Sandimmun Neoral

/ Novartis

The dose ranges given for oral administration are intended to serve as guidelines only.
The daily doses should always be given in two divided doses equally distributed throughout the day. It is recommended that this product be administered on a consistent schedule with regard to time of day and in relation to meals.
Neoral 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: Treatment with This product should be initiated within 12 hours before surgery at a dose of 10 to 15 mg/kg given in 2 divided doses. This dose should be maintained as the daily dose for 1 to 2 weeks post-operatively, being gradually reduced in accordance with blood levels according to local immunosuppressive protocols until a recommended maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached. When This product is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple medicinal product therapy), lower doses (e.g. 3 to 6 mg/kg given in 2 divided doses for the initial treatment) may be used.
Bone marrow transplantation: The initial dose should be given on the day before transplantation. In most cases, Sandimmun concentrate for solution for infusion is preferred for this purpose. The recommended intravenous dose is 3 to 5 mg/kg/day. Infusion is continued at this dose level during the immediate post-transplant period of up to 2 weeks, before a change is made to oral maintenance therapy with This product at daily doses of about 12.5 mg/kg given in 2 divided doses. Maintenance treatment should be continued for at least 3 months (and preferably for 6 months) before the dose is gradually decreased to zero by 1 year after transplantation. If This product is used to initiate therapy, the recommended daily dose is 12.5 to 15 mg/kg given in 2 divided doses, starting on the day before transplantation. Higher doses of This product, or the use of Sandimmun intravenous therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease absorption. In some patients, GVHD (Graft versus host disease) occurs after discontinuation of ciclosporin treatment, but usually responds favourably to re-introduction of therapy. In such cases an initial oral loading dose of 10 to 12.5 mg/kg should be given, followed by daily oral administration of the maintenance dose previously found to be satisfactory. Low doses of This product should be used to treat mild, chronic GVHD.
Non-transplantation indications: When using This product in any of the established non-transplantation indications, the following general rules should be adhered to: Before initiation of treatment a reliable baseline level of renal function should be established by at least two measurements. The estimated glomerular filtration rate (eGFR) by the MDRD formula can be used for estimation of renal function in adults and an appropriate formula should be used to assess eGFR in paediatric patients. Since Neoral can impair renal function, it is necessary to assess renal function frequently. If eGFR decreases by more than 25% below baseline at more than one measurement, the dosage of Neoral should be reduced by 25 to 50%. If the eGFR decrease from baseline exceeds 35%, further reduction of the dose of Neoral should be considered. These recommendations apply even if the patient`s values still lie within the laboratory`s normal range. If dose reduction is not successful in improving eGFR within one month, Neoral treatment should be discontinued. Regular monitoring of blood pressure is required. The determination of bilirubin and parameters that assess hepatic function are required prior to starting therapy and close monitoring during treatment is recommended. Determinations of serum lipids, potassium, magnesium and uric acid are advisable before treatment and periodically during treatment. Occasional monitoring of ciclosporin blood levels may be relevant in non-transplant indications, e.g. when Neoral is co-administered with substances that may interfere with the pharmacokinetics of ciclosporin, or in the event of unusual clinical response (e.g. lack of efficacy or increased drug intolerance such as renal dysfunction). The normal route of administration is by mouth. If the concentrate for solution for infusion is used, careful consideration should be given to administering an adequate intravenous dose that corresponds to the oral dose. Consultation with a physician with experience of use of ciclosporin is recommended. Except in patients with sight-threatening endogenous uveitis and in children with nephrotic syndrome, the total daily dose must never exceed 5 mg/kg. For maintenance treatment the lowest effective and well tolerated dosage should be determined individually. In patients in whom within a given time (for specific information see below) no adequate response is achieved or the effective dose is not compatible with the established safety guidelines, treatment should be discontinued.
Endogenous uveitis: For inducing remission, initially 5 mg/kg/day orally given in 2 divided doses are recommended until remission of active uveal inflammation and improvement in visual acuity are achieved. In refractory cases, the dose can be increased to 7 mg/kg/day for a limited period. To achieve initial remission, or to counteract inflammatory ocular attacks, systemic corticosteroid treatment with daily doses of 0.2 to 0.6 mg/kg prednisone or an equivalent may be added if This product alone does not control the situation sufficiently. After 3 months, the dose of corticosteroids may be tapered to the lowest effective dose. For maintenance treatment, the dose should be slowly reduced to the lowest effective level. During the remission phases, this should not exceed 5 mg/kg/day. Infectious causes of uveitis should be ruled out before immunosuppressants can be used.
