Sandimmun Neoral Dosage/Direction for Use

Dosage: The daily doses of Sandimmun Neoral should always be given in 2 divided doses.
Transplantation: Solid Organ Transplantation: Treatment with Sandimmun Neoral should be initiated within 12 hrs before surgery at a dose of 10-15 mg/kg given in 2 divided doses. This dose should be maintained as the daily dose for 1-2 weeks postoperatively before being gradually reduced in accordance with blood levels until a maintenance dose of about 2-6 mg/kg given in 2 divided doses is reached.
When Sandimmun Neoral is given with other immunosuppressants (eg, with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (eg, 3-6 mg/kg given in 2 divided doses for the initial treatment) may be used.
If the Sandimmun concentrate for IV infusion is used, the recommended dose is approximately ¹/₃ of the appropriate Sandimmun Neoral dose. It is also recommended that patients be put on oral therapy as soon as possible.
Bone Marrow Transplantation: The initial dose should be given on the day before transplantation. In most cases, IV infusion is preferred for this purpose; the recommended dose is 3-5 mg/kg/day. Infusion is continued at this dose level during the immediate post-transplant period of up to 2 weeks before a change is made to oral maintenance therapy with Sandimmun Neoral at daily doses of about 12.5 mg/kg given in 2 divided doses. Maintenance treatment should be continued for at least 3 months (and preferably for 6 months) before the dose is gradually decreased to 0 by 1 year after transplantation. If Sandimmun Neoral is used to initiate therapy, the recommended daily dose is 12.5-25 mg/kg given in 2 divided doses, starting on the day before transplantation.
Higher doses of Sandimmun Neoral, or the use of IV therapy, may be necessary in the presence of GI disturbances which might decrease drug absorption.
In some patients, GVHD occurs after discontinuation of Sandimmun treatment, but usually responds favorably to reintroduction of therapy. Low doses of Sandimmun Neoral should be used to treat mild, chronic GVHD.
Nontransplantation: Endogenous Uveitis: For inducing remission, initially 5 mg/kg/day orally given in 2 divided doses are recommended until remission of active uveal inflammation and improvement in visual acuity is achieved. In refractory cases, the dose can be increased to 7 mg/kg/day for a limited period.
To achieve initial remission or to counteract inflammatory ocular attacks, systemic corticosteroid treatment with daily doses of prednisone 0.5-0.6 mg/kg or an equivalent may be added if Sandimmun Neoral alone does not control the situation sufficiently.
For maintenance treatment, the dose should be slowly reduced to the lowest effective level which, during the remission phases, should not exceed 5 mg/kg/day.
Nephrotic Syndrome: For inducing remission, the recommended daily dose, given in 2 divided oral doses, is 5 mg/kg for adults and 6 mg/kg for children, if, except for proteinuria, renal function is normal. In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.
The combination of Sandimmun Neoral with low doses of oral corticosteroids is recommended if the effect of Sandimmun Neoral alone is not satisfactory, especially in steroid-resistant patients.
If no improvement has been observed after 3 months' treatment, Sandimmun Neoral therapy should be discontinued.
The doses need to be adjusted individually according to efficacy (proteinuria) and safety (primarily serum creatinine), but should not exceed 5 mg/kg/day in adults and 6 mg/kg/day in children.
For maintenance treatment, the dose should be slowly reduced to the lowest effective level.
Rheumatoid Arthritis: For the first 6 weeks of treatment, the recommended dose is 2.5 mg/kg/day orally given in 2 divided doses. If the effect is insufficient, the daily dose may then be increased gradually as tolerability permits, but should not exceed 4 mg/kg. To achieve full effectiveness, up to 12 weeks of Sandimmun Neoral therapy may be required.
For maintenance treatment, the dose has to be titrated individually according to tolerability. If a patient is on an effective maximum tolerable dose with no further improvements expected, and has been stable for at least 3 months, the dose of Sandimmun Neoral should be decreased at 0.5 mg/kg/day increments monthly or bimonthly to the lowest effective dose.
If there is essentially no clinical response by 6 months, the maximal tolerable dose has been administered for 3 months, Sandimmun Neoral should be discontinued. (After 3 months of Sandimmun Neoral therapy without response, blood level monitoring of ciclosporin may be of value to evaluate compliance and/or drug absorption.)
Dose adjustment based on creatinine values: If the serum creatinine remains increased by >30% above creatinine concentration recorded before starting ciclosporin at more than one measurement, the dosage of Sandimmun Neoral should be reduced. If the serum creatinine increases by >50%, a dosage reduction by 50% is mandatory. These recommendations apply even if the patient's values still lie within the laboratory normal range. If the dose reduction is not successful in reducing levels within 1 month, Sandimmun Neoral treatment should be discontinued.
