Sandimmun. Sandimmun Neoral 50 mg/1 ml/100 mg/25 mg Capsules

Transplantation indications: Prophylaxis of graft rejection following transplantation of kidney, liver, pancreas, heart, combined heart-lung, lung and bone marrow allogenic transplantation; and for the prevention of graft-versus-host (GVHD) disease following bone marrow transplantation. It may also be used in the treatment of transplant rejection in patients previously receiving other immunosuppressive agents. SANDIMMUN has also been used, with less effect, in the treatment of established graft-versus-host disease. SANDIMMUN concentrate for solution for infusion/SANDIMMUN NEORAL may be used alone or with corticosteroids.

Psoriasis: Treatment of patients with severe psoriasis, in whom conventional therapy is ineffective or inappropriate and the risks of treatment are justified.

Rheumatoid arthritis: Treatment of severe, active rheumatoid arthritis in patients in whom classical slow-acting anti-rheumatic agents are inappropriate or ineffective.

Atopic dermatitis: Treatment of severe atopic dermatitis where conventional therapy has proved ineffective or is inappropriate.

Dosage The daily doses of SANDIMMUN NEORAL should always be given in 2 divided doses. Because of considerable inter- and intra-individual variations in absorption and elimination and the possibility of pharmacokinetic interactions, doses should be titrated individually according to clinical response and tolerability. In transplant patients, routine monitoring of ciclosporin trough blood levels is required to avoid adverse effects due to high levels and to prevent organ rejection due to low levels (see section 4.5). In patients treated for non-transplant indications, monitoring of ciclosporin blood levels is of limited value except in the case of unexpected treatment failure or relapse, where it may be appropriate to establish the possibility of very low levels caused by non-compliance, impaired gastrointestinal absorption, or pharmacokinetic interactions (see section 4.5).

General target population Transplantation Solid organ transplantation Treatment with SANDIMMUN NEORAL 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 before being gradually reduced in accordance with blood levels until a maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached. When SANDIMMUN NEORAL 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. If the SANDIMMUN concentrate for solution for infusion is used, the recommended dose is approximately one-third of the appropriate SANDIMMUN NEORAL dose, and it is recommended that patients be put on oral therapy as soon as possible.

Treatment with SANDIMMUN concentrate for solution for infusion should be initiated within 12 hours before surgery at a dose of 3 to 5 mg/kg. This dose should be maintained as the daily dose for 1 to 2 weeks post-operatively before being gradually reduced in accordance with blood levels until a maintenance dose of about 0.7 to 2 mg/kg given in 2 divided doses is reached.

Bone marrow transplantation The initial dose should be given on the day before transplantation. In most cases, SANDIMMUN intravenous (i.v.) infusion is preferred for this purpose; the recommended i.v. dose is 3 to 5 mg/kg per 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 SANDIMMUN NEORAL at a daily dose 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 SANDIMMUN NEORAL 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 SANDIMMUN NEORAL, or the use of i.v. therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease absorption.

In some patients, GVHD occurs after discontinuation of ciclosporin treatment, but usually responds favorably 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 ciclosporin should be used to treat mild, chronic GVHD.

Non-transplant indications: When using SANDIMMUN NEORAL in any of the established non-transplant indications, the following general rules should be adhered to: - Before initiation of treatment a reliable baseline level of serum creatinine should be established by at least two measurements, and renal function must be assessed regularly throughout therapy to allow dosage adjustment. - The only accepted route of administration is by mouth (the CONCENTRATE FOR SOLUTION FOR INFUSION must not be used), and the daily dose should be given in two divided doses. - 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 with SANDIMMUN NEORAL should be discontinued.

Psoriasis: For inducing remission, the recommended dose is 2.5 mg/kg/day given in two divided oral doses. If there is no improvement after 1 month, the daily dose may be gradually increased but should not exceed 5 mg/kg/day. 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 safety guidelines given below (see section 4.4). An initial dose of 5 mg/kg/day is justified in patients whose condition requires rapid improvement. For maintenance treatment, the dosage should be titrated individually to the lowest effective level. Dose adjustments should be made in increments of 0.5 to 1 mg/kg body mass.

Rheumatoid arthritis: For the first 6 weeks of treatment, the recommended dose is 2.5 mg/kg per day, given orally in two divided doses. If the clinical effect is considered insufficient, the daily dose may then be increased gradually as tolerability permits. The maximum dosage is 5 mg/kg/day, however there is limited experience with dosages above 4 mg/kg/day. If, after 3 months of treatment at the maximum permitted or tolerable dose the response is considered inadequate, treatment should be discontinued. For maintenance treatment the dose has to be titrated individually according to tolerability. If a patient is on an effective maximum tolerable dose with no further improvements expected, and has been stable for at least 3 months, the dose of SANDIMMUN NEORAL should be decreased at 0.5 mg/kg per day increments monthly or bi-monthly to the lowest effective dose. If there is essentially no clinical response by 6 months, and the maximal tolerable dose has been administered for 3 months, SANDIMMUN NEORAL should be discontinued. After 3 months of SANDIMMUN NEORAL therapy without response, blood level monitoring of ciclosporin may be of value to evaluate patient compliance and/or medicine absorption. SANDIMMUN NEORAL may be given in combination with low-dose corticosteroids and/or non-steroidal anti-inflammatory medicines. SANDIMMUN NEORAL can also be combined with low-dose weekly methotrexate in patients who have insufficient response to methotrexate alone, by using initially 2.5 mg/kg SANDIMMUN NEORAL in 2 divided doses per day, with the option to increase the dose as tolerability permits.

