Novartis Pharmaceuticals UK Ltd

5.3       Preclinical safety data

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.

 Known hHypersensitivity 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 Ssection 4.5).

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

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, with dyspnoea, wheezing and non-cardiogenic pulmonary oedema; blood pressure changes and tachycardia.  Special caution is therefore necessary in patients who have previously received, by i.v. intravenous injections or intravenous infusions, preparations containing polyethoxylated castor oil (e.g. a preparation containing Cremophor® EL), andor in patients with an allergic predisposition. Thus, patients receiving SANDIMMUN Cconcentrate for Ssolution for Iinfusion should be under continuous observation for at least the first 30 minutes afterfollowing 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, Cciclosporin increases the risk of developing lymphomas and other malignancies including lymphomas, particularly those of the 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 exposureunprotected sun exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

Like other immunosuppressants, Cciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections with a variety of pathogens including bacteria, parasites, viruses and otheroften with  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.

SANDIMMUN can impair renal function.  Close monitoring of serum creatinine and urea is required and dosage adjustment may be necessary.  A frequent and potentially serious complication, Iincreases in serum creatinine and urea, may occurring during the first few weeks of SANDIMMUN therapy. These functional changes are generally dose-dependent and reversible, and usually responding to dosage reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) which, in renal transplant recipientspatients, must be distinguisheddifferentiated 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)affect liver function and dosage adjustment, based on the results of bilirubin and liver enzyme monitoring, may be necessary. 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.;  Iif hypertension develops, appropriate antihypertensive treatment must be instituted.

Since, on rare occasions, SANDIMMUN has been reported tocan induce a reversible slight increase in blood lipids., Iit is therefore advisable to perform lipid determinations before treatment and thereafter as appropriateafter 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 (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).

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

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; ursodeoxycholic 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-receptorantagonists (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 Ssection 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).

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.

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 Ssection 4.3).

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 Ssection 4.4).

Drugs known to reduce or increase the bioavailability of ciclosporin: in transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment areis 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 Ssection 4.2).

Pregnancy

Animal studies have shown reproductive toxicity in rats and rabbits.

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.

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. and mMothers receiving treatment with SANDIMMUN should not therefore, breast- feed their infants.

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, as well as other immunosuppressive regimens are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Ssection 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,Theare at increased risk of developing lymphomasmalignancies and or lymphoproliferative disorders and other malignancies(including lymphomas), particularly of the skin.some with reported fatalities,  The frequency of malignancies appears to be related toincreases with the degreeintensity and duration of therapyimmunosuppression rather than to the use of specific agents (refer tosee Ssection 4.4). Some malignancies may be fatal.

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).

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.

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.

5.1       Pharmacodynamic properties

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-versus-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 haemopoieisis and has no effect on the function of phagocytic cells.

Changes to the Sandimmun Concentrate  for Solution for Infusion SmPC  

Section 1. NAME OF THE MEDICINAL PRODUCT

changed from:

SANDIMMUN® Concentrate for Infusion 50mg/ml.

To:

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

Section 3. PHARMACEUTICAL FORM

Changed from:

Concentrate for iv infusion.

To:

Concentrate for solution for infusion.

The product name has subsequently been amended throughout the SmPC text to reflect the above.

Section 4.3 Contraindications:

Changed from:

Known hypersensitivity to ciclosporin.

To:

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

Update to Section 4.2 of the SmPC  with additional information on use in the elderly

Changed from:

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.

To:

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.

SECTION 4.4

Paragraph 6 in Precautions section:

….. The increased risk appears to be related to the degree and duration of immunosuppression rather than to the specific use if ciclosporin. Hence a treatment regimen containing immunosuppressants should be used with caution as this could lead to lymphoproliferative disorders and solid organ tumours, some with reported fatalities.

changed to:

….. 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.

SECTION 4.5

Paragraph entitled Drug interactions:

Second paragraph:

            P450

replaced with:

            CYP3A4

The following has also been added:

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.

Paragraph entitled Other relevant drug interactions:

Etoposide has been added to the 6^th paragraph, to read:

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

The following sentence has also been added at the end of this section:

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

SECTION 4.8

·         Incidences changed from percentages to ≥ 1/100 etc and formatting changed so that side effects are now tabulated instead of just being listed.

·         The following has been added:

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. 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).

SECTION 5.1

Changed from:

Pharmacotherapeutic group: Selective immunosuppressive agents, calcineurin inhibitors (ATC code L04A01).

to:

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

SECTION 10

Date of revision changed from 22 February 2008 to 11 August 2008

Section 4.4: Precautions

Information on vaccination during Sandimmun treatment has been moved from Section 4.5 to 4.4 of the SmPC.

The following statements have been added:

• In view of the potential risk of skin malignancy, patients on Sandimmun should be warned to avoid excess ultraviolet light exposure.

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

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

The statement regarding anaphylactoid reactions has been revised and includes the recommendation that adequate resuscitation facilities should be available.

Section 4.5 Interaction with other medicinal products and other forms of interaction

The key changes include:

Drugs that decrease ciclosporin levels: oxcarbazepine, sulfinpyrazone, terbinafine and bosentan added

Drugs that increase ciclosporin levels:  voriconazole, imatinib, colchicine added

Tacrolimus was previously listed and remains as a contraindication in section 4.3 of the SmPC.  Reference to tacrolimus has now also been added to section 4.5.

Interaction with methotrexate, lercandipine, sirolimus, everolimus and fibric acid derivatives included.

Digoxin: additional information on digitalis toxicity included

Use with potassium sparing drugs was previously mentioned and remains in Section 4.4 of the SmPC. It is now additionally included in section 4.5