SANDIMMUN® Concentrate for Solution for Infusion 50mg/ml.

Ciclosporin 50mg in 1ml.

Concentrate for solution for infusion.

Organ transplantation

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

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

Bone marrow transplantation

Prevention of graft rejection following bone marrow transplantation and prophylaxis of graft-versus-host disease (GVHD).

Treatment of established graft-versus-host disease (GVHD).

Organ transplantation

Initially, a single oral dose of 10-15mg/kg body weight, should be given 4-12 hours before transplantation. As a general rule, treatment should continue at a dose of 10-15mg/kg/day for 1-2 weeks post-operatively. Dosage should then be gradually reduced until a maintenance dose of 2-6mg/kg/day is reached. Dosage should be adjusted by monitoring ciclosporin blood levels and kidney function. When SANDIMMUN is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy) lower doses (e.g. 3-6mg/kg/day orally initially) may be used.

The use of the concentrate for solution for infusion is recommended in organ transplant patients who are unable to take SANDIMMUN orally (e.g. shortly after surgery) or in whom the absorption of the oral forms might be impaired during episodes of gastrointestinal disturbances. In such cases the intravenous dose is one third of the recommended oral dose. It is recommended, however, that patients are transferred to oral therapy as soon as the given circumstances allow.

Bone marrow transplantation/prevention and treatment of graft-versus-host disease (GVHD)

SANDIMMUN Concentrate for Solution for Infusion is usually preferred for initiation of therapy, although the oral forms may be used. The recommended dosage by the intravenous route is 3-5mg/kg/day, starting on the day before transplantation and continuing during the immediate post-transplant period of up to two weeks until oral maintenance therapy begins.

Treatment with SANDIMMUN should continue using the oral forms at a dosage of 12.5mg/kg/day for at least three and preferably six months before tailing off to zero. In some cases higher oral doses or the use of i.v. therapy may be necessary in the presence of gastrointestinal disturbances which might decrease absorption. If oral treatment is used to initiate therapy the recommended dose is 12.5-15mg/kg/day starting on the day before transplantation.

If GVHD develops after SANDIMMUN is withdrawn it should respond to reinstitution of therapy. Low doses should be used for mild, chronic GVHD.

Intravenous administration

When SANDIMMUN is administered by the intravenous route, the intravenous dose is one third of the recommended oral dose.

SANDIMMUN Concentrate for Solution for Infusion should be diluted 1:20 to 1:100 with normal saline or 5% glucose before use and given by slow intravenous infusion over 2-6 hours.

Use in the elderly

Experience in the elderly is limited but no particular problems have been reported following the use of the drug at the recommended dose. However, factors sometimes associated with ageing, in particular impaired renal function, make careful supervision essential and may necessitate dosage adjustment.

In rheumatoid arthritis clinical trials with 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 34 months of therapy.

Clinical studies of Neoral 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.

Use in children

Experience with SANDIMMUN in young children is still limited. Transplant recipients from three months of age have received the drug at the recommended dosage with no particular problems, although at dosages above the upper end of the recommended range, children seem to be more susceptible to fluid retention, convulsions and hypertension. This responds to dosage reduction.

Known hypersensitivity to ciclosporin or to any of the excipients of SANDIMMUN Concentrate for Solution for Infusion.

Concomitant use of tacrolimus is specifically contraindicated.

Concomitant use of rosuvastatin is specifically contraindicated (see Section 4.5).

SANDIMMUN Concentrate for Solution for Infusion should not be used in patients known to be hypersensitive to polyethoxylated castor oils.

SANDIMMUN can impair renal function. Close monitoring of serum creatinine and urea is required and dosage adjustment may be necessary. Increases in serum creatinine and urea occurring during the first few weeks of SANDIMMUN therapy are generally dose-dependent and reversible and usually respond to dosage reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant recipients, must be distinguished from chronic rejection.

In elderly patients, renal function should be monitored with particular care.

SANDIMMUN may also affect liver function and dosage adjustment, based on the results of bilirubin and liver enzyme monitoring, may be necessary.

Regular monitoring of blood pressure is required during SANDIMMUN therapy. If hypertension develops, appropriate antihypertensive treatment must be instituted.

Ciclosporin enhances the risk of hyperkalaemia, especially in patients with renal dysfunction. Caution is also required when ciclosporin is co-administered with potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) and potassium containing drugs as well as in patients on a potassium rich diet (see Section 4.5). Control of potassium levels in these situations is advisable.

Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peri-transplant period, particularly in the presence of neurological symptom/signs. If considered necessary, magnesium supplementation should be given.

Caution is required in treating patients with hyperuricaemia because SANDIMMUN can aggravate this condition (see Section 4.8).