Atopic dermatitis: Due to the variability of this condition, treatment must be individualised. The recommended dose range is 2.5 to 5 mg/kg per day given in two divided oral doses. If a starting dose of 2.5 mg/kg per day does not achieve a satisfactory response within 2 weeks of therapy, 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 per day. Once satisfactory response is achieved, the dose should be reduced gradually and, if possible, SANDIMMUN NEORAL should be discontinued. Subsequent relapse may be managed with a further course of SANDIMMUN NEORAL. Since there is no experience with long-term treatment, one cure should not exceed 8 weeks.

All indications: Known hypersensitivity to ciclosporin. When using SANDIMMUN concentrate for solution for infusion: hypersensitivity to Cremophoru00ae EL (polyoxyl castor oil). (see section 4.4) For non-transplant indications: Abnormal renal function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy.

All indications Medical supervision SANDIMMUN NEORAL and 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 medicine should be managed in facilities with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should receive complete information for the follow-up of the patient.

Polyoxyl castor oil in the i.v. formulation and anaphylactoid reactions SANDIMMUN concentrate for solution for infusion contains polyoxyl castor oil, which following i.v. administration has been reported to cause anaphylactoid reactions. These reactions can consist of flushing of the 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 polyoxyl castor oil (e.g. a preparation containing Cremophoru00ae 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. 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.

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. 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 NEORAL should be warned to avoid excess ultraviolet light exposure.

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.

Acute and chronic nephrotoxicity A frequent and potentially serious complication, an increase in serum creatinine and urea, may occur during the first few weeks of 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. Close monitoring of parameters that assess renal function is required. Abnormal values may necessitate dose reduction. (see sections 4.2 and 4.8).

Hepatotoxicity and liver injury Ciclosporin may also cause dose-dependent, reversible increases in serum bilirubin and, 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 co-medications 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 hepatic function is required. Abnormal values may necessitate dose reduction (see sections 4.2 and 5.2).

Elderly population (age 65 years and above) In elderly patients, renal function should be monitored with particular care.

Monitoring ciclosporin levels in transplant patients When SANDIMMUN is used in transplant patients, routine monitoring of ciclosporin blood levels is an important safety measure. For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent compound) is preferred; a 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 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.

Hypertension Regular monitoring of blood pressure is required during ciclosporin 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 (see section 4.5).

Blood lipids increased Since ciclosporin 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.

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 medicines (e.g., potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) and 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 symptoms/signs. If considered necessary, magnesium supplementation should be given.

Hyperuricaemia Caution is required in 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 (see section 4.5).

Caution should be observed while co-administering with drugs that substantially increase or decrease ciclosporin plasma concentrations, through inhibition or induction of CYP3A4 and/or Pglycoprotein. (see section 4.5). Renal toxicity should be monitored when initiating ciclosporin use together with active substances that increase ciclosporin levels or with substances that exhibit nephrotoxic synergy (see section 4.5). The clinical condition of the patient should be monitored closely. Monitoring of ciclosporin blood levels and adjustment of the ciclosporin dose may be required. Caution should be observed while co-administering ciclosporin with lercanidipine. Ciclosporin may increase blood levels of concomitant medications that are substrates for the multidrug efflux transporter P-glycoprotein or the organic anion transporter proteins (OATP) such as aliskiren, dabigatran or bosentan. Co-administration of ciclosporin with aliskiren is not recommended. Co-administration of ciclosporin together with dabigatran or bosentan should be avoided. These recommendations are based upon the potential clinical impact of these interactions (see section 4.5).

Pregnancy Animal studies have shown reproductive toxicity in rats and rabbits. There are no adequate or well-controlled clinical studies in pregnant women using ciclosporin. There is a moderate amount of data on the use of ciclosporin in pregnant patients from post-marketing experience, including published literature. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin-containing regimens, are at risk of premature delivery (<37 weeks). The data have not demonstrated a higher incidence of miscarriages, major birth defects, or maternal events as compared to the rates seen in the general population. Published data from National Transplantation Pregnancy Registry (NTPR), described pregnancy outcomes in female kidney (482), liver (97), and heart (43) transplant recipients receiving ciclosporin. The data indicated successful pregnancies with a live birth rate of 76% and 76.9%, and 64% in kidney, liver, and heart transplant recipients, respectively. Premature delivery (<37 weeks) was reported in 52%, 35%, and 35% of kidney, liver, and heart transplant recipients, respectively. The rates of miscarriages and major birth defects were reported to be comparable to the rates observed in the general population. No direct effect of ciclosporin on maternal hypertension, pre-eclampsia, infections, or diabetes can be established given the limitations inherent to registries and post-marketing safety reporting. 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. SANDIMMUN NEORAL should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. The ethanol content of the SANDIMMUN NEORAL formulations should also be taken into account in pregnant women (see section 4.4).