Nephrotic syndrome: For inducing remission, the recommended daily dose is given in 2 divided oral doses. If the renal function (except for proteinuria) is normal, the recommended daily dose is the following: – adults: 5 mg/kg, – children: 6 mg/kg. In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day. The combination with low doses of oral corticosteroids is recommended if the effect of This product alone is not satisfactory, especially in steroid-resistant patients. Time to improvement varies from 3 to 6 months depending on the type of glomerulopathy. If no improvement has been observed after this time to improvement period, This product therapy should be discontinued. The doses need to be adjusted individually according to efficacy (proteinuria) and safety (primarily serum creatinine), but should not exceed 5 mg/kg/day in adults and 6 mg/kg/day in children. For maintenance treatment, the dose should be slowly reduced to the lowest effective level.
Rheumatoid arthritis: For the first 6 weeks of treatment the recommended dose is2.5 mg/kg/day orally given in 2 divided doses. If the effect is insufficient, the daily dose may then be increased gradually as tolerability permits, but should not exceed 4 mg/kg. To achieve full effectiveness, up to 12 weeks of This product therapy may be required. For maintenance treatment the dose has to be titrated individually to the lowest effective level according to tolerability. This product can be given in combination with low-dose corticosteroids and/or non-steroidal anti-inflammatory drugs (NSAIDs). This product can also be combined with low-dose weekly methotrexate in patients who have insufficient response to methotrexate alone, by using 2.5 mg/kg in 2 divided doses per day initially, with the option to increase the dose as tolerability permits.
Psoriasis: This product treatment should be initiated by physicians with experience in the diagnosis and treatment of psoriasis. Due to the variability of this condition, treatment must be individualised. For inducing remission, the recommended initial dose is 2.5 mg/kg/day orally given in 2 divided doses. If there is no improvement after 1 month, the daily dose may be gradually increased, but should not exceed 5 mg/kg. Treatment should be discontinued in patients in whom sufficient response of psoriatic lesions cannot be achieved within 6 weeks on 5 mg/kg/day, or in whom the effective dose is not compatible with the established safety guidelines. Initial doses of 5 mg/kg/day are justified in patients whose condition requires rapid improvement. Once satisfactory response is achieved, This product may be discontinued and subsequent relapse managed with re-introduction at the previous effective dose. In some patients, continuous maintenance therapy may be necessary. For maintenance treatment, doses have to be titrated individually to the lowest effective level, and should not exceed 5 mg/kg/day given orally in two divided doses.
Atopic dermatitis: This product treatment should be initiated by physicians with experience in the diagnosis and treatment of atopic dermatitis. Due to the variability of this condition, treatment must be individualised. The recommended dose range in adults and adolescents above 16 years of age is 2.5 to 5 mg/kg/day given in 2 divided oral doses for a maximum of 8 weeks. If a starting dose of 2.5 mg/kg/day does not achieve a satisfactory response within 2 weeks, the daily dose may be rapidly increased to a maximum of 5 mg/kg. In very severe cases, rapid and adequate control of the disease is more likely to occur with a starting dose of 5 mg/kg/day. Once satisfactory response is achieved, the dose should be reduced gradually and, if possible, This product should be discontinued.Subsequent relapse may be managed with a further course of this product.
Switching between oral ciclosporin formulations: The switch from one oral ciclosporin formulation to another should be made under physician supervision, including monitoring of blood levels of ciclosporin for transplantation patients, to ensure that pre-conversion levels are attained.
Special populations
Patients with renal impairment: All indications: Ciclosporin undergoes minimal renal elimination and its pharmacokinetics are not extensively affected by renal impairment. However, due to its nephrotoxic potential, careful monitoring of renal function is recommended.
Non-transplantation indications: With the exception of patients being treated for nephrotic syndrome, patients with impaired renal function should not receive ciclosporin. In nephrotic syndrome patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.
Patients with hepatic impairment: Ciclosporin is extensively metabolised by the liver. An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. Dose reduction may be necessary in patients with severe liver impairment to maintain blood levels within the recommended target range and it is recommended that ciclosporin blood levels are monitored until stable levels are reached.
Paediatric population: Clinical studies have included children from 1 year of age. In several studies, paediatric patients required and tolerated higher doses of ciclosporin per kg body weight than those used in adults. Use in children for non-transplantation indications other than nephrotic syndrome cannot be recommended.
Elderly population (age 65 years and above): Experience in the elderly is limited. In rheumatoid arthritis clinical trials with oral 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: Oral use. Capsules should be swallowed whole. Oral Solution should be diluted, preferably with orange or apple juice. However, other drinks, such as soft drinks, can be used accordingly to individual taste. The solution should be stirred well immediately before it is taken. Owing to its possible interference with the cytochrome P450-dependent enzyme system, grapefruit or grapefruit juice should be avoided for dilution.
The syringe should not come in contact with the diluent. If the syringe is to be cleaned, do not rinse it but wipe the outside with a dry tissue.

