SANDIMMUN NEORAL CAPSULE 10 MG [SIN09871P]

Product Info

SANDIMMUN NEORAL CAPSULE 10 MG

[SIN09871P]

INDICATIONS

Transplantation indications

Solid organ transplantation

Prevention of graft rejection following kidney, liver, heart, combined heart-lung, lung or pancreas allogeneic transplantations.

Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.

Bone marrow transplantation

Prevention of graft rejection following bone marrow transplantation.

Prevention or treatment of graft-versus-host disease (GVHD).

Non-transplantation indications

Endogenous uveitis

Active sight-threatening intermediate or posterior uveitis of non-infectious aetiology in patients where conventional therapy fails, or causes unacceptable side effects.

Behçet uveitis with repeated inflammatory attacks involving the retina in patients whose kidney function is normal.

Nephrotic syndrome

Steroid-dependent and steroid-resistant nephrotic syndrome in adults and children, due to glomerular diseases such as minimal change nephropathy, focal and segmental glomerulosclerosis, or membranous glomerulonephritis and in whom conventional cytostatic therapy is ineffective, but only if kidney function indices are at least 50% of normal.

Sandimmun Neoral can be used to induce and maintain remissions. It can also be used to maintain steroid-induced remission, allowing withdrawal of steroids.

Rheumatoid arthritis

Treatment of severe, active rheumatoid arthritis in whom conventional therapy is ineffective or inappropriate.

Psoriasis

Treatment of severe psoriasis in patients in whom conventional therapy is inappropriate or ineffective.

Atopic dermatitis

Sandimmun Neoral is indicated in patients with severe atopic dermatitis in which conventional therapy is ineffective or inappropriate.

DOSAGE AND ADMINISTRATION

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 section INTERACTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information), 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 section WARNINGS AND PRECAUTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

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 section WARNINGS AND PRECAUTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

General target population

Transplantation

Solid organ transplantation

Treatment with Sandimmun Neoral 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 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.

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. 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 section WARNINGS AND PRECAUTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

• 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 refractory cases of 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 below) 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.

Sandimmun Neoral should be withdrawn if there is no improvement after three months.

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 section WARNINGS AND PRECAUTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Treatment should be withdrawn if no response is apparent after 3 months.

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 section WARNINGS AND PRECAUTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information)

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.

Atopic dermatitis

Due to the variability of this condition, treatment must be individualized. The recommended dose range in adults and adolescents above 16 years of age is 2.5 to 5 mg/kg per day given in 2 divided oral doses. If a starting dose of 2.5 mg/kg per day does not achieve a satisfactory response within two weeks of therapy, 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 is more likely to occur with a starting dose of 5 mg/kg per day. Once satisfactory response is achieved, the dose should be reduced gradually and, if possible, Sandimmun Neoral should be discontinued. Subsequent relapse may be managed with a further course of Sandimmun Neoral.

Experience with Sandimmun in the long term treatment of atopic dermatitis is limited and it is therefore recommended that individual treatment cycles be limited to a maximum of 8 weeks.

Treatment should be withdrawn in patients who do not respond adequately following one month of treatment at 5mg/kg/day.

Special populations

Renal impairment

All indications

Ciclosporin undergoes minimal renal elimination, and its pharmacokinetics is not significantly affected by renal impairment (see section CLINICAL PHARMACOLOGY – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). However, due to its nephrotoxic potential (see section ADVERSE DRUG REACTIONS), a careful monitoring of the renal function is recommended (see section WARNINGS AND PRECAUTIONS – subsection All indications) – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information.

Non-transplant indications

Patients with impaired renal function, except nephrotic syndrome patients, should not receive ciclosporin (see section WARNING AND PRECAUTIONS – subsection additional precautions in non-transplant indications – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). 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 section CLINICAL PHARMACOLOGY – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Dose reduction may be necessary in patients with severe liver impairment to maintain blood levels within the recommended target range (see section WARNINGS AND PRECAUTIONS and also section CLINICAL PHARMACOLOGY – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Use in Pediatrics

Sandimmun Neoral use in patients under 16 years for non-transplant indications other than nephrotic syndrome cannot be recommended. (see section WARNINGS AND PRECAUTIONS – subsection additional precautions in non-transplant indications – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

In transplantation, the experience with ciclosporin in children also is still limited. However, clinical studies have included children from 1 year of age using standard ciclosporin dosage with no particular problems. In several studies, paediatric patients required and tolerated higher doses of ciclosporin per kg body weight than those used in adults.

Geriatrics (65 years of age or 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 (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 (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’ in section WARNINGS AND PRECAUTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). 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

The dose ranges given for oral administration are intended to serve as guidelines only. Routine monitoring of ciclosporin blood levels is required. 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

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 section INTERACTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). 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 section INSTRUCTIONS FOR USE AND HANDLING – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

CONTRAINDICATIONS

Hypersensitivity to ciclosporin or to any of the excipients of Sandimmun Neoral.

The following additional contraindications apply to the non-transplant indications:

Kidney failure, except in patients with nephrotic syndrome, in whom disease-related moderate increases in baseline serum creatinine values (max. 200micromole/L in adults and max. 140micromole/L in children) improve and cautious therapy (max. 2.5mg/kg/day) is thus permitted.

Uncontrolled hypertension

Uncontrolled infection

History of known or diagnosed malignancy of any kind except premalignant or malignant skin changes.