Ciclosporin increases the risk of malignancies including lymphomas, skin and other tumours. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents. Hence a treatment regimen containing multiple immunosuppressants (including ciclosporin) should 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 should be warned to avoid excess ultraviolet light exposure.

Ciclosporin predisposes patients to infection with a variety of pathogens including bacteria, parasites, viruses and other opportunistic pathogens. This appears to be related to the degree and duration of immunosuppression rather than to the specific use of ciclosporin. 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.

In SANDIMMUN-treated renal transplant recipients, a machine perfusion time of more than 24 hours and a reanastomosis time of more than 45 minutes can have a significant effect on graft function. Both factors appear to increase the incidence of acute tubular necrosis.

The concentrate for solution for infusion contains polyethoxylated castor oil, which has been reported to cause anaphylactoid reactions. These reactions can consist of flushing of face and upper thorax; acute respiratory distress with dyspnoea, wheezing and non-cardiogenic pulmonary oedema; blood pressure changes and tachycardia. Special caution is therefore necessary in patients who have previously received intravenous injections or intravenous infusions containing polyethoxylated castor oil, or 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 following start of the infusion and at frequent intervals thereafter. If anaphylaxis occurs, the infusion should be discontinued. Adequate resuscitation facilities should be available.

SANDIMMUN can induce a reversible increase in blood lipids. It is therefore advisable to perform lipid determinations before treatment and thereafter as appropriate.

Ciclosporin may increase the risk of Benign Intracranial Hypertension. Patients presenting with signs of raised intracranial pressure should be investigated and if Benign Intracranial Hypertension is diagnosed, ciclosporin should be withdrawn due to the possible risk of permanent visual loss.

During treatment with ciclosporin, vaccination may be less effective; the use of live attenuated vaccines should be avoided.

Caution should be observed while co-administering lercanidipine with ciclosporin (see Section 4.5).

Food interactions

The concomitant intake of a fat rich meal or grapefruit juice has been reported to increase the bioavailability of ciclosporin.

Drug interactions

Of the many drugs reported to interact with ciclosporin, those for which the interactions are adequately substantiated and considered to have clinical implications are listed below.

Various agents are known to either increase or decrease plasma or whole blood ciclosporin levels usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular CYP3A4. Ciclosporin is also an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase plasma levels of comedications that are substrates of this enzyme and/or transporter.

Drugs that decrease ciclosporin levels:

Barbiturates, carbamazepine, oxcarbazepine, phenytoin; rifampicin, octreotide, orlistat, hypericum perforatum (St John's Wort); ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase ciclosporin levels:

Macrolide antibiotics (e.g. erythromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high dose); allopurinol; amiodarone; ursodeoxycholic acid; protease inhibitors, imatinib; colchicine.

Other relevant drug interactions

Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); non-steroidal anti-inflammatory drugs (including diclofenac, naproxen, sulindac); melphalan; methotrexate.

Concomitant use with tacrolimus should be avoided due to increased potential for nephrotoxicity.

The concurrent administration of nifedipine with ciclosporin may result in an increased rate of gingival hyperplasia compared with that observed when ciclosporin is given alone.

Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased threefold and the AUC of ciclosporin was increased 21%. Therefore caution is recommended when co-administering ciclosporin together with lercanidipine (see Section 4.4).

The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its first-pass effect. If non-steroidal anti-inflammatory drugs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.

Ciclosporin may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and etoposide.

Severe digitalis toxicity has been seen within days of starting ciclosporin in several patients taking digoxin.

Administration of ciclosporin may enhance the potential of HMG-CoA reductase inhibitors (statins) and colchicine to induce muscular toxicity e.g. muscle pain and weakness, myositis and occasionally rhabdomyolysis. If ciclosporin is to be concomitantly administered with a statin then the prescriber should refer to the product information for the relevant statin as the dose may need to be reduced. Rosuvastatin is specifically contraindicated with ciclosporin (see Section 4.3).

Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus and sirolimus.

Caution is required for concomitant use of potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium containing drugs since they may lead to significant increases in serum potassium (see Section 4.4).

Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.

Recommendations

If the concomitant use of drug known to interact with ciclosporin cannot be avoided, the following basic recommendations should be observed.

During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered drug should be reduced or alternative treatment considered.

In graft recipients there have been isolated reports of considerable but reversible impairment of kidney function (with corresponding increase in serum creatinine) following concomitant administration of fibric acid derivatives (e.g. bezafibrate, fenofibrate). Kidney function must therefore be closely monitored in these patients. In the event of significant impairment of kidney function the co-medication should be withdrawn.

