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 3-4 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.

Hypersensitivity to ciclosporin or to any of the excipients of SANDIMMUN Concentrate for Solution for Infusion including hypersensitivity to polyethoxylated castor oil.

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 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 the drug 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.

SANDIMMUN concentrate for solution for infusion contains polyethoxylated castor oil, which following i.v. administration has been reported to cause anaphylactoid reactions. These reactions can consist of flushing of face and upper thorax, and non-cardiogenic pulmonary oedema with acute respiratory distress, dyspnoea, wheezing and blood pressure changes and tachycardia. Special caution is therefore necessary in patients who have previously received, by i.v. injection or infusion, preparations containing polyethoxylated castor oil (e.g. a preparation containing Cremophor® EL), 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. Adequate resuscitation facilities should be available. An aqueous solution of adrenaline 1:1000 and a source of oxygen should be available at the bedside. Prophylactic administration of an antihistaminic (H1 + H2 blocker) prior to Sandimmun concentrate for solution for infusion has also been successfully employed to prevent the occurrence of anaphylactoid reactions.

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.

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 unprotected sun exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

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.

A frequent and potentially serious complication, increase in serum creatinine and urea, may occur during the first few weeks of SANDIMMUN therapy. These functional changes are dose-dependent and reversible, usually responding to dose reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant patients, must be differentiated from changes due to chronic rejection. SANDIMMUN may also cause dose-dependent, reversible increases in serum bilirubin and, occassionally, in liver enzymes (see section 4.8). 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 comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.8). Close monitoring of parameters that assess renal and hepatic function is required. Abnormal values may necessitate dose reduction.

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.

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

For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent drug) is preferred; a HPLC method, which also measures the parent drug, 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 nonspecific monoclonal antibody should be performed, to ensure a dosage that provides adequate immunosuppression.

It must be remembered that the ciclosporin concentration in blood, plasma, or serum is only one of many factors contributing to the clinical status of the patient. Results should therefore serve only as a guide to dosage in relationship to other clinical and laboratory parameters.

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

Since, on rare occasions, SANDIMMUN has been reported to induce a reversible slight increase in blood lipids, it is advisable to perform lipid determinations before treatment and after the first month of therapy. In the event of increased lipids being found, restriction of dietary fat and, if appropriate, a dose reduction, should be considered.

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. 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.

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).

Ciclosporin may increase blood levels of concomitant medications that are substrates of P-glycoprotein (Pgp) such as aliskiren (see section 4.5).

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.

SANDIMMUN concentrate for solution for infusion contains 34.4% ethanol. A 100 mg dose of SANDIMMUN concentrate contains 556 mg of ethanol, also equivalent to nearly 15 ml of beer or 5 ml of wine. This may be harmful in alcoholic patients and should be taken into account in pregnant or breast feeding women, in patients presenting with liver disease or epilepsy, or if the medicine is being given to a child.

Food interactions

The concomitant intake of 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; nafcillin, sulfadimidine i.v.; rifampicin, octreotide, probucol, orlistat, hypericum perforatum (St John's Wort); ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase ciclosporin levels:

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

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, histamine H2-receptor antagonists (e.g. cimetidine, ranitidine; methotrexate (see section 4.4).

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).

Ciclosporin is a highly potent Pgp inhibitor and may increase blood levels of concomitant medications that are substrates of Pgp such as aliskiren. Following concomitant administration of ciclosporin and aliskiren, the Cmax of aliskiren was increased by approximately 2.5 fold and the AUC by approximately 5 fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered. Caution is recommended when co-administering ciclosporin together with aliskiren (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. There are also reports on the potential of ciclosporin to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine is used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage or its withdrawal.

Literature and post marketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of ciclosporin with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely, fluvastatin. When concurrently administered with ciclosporin, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis.

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 comedication 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 is 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.

Pregnancy

Animal studies have shown reproductive toxicity in rats and rabbits.

Experience with SANDIMMUN in pregnant women is limited. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin containing regimens, are at risk of premature delivery (<37 weeks).

A limited number of observations in children exposed to ciclosporin in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.

However there are no adequate and well-controlled studies in pregnant women and, therefore, SANDIMMUN should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.

Lactation

Ciclosporin passes into the breast milk. Mothers receiving treatment with SANDIMMUN should not breast-feed.

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. 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.

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 immunosuppressive therapies, including ciclosporin and ciclosporin-containing 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):

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. The frequency of malignancies increases with the intensity and duration of therapy (see section 4.4). Some malignancies may be fatal.

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

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 comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see section 4.4).

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 i.v. 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 symptomatictreatment 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.

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.

Successful solid organ and bone marrow allogeneic transplants have been performed in man, using ciclosporin to prevent and treat rejection and GVHD. Ciclosporin has been used both in Hepatitis C Virus (HCV) positive and HCV negative liver transplants recipients. Marked beneficial effects of ciclosporin therapy have also been shown in patients with severe psoriasis, atopic dermatitis, and rheumatoid arthritis, conditions that may be considered to have an immunological mechanism.

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.

Ciclosporin gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally). At toxic doses (rats at 30 mg/kg and rabbits at 100 mg/kg per day orally), ciclosporin was embryo- and fetotoxic as indicated by increased prenatal and postnatal mortality, and reduced fetal weight together with related skeletal retardations.

In two published research studies, rabbits exposed to ciclosporin in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension, and progressive renal insufficiency up to 35 weeks of age.

Pregnant rats which received 12 mg/kg/day of ciclosporin intravenously (twice the recommended human intravenous dose) had foetuses with an increased incidence of ventricular septal defect.

These findings have not been demonstrated in other species and their relevance for humans is unknown. The safety margins based on plasma concentration at the NOAEL have not been determined.

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16 mg/kg per day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study conducted at 0.5, 2, and 8 mg/kg per day, pancreatic islet cell adenomas significantly exceeded the control rate at the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.

No impairment in fertility was demonstrated in studies in male and female rats.

Ciclosporin has not been found mutagenic/genotoxic in the Ames test, the v79–hgprt test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone marrow, the mouse dominant lethal assay, and the DNA repair test in sperm from treated mice. A study analyzing sister chromatid exchange (SCE) induction by ciclosporin using human lymphocytes in vitro gave indication of a positive effect (i.e. induction of SCE) at high concentrations in this system.

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin. The risk of malignancies during ciclosporin treatment is higher than in the normal, healthy population, but similar to that in patients receiving other immunosuppressive therapies. It has been reported that reduction or discontinuance of immunosuppression may cause the lesions to regress.

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°C.

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

7 February 2012

POM