Sandimmun Concentrate for Infusion

/ Novartis

General target population
Solid organ transplantation: 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. When Sandimmun concentrate for solution for infusion is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (e.g. 1 to 2 mg/kg given in 2 divided doses for the initial treatment) may be used. The recommended dose of Sandimmun concentrate for solution for infusion is approximately one third of the appropriate oral dose. It is recommended that patients be put on oral therapy as soon as possible.
Bone marrow transplantation: The initial dose should be given on the day before transplantation. For the initiation of Sandimmun therapy the preferred route of administration is by intravenous infusion. 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. 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. Continuation of ciclosporin treatment via i.v. therapy may be necessary in the presence of oral ciclosporin induced gastrointestinal disturbances which might decrease drug 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.
Special population Renal impairment: Ciclosporin undergoes minimal renal elimination and its pharmacokinetics is not affected by renal impairment. However, due to its nephrotic potential, a careful monitoring of the renal function is recommended.
Hepatic impairment: Ciclosporin is extensively metabolized by the liver. The terminal half-life varied between 6.3 hours in healthy volunteers to 20.4 hours in severe liver patients. Dose reduction may be necessary in patients with severe liver impairment to  maintain blood levels within the recommended target range. Pediatrics Experience with Sandimmun in children is still limited. However, children from 1 year of age have received Sandimmun in standard dosage with no particular problems. In several studies, pediatric patients required and tolerated higher doses of Sandimmun per kg body weight than those used in adults.
Geriatrics (65 years old and above): Experience with Sandimmun in the elderly is limited, but no particular problems have been reported following the use of the drug at the recommended dose. In rheumatoid arthritis clinical trials with oral 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.
For full details see prescribing information.

Solid organ transplantation: Prophylaxis of organ rejection in kidney, liver, heart allogenic 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: Bone marrow transplantation.

Hypersensitivity to ciclosporin or to any of the excipients of Sandimmun concentrate for solution for infusion including polyethoxylated castor oil. Concomitant use of tacrolimus is specifically contraindicated. Concomitant use of rosuvastatin is specifically contraindicated.

All indications
Medical supervision: 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.
Polyethoxylated castor oil in the i.v. formulation and anaphylactoid reactions: 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 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 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. 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 concentrate for solution for infusion 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 Sandimmun therapy. These functional changes are dosedependent and reversible, usually responding to dose reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g. arteriolar hyalinosis, tubular atrophy and 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.
Hepatotoxicity and liver injury: Sandimmun may also cause dose-dependent, reversible increases in serum bilirubin and, occasionally, in liver enzymes. There have been solicited and spontaneous post-marketing 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. Abnormal values may necessitate dose reduction. Geriatrics In elderly patients, renal function should be monitored with particular care. Monitoring ciclosporin levels in transplant patients Routine monitoring of ciclosporin blood levels is an important safety measures. 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 non-specific 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 Sandimmun 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 lipid increased: Since 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.
Hyperkalemia: Ciclosporin enhances the risk of hyperkalemia, especially in patients with renal dysfunction. Caution is also required when ciclosporin is coadministered 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.
Hypomagnesemia: Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peritransplant period, particularly in the presence of neurological symptom/signs. If considered necessary, magnesium supplementation should be given.
Hyperuricemia: Caution is required in treating patients with hyperuricemia.
Live-attenuated vaccines: During treatment with ciclosporin, vaccination may be less effective; the use of liveattenuated vaccines should be avoided.
Interactions: Caution should be observed while co-administering lercanidipine with ciclosporin. Ciclosporin may increase blood levels of concomitant medications that are substrates of Pglycoprotein (Pgp) such as aliskiren.
Special excipients: Ethanol The ethanol content should be taken into account when given to pregnant or breast-feeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients or if Sandimmun is given to a child.

Blood and lymphatic system disorders Common: Leucopenia
Metabolism and nutrition disorders Very common: Anorexia, hyperglycemia
Nervous system disorders Very common: Tremor, headache.  Common: Convulsions, paraesthesia
Vascular disorders Very common: Hypertension. Common: Flushing
Gastrointestinal disorders Very common: Nausea, vomiting, abdominal discomfort, diarrhea, gingival hyperplasia. Common: Peptic ulcer
Hepatobiliary disorders Common: Hepatotoxicity
Skin and subcutaneous tissue disorders Very common: Hirsutism. Common: Acne, rash
Renal and urinary disorders Very common: Renal dysfunction
Reproductive system and breast disorders Rare: Menstrual disturbances
General disorders and administration site conditions Common: Pyrexia, edema.
For full details see prescribing information.

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.
Interactions resulting in concomitant use not being recommended: During treatment with ciclosporin, vaccination may be less effective, the use of liveattenuated vaccines should be avoided.
Interactions to be considered: 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. 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. 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 coadministering ciclosporin together with aliskiren.
Interactions increasing or decreasing ciclosporin levels to be considered: 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. If the concomitant use of drugs known to interact with ciclosporin cannot be avoided, in transplant patients, frequent measurements of ciclosporin levels and, if necessary, ciclosporin dosage adjustment is required, particularly during the introduction or withdrawal of the coadministered drug.
Interactions decreasing ciclosporin levels: Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine i.v., rifampicin, octreotide, probucol, orlistat; hypericum perforatum (St. John’s wort); ticlopidine, sulfinpyrazone, terbinafine, bosentan. Interactions increasing 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, colchicine; nefazodone.
For full details see prescribing information.

Pregnancy: Animal studies have shown reproductive toxicity in rats and rabbits. There is a moderate amount of data on the use of Sandimmun in pregnant patients. 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 is available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal. However there are no adequate data in pregnant women and, therefore, Sandimmun should not be used during pregnancy unless the expected benefit to the mother outweighs the potential risk to the fetus. The ethanol content should also be taken into account in pregnant women.
Breast-feeding: Ciclosporin passes into breast milk. The ethanol content of Sandimmun should also be taken into account. Mothers receiving treatment with Sandimmun should not breast-feed. Because of the potential of Sandimmun to cause serious adverse drug reactions in breastfed 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. Fertility There is limited data on the effect of Sandimmun on human fertility. No impairment in fertility was demonstrated in studies in male and female rats.

The oral LD50 of ciclosporin is 2329 mg/kg in mice, 1480 mg/kg in rats and > 1000 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 overdose 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 overdose with ciclosporin in premature neonates.
Treatment: In all cases of overdose, 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 dialyzable to any great extent, nor is it well cleared by charcoal hemoperfusion.

Storage: Store below 30ºC.