Breast-feeding Ciclosporin passes into breast milk. Mothers receiving treatment with SANDIMMUN should not breast-feed because of the potential of SANDIMMUN 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 product, taking into account the benefit of breast-feeding for the newborn/infant and the importance of the medicinal product to the mother. The milk to maternal blood concentration ratio of ciclosporin was in the range of 0.17 to 1.4. Based on the infant milk intake, the highest estimated ciclosporin dose ingested by fully breast-fed infant was approximately 2% of maternal weight adjusted dose. The ethanol content of the SANDIMMUN formulations should also be taken into account in women who are breast-feeding (see section 4.4).

Fertility There is limited data on the effect of SANDIMMUN human fertility.

SANDIMMUN NEORAL may cause neurological and visual disturbances (see section 4.8). Caution should be exercised when driving a motor vehicle or operating machines. No studies on the effects of SANDIMMUN NEORAL on the ability to drive and use machines have been performed.

Summary of the safety profile The principal adverse reactions observed in clinical trials and associated with the administration of ciclosporin include renal dysfunction, tremor, 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. Anaphylactoid reactions have been observed following intravenous administration (see section 4.4).

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 leukopathy (PML). Serious and/or fatal outcomes have been reported.

Neoplasms benign, malignant and unspecified (including cysts and polyps) Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin containing regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and duration of therapy (see section 4.4). Some malignancies may be fatal.

Tabulated summary of adverse drug reactions from clinical trials Adverse drug reactions from clinical trials (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (u22651/10); common (u22651/100, <1/10); uncommon (u22651/1,000, <1/100); rare (u22651/10,000, <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1: Adverse drug reactions from clinical trials Blood and lymphatic system disorders Common Leucopenia Uncommon Thrombocytopenia, anaemia Rare Haemolytic uraemic syndrome, microangiopathic haemolytic anaemia Not known* Thrombotic microangiopathy, thrombotic thrombocytopenic purpura Metabolism and nutrition disorders Very common Hyperlipidaemia Common Hyperglycaemia, anorexia, hyperuricaemia, hyperkalaemia, hypomagnesaemia Nervous system disorders Very common Tremor, headache Common Convulsions, paraesthesia Uncommon Encephalopathy including Posterior Reversible Encephalopathy Syndrome (PRES), signs and symptoms such as convulsions, confusion, disorientation, decreased responsiveness, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis and cerebellar ataxia Rare Motor polyneuropathy Very rare Optic disc oedema, including papilloedema, with possible visual impairment secondary to benign intracranial hypertension Not known* Migraine Vascular disorders Very common Hypertension Common Flushing Gastrointestinal disorders Common Nausea, vomiting, abdominal discomfort/pain, diarrhoea, gingival hyperplasia, peptic ulcer Rare Pancreatitis Hepatobiliary disorders Common Hepatic function abnormal (see section 4.4) Not known* Hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure with some fatal outcome (see section 4.4) Skin and subcutaneous tissue disorders Very common Hirsutism Common Acne, hypertrichosis Uncommon Allergic rashes Musculoskeletal and connective tissue disorders Common Myalgia, muscle cramps Rare Muscle weakness, myopathy Not known* Pain of lower extremities Renal and urinary disorders Very common Renal dysfunction (see section 4.4) Reproductive system and breast disorders Rare Menstrual disturbances, gynaecomastia General disorders and administration site conditions Common Pyrexia, fatigue Uncommon Oedema, weight increase * Adverse events reported from post marketing experience where the ADR frequency is not known due to the lack of a real denominator.

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 comorbidities, 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 (see section 4.4).

Acute and chronic nephrotoxicity Patients receiving calcineurin inhibitor (CNI) therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of acute or chronic nephrotoxicity. There have been reports from clinical trials and from the post-marketing setting associated with the use of SANDIMMUN. Cases of acute nephrotoxicity reported disorders of ion homeostasis, such as hyperkalaemia, hypomagnesaemia, and hyperuricaemia. Cases reporting chronic morphological changes included arteriolar hyalinosis, tubular atrophy and interstitial fibrosis (see section 4.4).

Pain of lower extremities Isolated cases of pain of lower extremities have been reported in association with ciclosporin. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS).

Paediatric population Clinical studies have included children from 1 year of age using standard ciclosporin dosage with a comparable safety profile to adults.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Little experience is available with acute overdosage. Signs of nephrotoxicity might occur. Oral doses 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 intoxications have been reported following accidental parenteral overdosage in premature neonates. Treatment: Symptomatic treatment and general supportive measures should be followed in all cases of overdosage. Forced emesis and gastric lavage could be of value within the first few hours after intake of the oral dosage forms. SANDIMMUN concentrate for solution for infusion/SANDIMMUN NEORAL is not dialysable to any great extent, nor is it effectively cleared with charcoal haemoperfusion.