Sandimmun Neoral

Each capsule and oral soln also contain dL-α-tocopherol, anhydrous ethanol, propylene glycol, corn oil mono-di-triglycerides and macrogolglycerol hydroxystearate/polyoxyl 40 hydrogenated castor oil as excipients. The capsule shell contains black iron oxide (E172) (25- and 100-mg capsules), titanium dioxide (E171), glycerol 85%, propylene glycol and gelatine.
Imprint: Carminic acid (E120).

Pharmacotherapeutic Group: Selective immunosuppressive agent. ATC Code: L04AA01.
Pharmacology: Pharmacodynamics: Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide consisting of 11 amino acids. It is a potent immunosuppressive agent which, in animals, prolongs survival of allogeneic transplants of skin, heart, kidney, pancreas, bone marrow, small intestine or lung. Studies suggest that ciclosporin inhibits the development of cell-mediated reactions, including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-versus-host disease (GVHD) and also T-cell-dependent antibody production. At the cellular level, it inhibits production and release of lymphokines including interleukin 2 (T-cell growth factor, TCGF). Ciclosporin appears to block the resting lymphocytes in the G₀ or G₁ phase of the cell cycle and inhibits the antigen-triggered release of lymphokines by activated T-cells.
All available evidence suggest that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not depress hemopoiesis and has no effect on the function of phagocytic cells. Patients treated with Sandimmun are less prone to infection than those receiving other immunosuppressive therapy.
Successful solid organ and bone marrow transplantations have been performed in man using Sandimmun to prevent and treat rejection and GVHD. Beneficial effects of Sandimmun therapy have also been shown in a variety of conditions that are known, or may be considered, to be of autoimmune origin.
Pharmacokinetics: Sandimmun Neoral is a new pharmaceutical form of the active ingredient ciclosporin based on the microemulsion principle, which reduces the variability of pharmacokinetic parameters and provides dose linearity of ciclosporin exposure with a more consistent absorption profile and less influence from concomitant food intake. The formulation is a microemulsion preconcentrate, which in pharmacokinetic and clinical studies has demonstrated that the correlation between trough concentration and exposure to ciclosporin is much stronger when ciclosporin is given as Sandimmun Neoral than when it is given as Sandimmun. The formation of the microemulsion itself takes place in the presence of water, either in the form of a beverage or in the form of gastric fluid.
When Sandimmun Neoral is given, it provides improved dose linearity in ciclosporin exposure (AUC_B), a more consistent absorption profile and less influence from concomitant food intake and from diurnal rhythm than does Sandimmun. These properties combined yield a lower within-patient variability in pharmacokinetics of ciclosporin and a stronger correlation between trough concentration and total exposure (AUC_B). As a consequence of these additional advantages, the time schedule of Sandimmun Neoral administration need no longer take that of meals into account. In addition, Sandimmun Neoral produces a more uniform exposure to ciclosporin throughout the day and from day to day on a maintenance regimen.
Sandimmun Neoral soft gelatine capsules and Sandimmun Neoral oral solution are bioequivalent. The data available indicate that following a 1:1 conversion from Sandimmun to Sandimmun Neoral, trough concentrations in whole blood are comparable, thereby remaining in the desired therapeutic trough level range. Compared to Sandimmun (with which peak blood concentrations are achieved within 1-6 hrs), Sandimmun Neoral is more quickly absorbed (resulting in a 1 hr earlier mean t_max and a 59% higher mean C_max) and exhibits, on average, a 29% higher bioavailability.
Ciclosporin is distributed largely outside the blood volume. In the blood, 33-47% is present in plasma, 4-9% in lymphocytes, 5-12% in granulocytes and 41-58% in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.
Ciclosporin is extensively biotransformed to approximately 15 metabolites. There is no single major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is excreted in the urine as unchanged drug.
There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the assay applied and on the target population. The terminal half-life ranged from 6.3 hrs in healthy volunteers to 20.4 hrs in patients with severe liver disease.
Toxicology: Preclinical Safety Data: Ciclosporin gave no evidence of mutagenic or teratogenic effects in appropriate test systems. Only at dose levels toxic to dams were adverse effects seen in reproduction studies in rats. At toxic doses (rats at 30 mg/kg and rabbits at 100 mg/kg/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 the well-tolerated dose range (rats up to 17 mg/kg and rabbits up to 30 mg/kg/day orally), ciclosporin proved to be without any embryolethal or teratogenic effects.
Carcinogenicity: 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/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/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 of 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 (ie, 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.

