Sandimmun/Sandimmun Neoral Dosage/Direction for Use

Sandimmun: The dosage recommendations given as follows are intended as guidelines only. The recommended dose is 3 to 5 mg/kg, which corresponds to approx. one-third of the appropriate oral dose. Routine monitoring of blood ciclosporin levels is essential and may be done by RIA using monoclonal antibodies. The results obtained serve as a guide to determining the dosage required by the individual patient so that the target concentration can be achieved.
Organ transplantation: In cases where Sandimmun is given in conjunction with other immunosuppressive agents (e.g. corticosteroids or as part of a 3- or 4-drug regimen), lower doses may be given (e.g. 1 to 2 mg/kg/day i.v., followed initially by 3 to 6 mg/kg/day orally). Patients should be switched to oral therapy with Sandimmun Neoral as soon as possible.
Bone marrow transplantation: The starting dose should be given on the day before transplantation. In most cases, an i.v. infusion at the dosage of 3 to 5 mg/kg/day is recommended. This should be repeated daily in the immediate post-operative period for a maximum of two weeks before switching the patient to oral maintenance therapy with approx. 12.5 mg/kg/day.
Continuation of i.v. infusion may be required in patients with gastrointestinal disorders impairing absorption.
GVHD may occur in some patients following withdrawal of Sandimmun but usually responds to reinstitution.
Paediatric use: Limited data on ciclosporin is available in children. No data are available on the use of Sandimmun in the treatment of infants. No particular problems were reported in children over one year of age given the standard dosage of Sandimmun. Several paediatric studies have shown that children both need and tolerate higher doses of ciclosporin per kg body weight than adults. Patients with severe hepatic dysfunction require close monitoring of serum creatinine and, where possible, of ciclosporin levels, with dosage adjustment, if necessary.
Use in elderly patients: In clinical studies of the use of oral ciclosporin in rheumatoid arthritis, 17.5% of the patients were 65 years of age or older. After 3 to 4 months of treatment, these patients were more likely to develop systolic hypertension and to show increases in serum creatinine exceeding the baseline value by 50% or more.
Clinical studies with Sandimmun in graft recipients and psoriasis patients did not include a sufficient number of subjects 65 years of age or older to allow any conclusions as to whether their response differs from that of younger patients. In general, dose selection should be cautious in elderly patients, with consideration being given to the increased frequency of reduced hepatic, renal or cardiac function, concomitant disease or other drug therapy. Treatment should normally be started with a dose at the lower end of the dosage range.
Containers: See Cautions for Usage and Storage.
Sandimmun Neoral: Sandimmun Neoral, which is administered orally, is recommended for the majority of clinical conditions requiring ciclosporin therapy. Exceptions are listed in the prescribing information for Sandimmun concentrate for i.v. infusion. The following dosage information relates to oral administration.
The total daily dose of Sandimmun Neoral should always be taken in two divided doses (mornings and evenings).
If the prescribed dose cannot be precisely attained using capsules, particularly in patients with low body weight, the use of the oral solution is recommended.
Transplantation: The dosage recommendations given as follows are intended as guidelines only. Routine monitoring of blood ciclosporin levels is essential and may be done by RIA using monoclonal antibodies. The results obtained serve as a guide to determining the dose required to achieve the target concentration.
1. Organ transplantation: The starting dose is 10 to 15 mg/kg, given in two divided doses within 12 hours before transplantation. This dosage should be maintained for 1 to 2 weeks post-surgery. The dose may then be gradually reduced to a maintenance dose of 2 to 6 mg/kg/day (depending on blood ciclosporin levels), to be taken in two divided doses.
In renal transplant patients it has been found that doses below 3 to 4 mg/kg/day, which result in trough blood levels below 50 to 100 ng/ml, are associated with an increased risk of rejection.
In cases where Sandimmun Neoral is given in conjunction with other immunosuppressive agents (e.g. corticosteroids or as part of a 3- or 4-drug regimen), lower doses (e.g. 3 to 6 mg/kg/day orally as a starting dose) may be given.
