pharmacokinetics to clinical outcomes after liver transplantation. ESOT 8th Congress;September 1997; Budapest, Hungary. Abstract 233.

7. IKeown P Kahan BD, Johnston A, et al. Optimization of  cyclosporine therapy with new therapeutic drug monitoring strategies: report from the International Neoral TDM Advisory Consensus Meeting ~ancouver; Novembei; 1997). Ti~nsplant Proc. 1998;30:In press.

8. Johnston A, Sketris I, Marsden JT, et al. A limited sampling strategy for the measurement of cyclosporine AUC. Translant Proc. 1990; 22:1345.

9. Grevel J, Kahan BD. Abbreviated kinetic profiles in area-under-the-curve monitoring of cyclosporine therapy. Clin Chcmistriy. 1991 ;37:1905.

10. Amante M, Kahan BD. Abbreviated AUC strategy for monitoring cyclosporine microemulsion therapy in the immediate posttransplant period. Transplant Proc. 1996;28:2162.

11. Oellerich M, Armstrong VW, Kahan BD, et al. Lake Louise consensus conference on cyclosporine monitoring in oiaan transplantation: report of the consensus panel. TlierDnigMonit. 1995;17:642.

12. IKeown P Landsberg D, Halloran P et al. A randomized, prospective, multicenter pharmaco-epidemiologic study of cyclosponne microemulsion in stable renal graft recipients.Thinsplantation. 1 996;62:1 744.