Transplantation: Solid Organ Transplantation: Prevention of graft rejection following kidney, liver, heart, combined heart-lung, lung or pancreas allogeneic transplantations. Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.
Bone Marrow Transplantation: Prevention of graft rejection following bone marrow transplantation. Prevention or treatment of graft-versus-host disease (GVHD).
Nontransplantation: Endogenous Uveitis: Active sight-threatening intermediate or posterior uveitis of noninfectious etiology where conventional therapy fails or causes unacceptable side effects. Behcet uveitis with repeated inflammatory attacks involving the retina in patients 7-70 years with normal kidney function.
Nephrotic Syndrome: Steroid-dependent and -resistant nephrotic syndrome in adults and children, due to glomerular diseases eg, minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis.
Sandimmun Neoral can be used to induce remissions and to maintain them. It can also be used to maintain steroid-induced remission, allowing withdrawal of steroids.
Rheumatoid Arthritis: Treatment of severe, active rheumatoid arthritis in whom classical slow-acting antirheumatic agents are inappropriate or ineffective.
Psoriasis: Treatment of severe psoriasis in patients in whom conventional therapy is ineffective or inappropriate.

Dosage: The daily doses of Sandimmun Neoral should always be given in 2 divided doses.
Transplantation: Solid Organ Transplantation: Treatment with Sandimmun Neoral should be initiated within 12 hrs before surgery at a dose of 10-15 mg/kg given in 2 divided doses. This dose should be maintained as the daily dose for 1-2 weeks postoperatively before being gradually reduced in accordance with blood levels until a maintenance dose of about 2-6 mg/kg given in 2 divided doses is reached.
When Sandimmun Neoral is given with other immunosuppressants (eg, with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (eg, 3-6 mg/kg given in 2 divided doses for the initial treatment) may be used.
If the Sandimmun concentrate for IV infusion is used, the recommended dose is approximately ¹/₃ of the appropriate Sandimmun Neoral dose. It is also 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. In most cases, IV infusion is preferred for this purpose; the recommended dose is 3-5 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 Sandimmun Neoral 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 0 by 1 year after transplantation. If Sandimmun Neoral is used to initiate therapy, the recommended daily dose is 12.5-25 mg/kg given in 2 divided doses, starting on the day before transplantation.
Higher doses of Sandimmun Neoral, or the use of IV therapy, may be necessary in the presence of GI disturbances which might decrease drug absorption.
In some patients, GVHD occurs after discontinuation of Sandimmun treatment, but usually responds favorably to reintroduction of therapy. Low doses of Sandimmun Neoral should be used to treat mild, chronic GVHD.
Nontransplantation: 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 is 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 prednisone 0.5-0.6 mg/kg or an equivalent may be added if Sandimmun Neoral alone does not control the situation sufficiently.
For maintenance treatment, the dose should be slowly reduced to the lowest effective level which, during the remission phases, should not exceed 5 mg/kg/day.
Nephrotic Syndrome: For inducing remission, the recommended daily dose, given in 2 divided oral doses, is 5 mg/kg for adults and 6 mg/kg for children, if, except for proteinuria, renal function is normal. In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.
The combination of Sandimmun Neoral with low doses of oral corticosteroids is recommended if the effect of Sandimmun Neoral alone is not satisfactory, especially in steroid-resistant patients.
If no improvement has been observed after 3 months' treatment, Sandimmun Neoral 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 is 2.5 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 Sandimmun Neoral therapy may be required.
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/day increments monthly or bimonthly to the lowest effective dose.
If there is essentially no clinical response by 6 months, 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 compliance and/or drug absorption.)
Dose adjustment based on creatinine values: If the serum creatinine remains increased by >30% above creatinine concentration recorded before starting ciclosporin at more than one measurement, the dosage of Sandimmun Neoral should be reduced. If the serum creatinine increases by >50%, a dosage reduction by 50% is mandatory. These recommendations apply even if the patient's values still lie within the laboratory normal range. If the dose reduction is not successful in reducing levels within 1 month, Sandimmun Neoral treatment should be discontinued.