Renal transplantation in combination with everolimus: If ciclosporin is given concomitantly with everolimus for a prolonged period, an attempt should be made to reduce exposure to ciclosporin. Reduction of ciclosporin exposure should begin one month post-transplantation. The following target ranges for ciclosporin exposure are recommended: [Ciclosporin blood levels measured 2 hours after administration (C₂)]: weeks 0 to 4: 1,000 to 1,400 ng/ml; weeks 5 to 8: 700 to 900 ng/ml; weeks 9 to 12: 550 to 650 ng/ml; weeks 13 to 52: 350 to 450 ng/ml.
Prior to dose reduction of ciclosporin, it must be ensured that steady-state everolimus trough levels (C₀) are ≥ 3 ng/ml.
If reduction in ciclosporin exposure leads to signs of graft rejection, continuation of everolimus treatment must be reconsidered. In order to minimise the risk of failed efficacy, it is important to ensure that neither everolimus nor ciclosporin blood levels fall below the therapeutic range after transplantation.
Data on everolimus dosages are limited in long-term therapy (i.e. more than 12 months) in patients with ciclosporin trough levels (C₀) below 50 ng/ml, or C₂ levels below 350 ng/ml.
Cardiac transplantation in combination with everolimus: In heart transplant patients with renal dysfunction, the dose of ciclosporin should be reduced as much as possible during the maintenance phase (i.e. after 3 months) in order to improve renal function. If impairment of renal function progresses, or the calculated creatinine clearance falls to < 60 ml/min, the dosage should be adjusted. In heart transplant patients, the ciclosporin dose may be based on ciclosporin trough blood levels (also see prescribing information for everolimus).
In heart transplantation, data are limited on the combination with everolimus in patients with trough levels (C₀) of ciclosporin below 175 ng/ml in the first 3 months, below 135 ng/ml at 6 months and below 100 ng/ml after 6 months.
Prior to dose reduction of ciclosporin, it must be ensured that steady-state everolimus trough levels (C₀) are ≥ 3 ng/ml.
2. Bone-marrow transplantation: The starting dose should be given on the day before transplantation. It is recommended that patients started on oral therapy be given 12.5 to 15 mg/kg/day initially. The maintenance dose of approx. 12.5 mg/kg/day, administered in two divided doses, should be given for at least 3 to 6 months (preferably 6 months). The dose may then be gradually tapered off completely within a period of 1 year after transplantation.
Higher oral doses or administration by i.v. infusion may be required in patients with gastrointestinal disorders impairing absorption (see separate prescribing information for Sandimmun concentrate for i.v. infusion).
GVHD may occur in some patients following withdrawal of ciclosporin treatment, but it usually responds to reinstitution of therapy. In such cases, a starting dose of 10 to 12.5 mg/kg should be given, followed by the daily oral maintenance dose found to be satisfactory prior to withdrawal. Low doses of ciclosporin should be given to treat chronic mild GVHD.
Non-transplantation indications: Preliminary note: Monitoring of renal function and blood pressure.
As Sandimmun Neoral may impair renal function, a reliable baseline serum creatinine level - derived from at least two determinations - must be established prior to the start of therapy. Both determinations must indicate normal renal function. For this purpose, creatinine clearance can be calculated from the measured serum creatinine levels by means of a suitable equation (e.g. Dettli's). Serum creatinine should be monitored at weekly intervals during the first month of treatment and at monthly intervals thereafter or more frequently if the Sandimmun Neoral dosage is increased. If creatinine exceeds the baseline value by 20% to 30%, transient non-renal increases must be ruled out by means of repeat determinations.
If hypertension occurring during Sandimmun Neoral therapy cannot be normalised by means of appropriate antihypertensive therapy, the Sandimmun Neoral dose should be reduced or, if necessary, withdrawn (see Blood pressure monitoring under Precautions).
1. Endogenous uveitis: 5 mg/kg/day in two divided doses is recommended as the starting dose until uveitis subsides and visual acuity improves. In resistant cases, the dose may be temporarily increased to 7 mg/kg/day.
