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Dosage: The daily doses of Sandimmun Neoral should always be given in 2 divided doses.
Because of considerable inter- and intraindividual variations in absorption and elimination and the possibility of pharmacokinetic drug interactions (see Interactions), doses should be titrated individually according to clinical response and tolerability.
In transplant patients, routine monitoring of ciclosporin trough blood levels is required to avoid adverse effects due to high levels and to prevent organ rejection due to low levels (see Precautions).
In patients treated for non-transplant indications, monitoring of ciclosporin blood levels is of limited value except in the case of unexpected treatment failure or relapse, where it may be appropriate to establish the possibility of very low levels caused by non-compliance, impaired gastrointestinal absorption, or pharmacokinetic interactions (see Precautions).
General target population: Transplantation: Solid organ transplantation: Treatment with Sandimmun Neoral or Sandimmun should be initiated within 12 hours before surgery at a dose of 10 to 15 mg/kg given in 2 divided doses. This dose should be maintained as the daily dose for 1 to 2 weeks post-operatively before being gradually reduced in accordance with blood levels until a maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached.
When Sandimmun Neoral or Sandimmun is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (e.g. 3 to 6 mg/kg given in 2 divided doses for the initial treatment) may be used.
If the Sandimmun concentrate for solution for infusion is used, the recommended dose is approximately one-third of the appropriate Sandimmun Neoral dose, and it is 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, Sandimmun intravenous (i.v.) infusion is preferred for this purpose; the recommended i.v. dose is 3 to 5 mg/kg per 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 a daily dose 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 zero by 1 year after transplantation.
If Sandimmun Neoral is used to initiate therapy, the recommended daily dose is 12.5 to 15 mg/kg given in 2 divided doses, starting on the day before transplantation.
Higher doses of Sandimmun Neoral, or the use of i.v. therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease drug absorption.
In some patients, GVHD occurs after discontinuation of ciclosporin treatment, but usually responds favorably to re-introduction of therapy. In such cases, an initial oral loading dose of 10 to 12.5 mg/kg should be given, followed by daily oral administration of the maintenance dose previously found to be satisfactory. Low doses of ciclosporin should be used to treat mild, chronic GVHD.
Non-transplantation: When using Sandimmun Neoral in any of the established non-transplant indications, the following general rules should be adhered to: Before initiation of treatment a reliable baseline level of serum creatinine should be established by at least two measurements, and renal function must be assessed regularly throughout therapy to allow dosage adjustment (see Precautions).
The only accepted route of administration is by mouth (the concentrate for intravenous infusion must not be used), and the daily dose should be given in two divided doses.
Except in patients with sight-threatening endogenous uveitis and in children with nephrotic syndrome, the total daily dose must never exceed 5 mg/kg.
For maintenance treatment the lowest effective and well tolerated dosage should be determined individually.
In patients in whom within a given time (for specific information see as follows) no adequate response is achieved or the effective dose is not compatible with the established safety guidelines, treatment with Sandimmun Neoral should be discontinued.
Endogenous uveitis: For inducing remission, initially 5 mg/kg per day orally given in 2 divided doses are recommended until remission of active uveal inflammation and improvement in visual acuity are achieved. In refractory cases, the dose can be increased to 7 mg/kg per day for a limited period.
To achieve initial remission, or to counteract inflammatory ocular attacks, systemic corticosteroid treatment with daily doses of 0.2 to 0.6 mg/kg prednisone 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 per day.
Nephrotic syndrome: For inducing remission, the recommended daily dose is given in 2 divided oral doses.
If the renal function (except for proteinuria) is normal, the recommended daily dose is the following: 5 mg/kg for adults and 6 mg/kg for children.
In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg per 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 per day in adults and 6 mg/kg per 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 3 mg/kg per 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 5 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 to the lowest effective level according to tolerability.