Sandimmun Neoral can be given in combination with low-dose corticosteroids and/or nonsteroidal anti-inflammatory drugs. Sandimmun Neoral can also be combined with low-dose weekly methotrexate in patients who have insufficient response to methotrexate alone, by using initially Sandimmun Neoral 2.5 mg/kg in 2 divided doses/day, with the option to increase the dose as tolerability permits.
Psoriasis: Due to the variability of this condition, treatment must be individualized. 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, Sandimmun Neoral may be discontinued and subsequent relapse managed with reintroduction of Sandimmun Neoral 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.
Conversion from Sandimmun to Sandimmun Neoral: The available data indicate that after a 1:1 conversion from Sandimmun to Sandimmun Neoral, the trough concentrations of ciclosporin in whole blood are comparable. In many patients, however, higher peak concentrations (C_max) and an increased exposure to the drug (AUC) may occur. In a small percentage of patients, these changes are more marked and may be of clinical significance. Their magnitude depends largely on the individual variance in the absorption of ciclosporin from the originally used Sandimmun, which is known to be highly variable in its bioavailability. Patients with variable trough levels or very high doses of Sandimmun may be poor or inconsistent absorbers of ciclosporin (eg, patients with cystic fibrosis, liver transplant patients with cholestasis or poor bile secretion, children or some kidney transplant recipients) who may, on conversion to Sandimmun Neoral, become good absorbers. Therefore, in this population, the increase in bioavailability of ciclosporin following a 1:1 conversion from Sandimmun to Sandimmun Neoral might be greater than usually observed. The dose of Sandimmun Neoral should therefore be down titrated individually according to their target trough level range.
It needs to be emphasized that the absorption of ciclosporin from Sandimmun Neoral is less variable and the correlation between ciclosporin trough concentrations and exposure (in terms of AUC) is much stronger than with Sandimmun. This makes ciclosporin blood trough concentrations a more robust and reliable parameter for therapeutic drug monitoring.
Since the conversion from Sandimmun to Sandimmun Neoral may result in an increased drug exposure, the following rules must be observed:
Transplant Patients: Sandimmun Neoral should be started with the same daily dose as was previously used with Sandimmun. Ciclosporin trough concentrations in whole blood should be monitored initially within 4-7 days after the conversion to Sandimmun Neoral. In addition, clinical safety parameters eg, serum creatinine and blood pressure are to be monitored during the first 2 months after the conversion. If the ciclosporin trough blood levels are beyond the therapeutic range and/or worsening of the clinical safety parameters occur, the dosage must be adjusted accordingly.
Patients Treated for Nontransplant Indications: Sandimmun Neoral should be started with the same daily dose as was used with Sandimmun. Two, 4 and 8 weeks after the conversion, serum creatinine levels and blood pressure should be monitored. If serum creatinine levels or blood pressure significantly exceed the preconversion levels or if serum creatinine levels increase to >30% above creatinine levels prior to Sandimmun therapy at more than one measurement, the dose should be reduced (see also Precautions). In case of unexpected toxicity or inefficacy of ciclosporin, blood trough levels should also be monitored.
Administration: The dose ranges given for oral administration and IV administration are intended to serve as guidelines only. The recommended dose of Sandimmun concentrate for IV infusion is approximately ¹/₃ of the appropriate oral dose. Routine monitoring of ciclosporin blood levels is required; this can be carried out by means of a RIA method based on monoclonal antibodies. The results obtained will serve as a guide for determining the actual dosage required to achieve the desired target concentrations in individual patients.
Oral Administration: The daily doses of Sandimmun Neoral should always be given in 2 divided doses.
Capsules should be swallowed whole.
The oral solution should be diluted with, preferably, orange or apple juice; however, other drinks eg, softdrinks can be used according to individual taste. Immediately before taking the oral solution, it should be stirred well. Owing to its possible interference with the P-450-dependent enzyme system, 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 (see Cautions for Usage: Instructions for Use/Handling).