Transplantation indications
Solid organ transplantation: Prophylaxis of organ rejection in kidney, liver, heart allogeneic transplants in conjunction with corticosteroids. May also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents.
Bone marrow transplantation
Non-transplantation indications
Endogenous uveitis
Nephrotic syndrome: Nephritic syndrome type MCD (minimal change disease) in cases where conventional therapy has failed.
Rheumatoid arthritis: Severe cases in which standard treatments are ineffective or inappropriate
Psoriasis: Severe psoriasis above age 16 that did not respond to other treatment.
Atopic dermatitis: Atopic dermatitis in adults only up to 8 weeks, for severe cases in which conventional therapy is ineffective or inappropriate.

Hypersensitivity to the active substance or to any of the excipients.
Combination with products containing Hypericum perforatum (St John’s Wort).
Combination with medicines that are substrates for the multidrug efflux transporter P-glycoprotein or the organic anion transporter proteins (OATP) and for which elevated plasma concentrations are associated with serious and/or life-threatening events, e.g. bosentan, dabigatran etexilate and aliskiren.

Medical supervision: This product 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.
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 This product, 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 therapy. These functional changes are dose-dependent and are initially 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. Frequent monitoring of renal function is therefore required according to local guidelines for the indication in question.
Hepatotoxicity: This product may also cause dose-dependent, reversible increases in serum bilirubin and in liver enzymes. 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. In some cases, mainly in transplant patients, fatal outcomes have been reported. Close monitoring of parameters that assess hepatic function is required and abnormal values may necessitate dose reduction.
Elderly population (age 65 years and above): In elderly patients, renal function should be monitored with particular care.
Monitoring ciclosporin levels: When this product 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. In non-transplant patients, occasional monitoring of ciclosporin blood levels is recommended, e.g. when This product is co-administered with substances that may interfere with the pharmacokinetics of ciclosporin, or in the event of unusual clinical response (e.g. lack of efficacy or increased drug intolerance such as renal dysfunction). 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.
Hypertension: Regular monitoring of blood pressure is required during this therapy. If hypertension develops, appropriate antihypertensive treatment must be instituted. Preference should be given to an antihypertensive agent that does not interfere with the pharmacokinetics of ciclosporin, e.g. isradipine.
Blood lipids increased: Since This product 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 theevent of increased lipids being found, restriction of dietary fat and, if appropriate, a dose reduction, should be considered.
Hyperkalaemia: 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. potassiumsparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable.
Hypomagnesaemia: 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.
Hyperuricaemia: Caution is required when treating patients with hyperuricaemia.
Live-attenuated vaccines: During treatment with ciclosporin, vaccination may be less effective. The use of live attenuated vaccines should be avoided.
Interactions: Caution should be observed when co-administering ciclosporin with drugs that substantially increase or decrease ciclosporin plasma concentrations, through inhibition or induction of CYP3A4 and/or Pglycoprotein. Renal toxicity should be monitored when initiating ciclosporin use together with active substances that increase ciclosporin levels or with substances that exhibit nephrotoxic synergy. Concomitant use of ciclosporin and tacrolimus should be avoided. Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein and organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter. Caution should be observed while co-administering ciclosporin with such drugs or concomitant use should be avoided. Ciclosporin increases the exposure to HMG-CoA reductase inhibitors (statins). When concurrently  administered with ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins should be avoided according to their 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. Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased three-fold and the AUC of ciclosporin was increased 21%. Therefore the simultaneous combination of ciclosporin and lercanidipine should be avoided. Administration of ciclosporin 3 hours after lercanidipine yielded no change of the lercanidipine AUC, but the ciclosporin AUC was increased by 27%. This combination should therefore be given with caution with an interval of at least 3 hours.
Special excipients: Polyoxyl 40 hydrogenated castor oil: Sandimmun Neoral contains polyoxyl 40 hydrogenated castor oil, which may cause stomach upsets and diarrhoea.
Ethanol: Sandimmun Neoral contains around 12% vol. ethanol. A 500 mg dose of Sandimmun Neoral contains 500 mg ethanol, equivalent to nearly 15 ml beer or 5 ml 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 patients is a child.
For additional precautions see prescribing information for full details.

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.
See prescribing information for full details.