Sandimmun Neoral can be given in combination with low-dose corticosteroids and/or non-steroidal anti-inflammatory drugs (see Precautions). Sandimmun Neoral can also be combined with low-dose weekly methotrexate in patients who have insufficient response to methotrexate alone, by using initially 2.5 mg/kg Sandimmun Neoral in 2 divided doses per 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 per 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 per day, or in whom the effective dose is not compatible with the established safety guidelines (see Precautions).
Initial doses of 5 mg/kg per 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 re-introduction 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 per day.
Special populations: Renal impairment: All indications: Ciclosporin undergoes minimal renal elimination and its pharmacokinetics is not affected by renal impairment (see Pharmacology under Actions). However, due to its nephrotoxic potential (see Adverse Reactions), a careful monitoring of the renal function is recommended (see All indications under Precautions).
Non-transplant indications: Patients with impaired renal function, except nephrotic syndrome patients, should not receive ciclosporin (see Additional precautions in non-transplant indications under Precautions). In nephrotic syndrome patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg per day.
Hepatic impairment: Ciclosporin is extensively metabolized by the liver. The terminal half-life varied between 6.3 hours in healthy volunteers to 20.4 hours in severe liver disease patients (see Pharmacology under Actions). Dose reduction may be necessary in patients with severe liver impairment to maintain blood levels within the recommended target range (see Precautions and also Pharmacology under Actions).
Pediatric patients (below 18 years): Experience with ciclosporin in children is still limited. Clinical studies have included children from 1 year of age using standard ciclosporin dosage with no particular problems. In several studies, pediatric patients required and tolerated higher doses of ciclosporin per kg body weight than those used in adults. Sandimmun Neoral use in children for non-transplant indications other than nephrotic syndrome cannot be recommended (see Additional precautions in non-transplant indications under Precautions).
Geriatric patients (65 years old and above): Experience with ciclosporin in the elderly is limited, but no particular problems have been reported following the use of the drug at the recommended dose.
In rheumatoid arthritis clinical trials with oral ciclosporin, 17.5% of patients were aged 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥50% above the baseline after 3 to 4 months of therapy.
Clinical studies of ciclosporin in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Conversion from oral 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 (Cmax) 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 (e.g. 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: In 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 to 7 days after the conversion to Sandimmun Neoral. In addition, clinical safety parameters such as 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.
In patients treated for non-transplant 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 pre-conversion levels or if serum creatinine levels increase to more than 30% above creatinine levels prior to Sandimmun therapy at more than one measurement, the dose should be reduced (see also 'Additional precautions' under Precautions). In case of unexpected toxicity or inefficacy of ciclosporin, blood trough levels should also be monitored.
Conversion between oral ciclosporin formulations: Switching from one oral ciclosporin formulation to another should be made with caution and under physician supervision. The introduction of the new formulation must be made with monitoring of blood levels of ciclosporin to ensure that pre-conversion levels are attained.
Method of administration: Oral administration: Sandimmun Neoral capsules should be swallowed whole.
Sandimmun Neoral oral solution should be diluted with, preferably, orange or apple juice; however, other drinks such as soft drinks 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 cytochrome P450-dependent enzyme system, grapefruit juice should be avoided for dilution (see Interactions). 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 Instructions for Use and Handling under Cautions for Usage).
Intravenous administration: The types of container suitable for the infusion solution are mentioned in Instructions for Use and Handling under Cautions for Usage.
Because of the risk of anaphylaxis (see Precautions), the use of the Sandimmun concentrate for solution for infusion should be reserved for organ transplant patients who are unable to take the drug orally (e.g shortly after surgery) or in whom the absorption of the oral forms might be impaired during episodes of gastrointestinal disorders. In such cases, it is recommended to change to oral administration as soon as feasible. Another well-established use of the concentrate for solution for infusion consists in the initial treatment of patients with bone marrow transplantation.
The concentrate for solution for infusion should be diluted 1:20 to 1:100 with normal saline or 5% glucose, and given as a slow i.v. infusion over approximately 2 to 6 hours.
Once an ampoule is opened, the content should be used immediately. Diluted infusion solutions must be discarded after 24 hours.