The oral LD₅₀ of ciclosporin is 2329 mg/kg in mice, 1480 mg/kg in rats and >1000 mg/kg in rabbits. The IV LD₅₀ is 148 mg/kg in mice, 104 mg/kg in rats and 46 mg/kg in rabbits.
No experience of acute overdosage of Sandimmun Neoral is available. Renal dysfunction which would be expected to resolve following drug withdrawal may occur. If indicated, general supportive measures should follow. Elimination can be achieved only by nonspecific measures including gastric lavage, as ciclosporin is not dialyzable to any great extent nor is it cleared well by charcoal hemoperfusion.

Hypersensitivity to ciclosporin; when using Sandimmun concentrate for IV Infusion: hypersensitivity to polyoxyethylated castor oil.
Rheumatoid arthritis and psoriasis patients with abnormal renal function, uncontrolled hypertension, uncontrolled infection or malignancies.
Psoriasis patients who are treated with Sandimmun Neoral should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy.
Use in lactation: Ciclosporin passes into breast milk. Mothers receiving treatment with Sandimmun Neoral should not breastfeed.

Sandimmun Neoral 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 Sandimmun 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 IV infusion contains polyoxyethylated castor oil, which following IV administration, has been reported to cause anaphylactoid reactions. These reactions can consist of flushing of the face and upper thorax, 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 IV injection or infusion, preparations containing polyoxyethylated castor oil (eg, 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 min 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.
Like other immunosuppresants, 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 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.
Like other immunosuppressants, ciclosporin predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. As this can lead to a fatal outcome, effective pre-emptive and therapeutic strategies should be employed particularly in patients on multiple long-term immunosuppressive therapy.
A frequent and potentially serious complication, an increase in serum creatinine and urea, may occur during the first few weeks of Sandimmun Neoral 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 (eg, interstitial fibrosis) which, in renal transplant patients must be differentiated from changes due to chronic rejection. Sandimmun Neoral may also cause dose-dependent, reversible increases in serum bilirubin and occasionally, in liver enzymes.
Close monitoring of parameters that assess renal and hepatic function is required. Abnormal values may necessitate dose reduction.
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; an HPLC method which also measures the parent drug can be used as well. If plasma or serum are 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 Neoral therapy; if hypertension develops, appropriate antihypertensive treatment must be instituted.
Since, on rare occasions, Sandimmun has been reported to induce a reversible slight increase in blood lipids, it is advisable to perform lipid determinations before treatment and after the first month of therapy. In the event of increased lipids being found, restriction of dietary fat and, if appropriate, a dose reduction, should be considered.
Ciclosporin enhances the risk of hyperkalaemia, especially in patients with renal dysfunction. Caution is also required when ciclosporin is co-administered with potassium-sparing drugs (eg, 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 Interactions). Control of potassium levels in these situations is advisable.
Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peri-transplant period, particularly in the presence of neurological symptom/signs. If considered necessary, magnesium supplementation should be given.
Caution is required in treating patients with hyperuricaemia.
During treatment with ciclosporin, vaccination may be less effective; the use of live attenuated vaccines should be avoided.
Caution should be observed while co-administering lercanidipine with ciclosporin (see Interactions).
Nontransplant Indications: Patients with impaired renal function (except in nephrotic syndrome patients with a permissible degree of renal impairment), uncontrolled hypertension, uncontrolled infections or any kind of malignancy should not receive ciclosporin.
Endogenous Uveitis: Since Sandimmun Neoral can impair renal function, it is necessary to assess renal function frequently and, if serum creatinine remains increased to >30% above baseline at more than one measurement, to reduce the dosage of Sandimmun Neoral by 25-50%. These recommendations apply even if the patient's values still lie within the laboratory's normal range.
There is only limited experience with the use of Sandimmun Neoral in children with endogenous uveitis.
Nephrotic Syndrome: Since Sandimmun Neoral can impair renal function, it is necessary to assess renal function frequently and, if the serum creatinine remains increased to >30% above baseline at more than one measurement, to reduce the dosage of Sandimmun Neoral by 25-50%. Patients with abnormal baseline renal function should initially be treated with 2.5 mg/kg/day and must be monitored very carefully.