Drugs known to reduce or increase the bioavailability of ciclosporin: in transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment are required, particularly during the introduction or withdrawal of the co-administered drug. In non-transplant patients the value of ciclosporin blood level monitoring is questionable, as in these patients the relationship between blood level and clinical effect is less well established. If drugs known to increase ciclosporin levels are given concomitantly, frequent assessment of renal function and careful monitoring for ciclosporin related side-effects may be more appropriate than blood level measurement.

The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of ciclosporin.

Non-steroidal anti-inflammatory drugs known to undergo strong first-pass metabolism (e.g. diclofenac) should be given at doses lower than those that would be used in patients not receiving ciclosporin. When diclofenac is given concomitantly with ciclosporin the dose of diclofenac should be reduced by approximately half (see Section 4.2).

If digoxin, colchicine or HMG-CoA reductase inhibitors (statins) are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the drugs, followed by reduction of its dosage or its withdrawal.

Ciclosporin is not teratogenic in animals. As the safety of SANDIMMUN in human pregnancy has not been fully established, it should only be used in pregnancy if the benefit outweighs any potential risks.

Ciclosporin passes into the breast milk and mothers receiving treatment with SANDIMMUN should not therefore, breast feed their infants.

No data exist on the effects of SANDIMMUN on the ability to drive and to use machines.

Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction.

Immune System Disorders

Not known: Anaphylactoid reactions can consist of non-cardiogenic pulmonary oedema, with acute respiratory distress, dyspnoea, wheezing, flushing of the face and upper thorax, and blood pressure changes and tachycardia.

Infections and infestations:

Patients receiving ciclosporin and ciclosporin-containing regimens as well as other immunosuppressive regimens are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Section 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 leukoencephalopathy (PML). Serious and/or fatal outcomes have been reported.

Neoplasms benign, malignant and unspecified (including cysts and polyps):

The increased risk of developing malignancies and lymphoproliferative disorders (including lymphomas), some with reported fatalities, appears to be related to the degree and duration of immunosuppression rather than to the use of specific agents (refer to Section 4.4).

Adverse reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: 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), including isolated reports.

Table 1

Little experience is available with overdosage. Symptomatic treatment and general supportive measures should be followed in all cases of overdosage.

Signs of nephrotoxicity might occur which would be expected to resolve following drug withdrawal. SANDIMMUN is not dialysable to any great extent nor is it well cleared by charcoal haemoperfusion. Hypertension and convulsions have been reported in some patients receiving SANDIMMUN therapy at doses above the recommended range and in others with high trough blood levels of ciclosporin. This might, therefore, be expected as a feature of overdosage.

Pharmacotherapeutic group: Immunosuppressive agents, calcineurin inhibitors (ATC code L04A D01).

Ciclosporin A is a cyclic undecapeptide with immunosuppressant properties. Studies suggest that ciclosporin A inhibits the development of cell-mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-verus-host disease and also T-cell dependent antibody production. It also inhibits lymphokine production and release, including interleukin 2 or T-cell growth factor (TCGF). Ciclosporin appears to block the resting lymphocytes in the G₀ or G₁ phase of the cell cycle.

All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents it does not depress haemopoeisis and has no effect on the function of phagocytic cells.

SANDIMMUN Concentrate for Solution for Infusion has been shown to be bioequivalent to SANDIMMUN oral solution.

Absolute bioavailability is 25-50% at steady state and peak blood concentrations are achieved within 1-6 hours.

Ciclosporin A is distributed largely outside the blood volume. Within blood, 33-47% is present in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. In plasma, approximately 90% is bound to protein, mainly lipoproteins.

Ciclosporin is extensively biotransformed to approximately 15 metabolites, there being no single major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is excreted in the urine as unchanged drug. The terminal elimination half-life from blood is approximately 19 hours, irrespective of the dose or route of administration.

Absolute ethanol and polyethoxylated castor oil.

Sandimmun Concentrate for Solution for Infusion contains polyoxyethylated castor oil, which can cause phthalate stripping from PVC. If available, glass containers should be used for infusion. Plastic bottles should be used only if they conform to the requirements for “Sterile plastic containers for human blood and blood components”. If polyvinyl chloride bags are used, they should comply with the requirements for “Empty sterile containers of plasticised poly (vinyl chloride) for human blood and blood components” of the current European Pharmacopoeia. Containers and stoppers should be free of silicon oil and fatty substances.

4 years.

Store below 30^oC.

SANDIMMUN Concentrate for Solution for Infusion is available in 1ml and 5ml uncoloured glass ampoules.

Not stated.

Novartis Pharmaceuticals UK Limited

Trading as SANDOZ PHARMACEUTICALS

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

PL 00101/0153

17 February 1983 / 17 February 1998

17 November 2009

POM