To achieve particularly rapid remission and thus combat acute inflammatory episodes in the eye, and/or if Sandimmun Neoral alone proves insufficiently effective, a systemic corticosteroid - either prednisone (0.2 to 0.6 mg/kg/day) or an equivalent substance - may be added.
Sandimmun Neoral should be withdrawn if no improvement is evident after three months of treatment.
For maintenance therapy, the dosage should gradually be reduced to the lowest effective dose, which should not exceed 5 mg/kg/day during periods of remission.
The daily dose must be reduced by 25% to 50% if serum creatinine exceeds the baseline value by more than 30% in more than one measurement, even if it is still within the normal range (see Monitoring of renal function). If the dose reduction has no effect within one month, Sandimmun Neoral must be withdrawn.
2. Dermatological indications: Special instructions: Prior to treatment, the patient must be fully informed about the benefits and possible risks of Sandimmun Neoral therapy and about the frequent problem of recurrence following withdrawal.
Patients with renal impairment, uncontrolled hypertension or infection, or a malignancy of any type - apart from skin malignancies (see Psoriasis: skin tumours as follows and
Contraindications) - should not be given Sandimmun Neoral. Caution is indicated in patients with hyperkalaemia or hyperuricaemia (see Biochemical changes under Precautions).
a) Psoriasis: To induce remission, the recommended starting dose is 2.5 mg/kg/day in two divided doses, increasing gradually - if there is no improvement after one month - by 0.5 to 1 mg/kg per month up to a maximum of 5 mg/kg/day.
A starting dose of 5 mg/kg/day, given in two divided doses, is justified in patients whose condition requires particularly rapid improvement.
For maintenance treatment, the dose should be individually adjusted to the lowest effective level and should not exceed 5 mg/kg/day.
Treatment should be withdrawn in patients in whom no sufficient improvement in psoriatic lesions is achieved within one month of treatment at 5 mg/kg/day.
Sandimmun Neoral should be gradually withdrawn if remission is maintained for a period of 6 months. However, the risk of recurrence following withdrawal is very high.
Skin tumours: Development of malignancies (particularly of the skin) has been reported in psoriasis patients treated with Sandimmun Neoral as well as in those receiving conventional immunosuppressive therapy. Skin lesions that are not typical of psoriasis and that might possibly be malignant or premalignant should be biopsied before Sandimmun Neoral is given. Patients found to have malignant or premalignant skin changes should only be given Sandimmun Neoral after curative treatment of these lesions and if no other potentially effective therapy is available (see Contraindications).
b) Atopic dermatitis: The recommended dose range in adults and adolescents above 16 years of age is 2.5 to 5 mg/kg/day, given in two divided doses.
If the response is not satisfactory after two weeks at a starting dose of 2.5 mg/kg/day, the daily dose may be rapidly increased to a maximum of 5 mg/kg.
In very severe cases, rapid and adequate control of the disease may be achieved with a starting dose of 5 mg/kg/day.
Treatment should be withdrawn in patients in whom no sufficient improvement in atopic dermatitis is achieved within one month of treatment at 5 mg/kg/day.
Current experience with Sandimmun Neoral in the long-term treatment of atopic dermatitis is limited and it is therefore recommended that individual treatment cycles be restricted to a maximum of 8 weeks.
Skin infections: Active herpes simplex infections should be allowed to clear before starting Sandimmun Neoral therapy. However, they are not necessarily a reason for withdrawal of the medicine if they occur during treatment, unless infection is severe.
Skin infections with Staphylococcus aureus are not an absolute contraindication for Sandimmun Neoral therapy, but should be treated with appropriate antibiotics. Oral erythromycin should be avoided, as it may increase blood ciclosporin levels (see Interactions). If there is no alternative, blood ciclosporin levels, renal function and signs of adverse effects should be closely monitored.
3. Rheumatoid arthritis: Special instructions: Prior to treatment, the patient must be fully informed about the benefits and possible risks of Sandimmun Neoral therapy, and about the frequent problem of recurrence following withdrawal.