In some patients, it may be difficult to detect Sandimmun Neoral-induced renal dysfunction because of changes in renal function related to the nephrotic syndrome itself. This explains why, in rare cases, Sandimmun Neoral-associated structural kidney alterations have been observed without increases in serum creatinine. Renal biopsy should be considered for patients with steroid-dependent minimal change nephropathy in whom Sandimmun Neoral therapy has been maintained for >1 year.
In patients with nephrotic syndrome treated with immunosuppressants (including Sandimmun), the occurrence of malignancies (including Hodgkin's lymphoma) has occasionally been reported.
Rheumatoid Arthritis: Since Sandimmun Neoral can impair renal function, a reliable baseline level of serum creatinine should be established by at least 2 measurements prior to treatment, and serum creatinine should be monitored at 2-weekly intervals during the first 3 months of therapy and thereafter once a month. After 6 months of therapy, serum creatinine needs to be measured every 4-8 weeks depending on the stability of the disease, its co-medication and concomitant diseases. More frequent checks are necessary when the Sandimmun Neoral dose is increased or concomitant treatment with a nonsteroidal anti-inflammatory drug is initiated or its dosage increased.
If the serum creatinine remains increased to >30% above baseline at more than one measurement, the dosage of Sandimmun Neoral should be reduced. If the serum creatinine increases by >50%, a dosage reduction by 50% is mandatory. These recommendations apply even if the patient's values still lie within the laboratory's normal range. If dose reduction is not successful in reducing levels within 1 month, Sandimmun Neoral treatment should be discontinued.
Discontinuation of Sandimmun may also become necessary if hypertension developing during Sandimmun Neoral therapy cannot be controlled by appropriate antihypertensive therapy.
As with other long-term immunosuppressive treatments, an increased risk of lymphoproliferative disorders must be borne in mind. Special caution should be observed if Sandimmun Neoral is used in combination with methotrexate.
Psoriasis: Since Sandimmun Neoral can impair renal function, a reliable baseline level of serum creatinine should be established by at least 2 measurements prior to treatment, and serum creatinine should be monitored at 2-weekly intervals for the first 3 months of therapy. Thereafter, if creatinine remains stable, measurements should be made at monthly intervals. If the serum creatinine increases and remains increased to >30% above baseline at more than one measurement, the dosage of Sandimmun Neoral must be reduced by 25-50%. These recommendations apply even if the patient's values still lie within the laboratory's normal range. If dose reduction is not successful in reducing levels within 1 month, Sandimmun Neoral treatment should be discontinued.
Discontinuation of Sandimmun Neoral therapy is also recommended if hypertension developing during Sandimmun Neoral treatment cannot be controlled with appropriate therapy.
Elderly patients should be treated only in the presence of disabling psoriasis and renal function should be monitored with particular care.
There is only limited experience with the use of Sandimmun Neoral in children with psoriasis.
In psoriatic patients on ciclosporin, as in those on conventional immunosuppressive therapy, development of malignancies (in particular of the skin) has been reported. Skin lesions not typical for psoriasis but suspected to be malignant or premalignant should be biopsied before Sandimmun Neoral treatment is started. Patients with malignant or premalignant alterations of the skin should be treated with Sandimmun Neoral only after appropriate treatment of such lesions and if no other option for successful therapy exists.
In a few psoriatic patients treated with Sandimmun, lymphoproliferative disorders have occurred. These were responsive to prompt drug discontinuation.
Patients on Sandimmun Neoral should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.
Effects on the Ability to Drive or Operate Machinery: No data exists on the effects of Sandimmun Neoral on the ability to drive and use machines.
Use in pregnancy: Ciclosporin is not teratogenic in animals. Experience with Sandimmun in pregnant women, however, is still limited. Data available from organ transplant recipients indicate that, compared with other immunosuppressive therapy, Sandimmun treatment imposes no increased risk of adverse effects on the course and outcome of pregnancy. However, there are no adequate and well-controlled studies in pregnant women, therefore Sandimmun Neoral should be used during pregnancy only if the potential benefit justifies risk to the fetus.

Use in pregnancy: Ciclosporin is not teratogenic in animals. Experience with Sandimmun in pregnant women, however, is still limited. Data available from organ transplant recipients indicate that, compared with other immunosuppressive therapy, Sandimmun treatment imposes no increased risk of adverse effects on the course and outcome of pregnancy. However, there are no adequate and well-controlled studies in pregnant women, therefore Sandimmun Neoral should be used during pregnancy only if the potential benefit justifies risk to the fetus.
Use in lactation: Ciclosporin passes into breast milk. Mothers receiving treatment with Sandimmun Neoral should not breastfeed.

