SANDIMMUN CONCENTRATE FOR

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 recommended 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.

, 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. 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.

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. 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. 2). 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.

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.

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. 2. , 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 using appropriate aseptic technique and given as a slow intravenous infusion over 2 to 6 hours.

6.

Summary of the safety profile The principal adverse reactions observed in clinical trials and associated with the administration of ciclosporin include renal dysfunction, tremor, hirsutism, hypertension, diarrhoea, anorexia, nausea and vomiting.

Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction. In the various indications the overall spectrum of side effects is essentially the same; there are, however, differences in incidence and severity.

As a consequence of the higher initial doses and longer maintenance therapy required after transplantation, side effects are more frequent and usually more severe in transplant patients than in patients treated for other indications.

4). 4). Both generalised and localised infections can occur. Pre-existing infections may also be aggravated and reactivation of polyomavirus infections may lead to polyomavirus- associated nephropathy (PVAN) or to JC virus associated progressive multifocal leukopathy (PML).

Serious and/or fatal outcomes have been reported. Neoplasms benign, malignant and unspecified (including cysts and polyps) Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin containing regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin.

4). Some malignancies may be fatal. Tabulated summary of adverse drug reactions from clinical trials Adverse drug reactions from clinical trials (Table 2) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first.

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000), not known (cannot be estimated from the available data).

4) Reproductive system and breast disorders Rare Menstrual disturbances, gynaecomastia General disorders and administration site conditions Common Pyrexia, fatigue Uncommon Oedema, weight increase * Adverse events reported from post marketing experience where the ADR frequency is not known due to the lack of a real denominator.

# Hearing impairment has been reported in the post-marketing phase in patients with high levels of ciclosporin. Other adverse drug reactions from post-marketing experience There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice hepatitis and liver failure in patients treated with ciclosporin.

Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and co-medications with hepatotoxic potential. 4). Acute and chronic nephrotoxicity Patients receiving calcineurin inhibitor (CNI) therapies, including ciclosporin and ciclosporin- containing regimens, are at increased risk of acute or chronic nephrotoxicity.

There have been reports from clinical trials and from the post-marketing setting associated with the use of Sandimmun. Cases of acute nephrotoxicity reported disorders of ion homeostasis, such as hyperkalaemia, hypomagnesaemia, and hyperuricaemia.

4). Pain of lower extremities Isolated cases of pain of lower extremities have been reported in […]

Medical supervision Sandimmun should be prescribed only by physicians who are experienced in immunosuppressive therapy and can provide adequate follow-up, including regular full physical examination, measurement of blood pressure and control of laboratory safety parameters.

Transplantation patients receiving this medicinal product should be managed in facilities with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should receive complete information for the follow-up of the patient.

Polyoxyl castor oil and anaphylactoid reactions Sandimmun concentrate for solution for infusion contains polyoxyl castor oil, which has been reported to cause anaphylactoid reactions following intravenous administration. These reactions can consist of flushing of the face and upper thorax, and non-cardiogenic pulmonary oedema, with acute respiratory distress, dyspnoea, wheezing, blood pressure changes and tachycardia.

, a preparation containing Cremophor® EL) by intravenous injection or infusion, and in patients with an allergic predisposition. Thus, patients receiving Sandimmun concentrate for solution for infusion should be under continuous observation for at least the first 30 minutes after the start of the infusion and at frequent intervals thereafter.

If anaphylaxis occurs, the infusion should be discontinued. An aqueous solution of adrenaline 1:1000 and a source of oxygen should be available by the bedside. Prophylactic administration of an antihistamine (H1 + H2 blocker) prior to Sandimmun concentrate for solution for infusion has also been successfully employed to prevent the occurrence of anaphylactoid reactions.

Lymphomas and other malignancies Like other immunosuppressants, ciclosporin increases the risk of developing lymphomas and other malignancies, particularly those of the skin. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents.

A treatment regimen containing multiple immunosuppressants (including ciclosporin) should therefore be used with caution as this could lead to lymphoproliferative disorders and solid organ tumours, some with reported fatalities. In view of the potential risk of skin malignancy, patients on Sandimmun, in particular those treated for psoriasis or atopic dermatitis, should be warned to avoid excess unprotected sun exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

Infections Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. Activation of latent polyomavirus infections that may lead to polyomavirus associated nephropathy (PVAN), especially to BK virus nephropathy (BKVN), or to JC virus associated progressive multifocal leukoencephalopathy (PML), have been observed in patients receiving ciclosporin.

These conditions are often related to a high total immunosuppressive burden and should be considered in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and/or fatal outcomes have been reported.

Effective pre-emptive and therapeutic strategies should be employed, particularly in patients on multiple long-term immunosuppressive therapy. Renal toxicity A frequent and potentially serious complication, an increase in serum creatinine and urea, may occur during Sandimmun therapy.

These functional changes are dose-dependent and are initially reversible, usually responding to dose reduction. , interstitial fibrosis) which, in renal transplant patients, must be differentiated from changes due to chronic rejection.

8). 8). There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co- morbidities, underlying conditions and other confounding factors including infectious complications and co-medications with hepatotoxic potential.

8). 2). Elderly population (age 65 years and above) In elderly patients, renal function should be monitored with particular care. 2) When Sandimmun is used in transplant patients, routine monitoring of ciclosporin blood levels is an important safety measure.

For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent compound) is preferred; a high- performance liquid chromatography (HPLC) method, which also measures the parent compound, can be used as well.

If plasma or serum is used, a standard separation protocol (time and temperature) should be followed. For the initial monitoring of liver transplant patients, either the specific monoclonal antibody should be used, or parallel measurements using both the specific monoclonal antibody and the non-specific monoclonal antibody should be performed, to ensure a dosage that provides adequate immunosuppression.

Hypertension Regular monitoring of blood pressure is required during Sandimmun therapy. If hypertension develops, appropriate […]

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