SANDIMMUN Concentrate for solution for infusion Ref.[6696] Active ingredients: Ciclosporin

Posology

The dose ranges given for oral administration are intended to serve as guidelines only.

Sandimmun should only be prescribed by, or in close collaboration with, a physician with experience of immunosuppressive therapy and/or organ transplantation.

Transplantation

Solid organ transplantation

The recommended dose of Sandimmun concentrate for solution for infusion is approximately one-third of the corresponding oral dose, and it is recommend that patients be switched to oral therapy as soon as possible.

For reference the initial oral dose of Sandimmun or Sandimmun Neoral is 10 to 15 mg/kg given in 2 divided doses which should be initiated within 12 hours before surgery. This dose should be maintained as the daily dose for 1 to 2 weeks post-operatively, being gradually reduced in accordance with blood levels according to local immunosuppressive protocols until a recommended maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached.

When oral Sandimmun or Sandimmun Neoral is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple medicinal product 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 concentrate for solution for infusion is preferred for this purpose. The recommended intravenous dose is 3 to 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 or Sandimmun Neoral at daily oral 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 zero by 1 year after transplantation.

If oral Sandimmun or 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 oral Sandimmun or Sandimmun Neoral, or the use of Sandimmun intravenous therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease absorption.

In some patients, GVHD occurs after discontinuation of ciclosporin treatment, but usually responds favourably 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 Sandimmun should be used to treat mild, chronic GVHD.

Special populations

Patients with renal impairment

All indications: Ciclosporin undergoes minimal renal elimination and its pharmacokinetics are not extensively affected by renal impairment (see section 5.2). However, due to its nephrotoxic potential (see section 4.8), careful monitoring of renal function is recommended (see section 4.4).

Patients with hepatic impairment

Ciclosporin is extensively metabolised by the liver. An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. Dose reduction may be necessary in patients with severe liver impairment to maintain blood levels within the recommended target range (see sections 4.4 and 5.2) and it is recommended that ciclosporin blood levels are monitored until stable levels are reached.

Paediatric population

Clinical studies have included children from 1 year of age. In several studies, paediatric patients required and tolerated higher doses of ciclosporin per kg body weight than those used in adults.

Use of Sandimmun in children for non-transplantation indications other than nephrotic syndrome cannot be recommended (see section 4.4).

Elderly population (age 65 years and above)

Experience with Sandimmun in the elderly is limited.

In rheumatoid arthritis clinical trials with ciclosporin, patients aged 65 or older 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.

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 medication and increased susceptibility for infections.

Method of administration

Intravenous administration.

Types of containers suitable for the infusion solution are mentioned in section 6.2.

Because of the risk of anaphylaxis (see section 4.4) the use of Sandimmun concentrate for solution for infusion should be reserved for organ transplant patients who are unable to take the medicinal product orally (e.g. shortly after surgery), or in whom absorption of the oral forms might be impaired during episodes of gastrointestinal disorders. In such cases, it is recommended to switch to oral administration as soon as feasible. Another well-established use of the concentrate for solution for infusion is the initial treatment of patients undergoing 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 intravenous infusion over 2 to 6 hours.

Once an ampoule is opened, the contents should be used immediately. Diluted infusion solutions must be discarded after 24 hours.

Precautions to be taken before handling or administering the medicinal product

For instructions on dilution of the medicinal product before administration, see section 6.6.

The oral LD₅₀ of ciclosporin is 2,329 mg/kg in mice, 1,480 mg/kg in rats and >1,000 mg/kg in rabbits. The intravenous LD₅₀ is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

Symptoms

Experience with acute overdosage of ciclosporin is limited. Oral doses of ciclosporin of up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and in a few patients moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with ciclosporin in premature neonates.

Treatment

In all cases of overdosage, general supportive measures should be followed and symptomatic treatment applied. Forced emesis and gastric lavage may be of value within the first few hours after oral intake. Ciclosporin is not dialysable to any great extent, nor is it well cleared by charcoal haemoperfusion.

Shelf life: 4 years.

This medicinal product does not require any special temperature storage conditions. Store in the original package. Once an ampoule has been opened, the contents should be used immediately. Following dilution, the solution should be used immediately. If it is not used immediately, the conditions and duration of storage are the responsibility of the user and storage should not be longer than 24 hours at 2 to 8°C, unless dilution has been carried out under controlled and validated aseptic conditions.

Sandimmun Concentrate for Solution for Infusion is available in 1ml and 5ml uncoloured glass (type I) ampoules.

The concentrate should be diluted 1:20 to 1:100 with normal saline or 5% glucose, and given as a slow intravenous infusion over approximately 2 to 6 hours. Diluted infusion solutions must be discarded after 24 hours.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.