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, the multidrug efflux transporter P-glycoprotein and organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporters. Medicinal products 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 medication. In nontransplant patients the relationship between blood level and clinical effects is less well established. If medicinal products 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.
Drugs that decrease ciclosporin levels: All inducers of CYP3A4 and/or P-glycoprotein are expected to decrease ciclosporin levels. Examples of drugs that decrease ciclosporin levels are: Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, intravenous sulfadimidine, probucol, orlistat, hypericum perforatum (St. John’s wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan. Products containing Hypericum perforatum (St John´s Wort) must not be used concomitantly with This product due to the risk of decreased blood levels of ciclosporin and thereby reduced effect. Rifampicin induces ciclosporin intestinal and liver metabolism. Ciclosporin doses may need to be increased 3- to 5-fold during co-administration. Octreotide decreases oral absorption of ciclosporin and a 50% increase in the ciclosporin dose or a switch to intravenous administration could be necessary.
Drugs that increase ciclosporin levels: All inhibitors of CYP3A4 and/or P-glycoprotein may lead to increased levels of cyclosporine. Macrolide antibiotics: Erythromycin can increase ciclosporin exposure 4- to 7-fold, sometimes resulting in nephrotoxicity. Clarithromycin has been reported to double the exposure of ciclosporin. Azitromycin increases ciclosporin levels by around 20%. Azole antibiotics: Ketoconazole, fluconazole, itraconazole and voriconazole could more than double ciclosporin exposure. Verapamil increases ciclosporin blood concentrations 2- to 3-fold. Co-administration with telaprevir resulted in approximately 4.64-fold increase in ciclosporin dose normalised exposure (AUC). Amiodarone substantially increases the plasma ciclosporin concentration concurrently with an increase in serum creatinine. This interaction can occur for a long time after withdrawal of amiodarone, due to its very long half-life (about 50 days). Danazol has been reported to increase ciclosporin blood concentrations by approximately 50%. Diltiazem (at doses of 90 mg/day) can increase ciclosporin plasma concentrations by up to 50%. Imatinib could increase ciclosporin exposure and Cmax by around 20%.
Food interactions: The concomitant intake of grapefruit and grapefruit juice has been reported to increase the bioavailability of ciclosporin.
Combinations with increased risk for nephrotoxicity: Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); fibric acid derivatives (e.g. bezafibrate, fenofibrate); NSAIDs (including diclofenac, naproxen, sulindac); melphalan histamine H2-receptor antagonists (e.g. cimetidine, ranitidine); methotrexate. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered. Concomitant use of ciclosporin and tacrolimus should be avoided due to the risk for nephrotoxicity and pharmacokinetic interaction via CYP3A4 and/or P-gp.
Impact of DAA therapy: The pharmacokinetics of ciclosporin may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of ciclosporin is warranted to ensure continued efficacy.
Effects of ciclosporin on other drugs: Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein (P-gp) and organic anion transporter proteins (OATP). Co-administration of drugs that are substrates of CYP3A4, P-gp and OATP with ciclosporin may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter. Some examples are listed below: Ciclosporin may reduce the clearance of digoxin, colchicine, HMG-CoA reductase inhibitors (statins) and etoposide. If any of these drugs are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the medicinal products, followed by reduction of its dosage or its withdrawal. When concurrently administered with ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins should be avoided according to their label recommendations. Exposure changes of commonly used statins with ciclosporin are summarised in prescribing information. 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.
See prescribing information for full details.
Paediatric population: Interaction studies have only been performed in adults.       

Pregnancy: Experience 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 This product should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus. The ethanol content of the This product formulations should also be taken into account in pregnant women.
Lactation: Ciclosporin passes into breast milk. The ethanol content of the formulations should also be taken into account in women who are breast-feeding. Mothers receiving treatment with This product should not breast-feed because of the potential of This product to cause serious adverse drug reactions in breast-fed newborns/infants. A decision should be made whether to abstain from breast-feeding or to abstain from using the medicinal drug, taking into account the importance of the medicinal product to the mother.

The oral LD50 of ciclosporin is 2,329 mg/kg in mice, 1,480 mg/kg in rats and > 1,000 mg/kg in rabbits. The intravenous LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
Symptoms: Experience with acute overdosage of ciclosporin is limited. Oral doses of ciclosporin of up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and in a few patients moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with ciclosporin in premature neonates.
Treatment: In all cases of overdosage, general supportive measures should be followed and symptomatic treatment applied. Forced emesis and gastric lavage may be of value within the first few hours after oral intake. Ciclosporin is not dialysable to any great extent, nor is it well cleared by charcoal haemoperfusion.