Patients with renal impairment, uncontrolled hypertension or infection, or a malignancy of any type should not be given Sandimmun Neoral. Caution is indicated in patients with hyperkalaemia or hyperuricaemia (see Biochemical changes under Precautions).
For the first 6 weeks of treatment, the recommended dose is 3 mg/kg/day, given in two divided doses. If the effect is considered insufficient, the daily dose may be increased gradually to a maximum of 5 mg/kg, subject to the conditions listed as follows.
For long-term treatment, the dose must be titrated individually on the basis of tolerability.
Sandimmun Neoral should be withdrawn if no improvement is evident after three months of treatment.
Sandimmun Neoral can be given in combination with low-dose corticosteroids and/or non-steroidal anti-inflammatory drugs (NSAIDs).
The daily Sandimmun Neoral dose must be reduced if serum creatinine exceeds the mean pre-treatment baseline by more than 30%, even if it is still within the normal range (see Monitoring of renal function). If the baseline value is exceeded by more than 50%, the dose must be halved. If the dose reduction has no effect within one month, Sandimmun Neoral must be withdrawn.
More frequent serum creatinine determinations are also necessary when an NSAID is introduced or when the dose of such an agent is increased.
As with other long-term immunosuppressive agents, the increased risk of lymphoproliferative disorders must be borne in mind (see Early detection of lymphoproliferative disorders and solid malignant tumours under Precautions).
4. Nephrotic syndrome: The recommended dose for induction of remission (to be taken in two divided doses) is 5 mg/kg/day in adults and 6 mg/kg/day in children. In such patients, ciclosporin can be used if creatinine levels are <200 µmol/l in adults and <140 µmol/l in children. The starting dose should not exceed 2.5 mg/kg/day (see Contraindications).
The dosage should be individually adjusted based on 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 therapy, the dosage should gradually be reduced to the lowest effective dose.
The dose should be reduced by 25% to 50% if serum creatinine exceeds the baseline value by more than 30%.
Sandimmun Neoral should be discontinued if no effect is apparent after three months of therapy.
Combination of Sandimmun Neoral with low-dosed oral corticosteroids is recommended in patients responding inadequately to Sandimmun Neoral alone, particularly those with steroid-resistant nephrotic syndrome.
Patients whose renal function is abnormal at baseline (maximum serum creatinine levels of 200 µmol/l in adults and 140 µmol/l in children) must be given a starting dose not exceeding 2.5 mg/kg/day and must be very closely monitored.
In some patients, it may be difficult to detect renal dysfunction caused by Sandimmun Neoral since nephrotic syndrome itself involves changes in renal function. This is why, in rare cases, Sandimmun Neoral-induced structural changes in the kidneys have been observed without any apparent increase in serum creatinine. Kidney biopsy should therefore be considered in patients with steroid-dependent minimal-change nephropathy receiving Sandimmun Neoral for longer than one year.
Paediatric use: There is limited data available on ciclosporin use in children. No data are available on the use of Sandimmun Neoral in the treatment of infants. No particular problems were reported in children over one year of age given the standard dosage of Sandimmun. Several paediatric studies have shown that children both need and tolerate higher doses per kg body weight of ciclosporin than adults. Patients with severe hepatic dysfunction require close monitoring of serum creatinine and, where possible, of ciclosporin levels, with dosage adjustment if necessary.
Use in elderly patients: In clinical studies on the use of oral ciclosporin in rheumatoid arthritis, 17.5% of the patients were 65 years of age or older. After 3 to 4 months of treatment, these patients were more likely to develop systolic hypertension and to show increases in serum creatinine exceeding the baseline value by 50% or more.
Clinical studies with Sandimmun Neoral in graft recipients and psoriasis patients did not include a sufficient number of patients 65 years of age or older to allow any conclusions as to whether their response differs from that of younger patients. In general, dose selection should be cautious in elderly patients, with consideration being given to the increased frequency of reduced hepatic, renal or cardiac function, concomitant disease or other drug therapy. Treatment should normally be started with a dose at the lower end of the dosage range.