Sandimmun Neoral can be given in combination with low-dose corticosteroids and/or nonsteroidal anti-inflammatory drugs. Sandimmun Neoral can also be combined with low-dose weekly methotrexate in patients who have insufficient response to methotrexate alone, by using initially Sandimmun Neoral 2.5 mg/kg in 2 divided doses/day, with the option to increase the dose as tolerability permits.
Psoriasis: Due to the variability of this condition, treatment must be individualized. For inducing remission, the recommended initial dose is 2.5 mg/kg/day orally given in 2 divided doses. If there is no improvement after 1 month, the daily dose may be gradually increased, but should not exceed 5 mg/kg. Treatment should be discontinued in patients in whom sufficient response of psoriatic lesions cannot be achieved within 6 weeks on 5 mg/kg/day, or in whom the effective dose is not compatible with the established safety guidelines.
Initial doses of 5 mg/kg/day are justified in patients whose condition requires rapid improvement. Once satisfactory response is achieved, Sandimmun Neoral may be discontinued and subsequent relapse managed with reintroduction of Sandimmun Neoral at the previous effective dose. In some patients, continuous maintenance therapy may be necessary.
For maintenance treatment, doses have to be titrated individually to the lowest effective level and should not exceed 5 mg/kg/day.
Conversion from Sandimmun to Sandimmun Neoral: The available data indicate that after a 1:1 conversion from Sandimmun to Sandimmun Neoral, the trough concentrations of ciclosporin in whole blood are comparable. In many patients, however, higher peak concentrations (C_max) and an increased exposure to the drug (AUC) may occur. In a small percentage of patients, these changes are more marked and may be of clinical significance. Their magnitude depends largely on the individual variance in the absorption of ciclosporin from the originally used Sandimmun, which is known to be highly variable in its bioavailability. Patients with variable trough levels or very high doses of Sandimmun may be poor or inconsistent absorbers of ciclosporin (eg, patients with cystic fibrosis, liver transplant patients with cholestasis or poor bile secretion, children or some kidney transplant recipients) who may, on conversion to Sandimmun Neoral, become good absorbers. Therefore, in this population, the increase in bioavailability of ciclosporin following a 1:1 conversion from Sandimmun to Sandimmun Neoral might be greater than usually observed. The dose of Sandimmun Neoral should therefore be down titrated individually according to their target trough level range.
It needs to be emphasized that the absorption of ciclosporin from Sandimmun Neoral is less variable and the correlation between ciclosporin trough concentrations and exposure (in terms of AUC) is much stronger than with Sandimmun. This makes ciclosporin blood trough concentrations a more robust and reliable parameter for therapeutic drug monitoring.
Since the conversion from Sandimmun to Sandimmun Neoral may result in an increased drug exposure, the following rules must be observed:
Transplant Patients: Sandimmun Neoral should be started with the same daily dose as was previously used with Sandimmun. Ciclosporin trough concentrations in whole blood should be monitored initially within 4-7 days after the conversion to Sandimmun Neoral. In addition, clinical safety parameters eg, serum creatinine and blood pressure are to be monitored during the first 2 months after the conversion. If the ciclosporin trough blood levels are beyond the therapeutic range and/or worsening of the clinical safety parameters occur, the dosage must be adjusted accordingly.
Patients Treated for Nontransplant Indications: Sandimmun Neoral should be started with the same daily dose as was used with Sandimmun. Two, 4 and 8 weeks after the conversion, serum creatinine levels and blood pressure should be monitored. If serum creatinine levels or blood pressure significantly exceed the preconversion levels or if serum creatinine levels increase to >30% above creatinine levels prior to Sandimmun therapy at more than one measurement, the dose should be reduced (see also Precautions). In case of unexpected toxicity or inefficacy of ciclosporin, blood trough levels should also be monitored.
Administration: The dose ranges given for oral administration and IV administration are intended to serve as guidelines only. The recommended dose of Sandimmun concentrate for IV infusion is approximately ¹/₃ of the appropriate oral dose. Routine monitoring of ciclosporin blood levels is required; this can be carried out by means of a RIA method based on monoclonal antibodies. The results obtained will serve as a guide for determining the actual dosage required to achieve the desired target concentrations in individual patients.
Oral Administration: The daily doses of Sandimmun Neoral should always be given in 2 divided doses.
Capsules should be swallowed whole.
The oral solution should be diluted with, preferably, orange or apple juice; however, other drinks eg, softdrinks can be used according to individual taste. Immediately before taking the oral solution, it should be stirred well. Owing to its possible interference with the P-450-dependent enzyme system, grapefruit juice should be avoided for dilution. The syringe should not come in contact with the diluent. If the syringe is to be cleaned, do not rinse it but wipe the outside with a dry tissue (see Cautions for Usage: Instructions for Use/Handling).