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.
Frequency Estimate: Very Common: ≥10%. Common: ≥1% to <10%. Uncommon: ≥0.1% to <1%. Rare: ≥0.01% to <0.1%. Very Rare: <0.01%.
Renal: Very common: Renal dysfunction (see Precautions).
Cardiovascular: Very common: Hypertension.
Nervous System: Very common: Tremor, headache. Common: Paraesthesia. Uncommon: Signs of encephalopathy eg, convulsions, confusion, disorientation, decreased responsiveness, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia. Rare: Motor polyneuropathy. Very rare: Optic disc oedema including papilloedema, with possible visual impairment secondary to benign intracranial hypertension.
Gastrointestinal Tract and Liver: Common: Anorexia, nausea, vomiting, abdominal pain, diarrhoea, gingival hyperplasia, hepatic dysfunction. Rare: Pancreatitis.
Metabolic: Very common: Hyperlipidaemia. Common: Hyperuricaemia, hyperkalaemia, hypomagnesaemia. Rare: Hyperglycaemia.
Musculoskeletal: Common: Muscle cramps, myalgia. Rare: Muscle weakness, myopathy.
Haemopoietic: Uncommon: Anaemia, thrombocytopenia. Rare: Microangiopathic haemolytic anaemia, haemolytic uraemic syndrome.
Skin and Appendages: Common: Hypertrichosis. Uncommon: Allergic rashes.
Body as a Whole: Common: Fatigue. Uncommon: Oedema, increased weight.
Endocrine: Rare: Menstrual disturbances, gynecomastia.

Food: The concomitant intake of grapefruit juice has been reported to increase the bioavailability of ciclosporin.
Drug Interactions: Of the many drugs reported to interact with ciclosporin, those for which the interactions are adequately substantiated and considered to have clinical implications are listed as follows.
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 cytochrome P-450 enzymes.
Drugs that Decrease Ciclosporin Levels: Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine IV; rifampicin; octreotide; probucol; orlistat; Hypericum perforatum (St. John's wort); ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Drugs that Increase Ciclosporin Levels: Macrolide antibiotics (eg, 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.
Other Relevant Drug Interactions: Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy eg, aminoglycosides (including gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); NSAIDs (including diclofenac, naproxen, sulindac); melpahalan, histamine H₂-receptor antagonists (eg, cimetidine, ranitidine), methotrexate (see Precautions).
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 3-fold and the AUC of ciclosporin was increased 21%. Therefore, caution is recommended when co-administering ciclosporin together with lercanidipine (see Precautions).
The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its high first-pass effect. If NSAIDs with a low first-pass effect (eg, acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.
Ciclosporin may reduce the clearance of digoxin, colchicine, prednisolone and HMG-CoA reductase inhibitors (statins).
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 eg, myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine are 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 postmarketing 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.
Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus and sirolimus.
Caution is required for concomitant use of potassium-sparing drugs (eg, 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 Precautions).
Recommendations: If the concomitant use of drugs known to interact with ciclosporin cannot be avoided, the following basic recommendations should be observed: During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered drug should be reduced or alternative treatment considered.
In graft recipients, there have been isolated reports of considerable but reversible impairment of kidney function (with corresponding increase in serum creatinine) following concomitant administration of fibric acid derivatives (eg, bezafibrate, fenofibrate). Kidney function must therefore be closely monitored in these patients. In the event of significant impairment of kidney function, the co-medication should be withdrawn.
Drugs Known to Reduce or Increase the Bioavailability of Ciclosporin: In transplant patients, frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment are 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 effects 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.
Nonsteroidal anti-inflammatory drugs known to undergo strong first-pass metabolism (eg, diclofenac) should be given at doses lower than those that would be used in patients not receiving ciclosporin.
If digoxin, colchicine or HMG-CoA reductase inhibitors (statins) are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the drugs, followed by reduction of dosage or by withdrawal.

Instructions for Use/Handling: Initial Use of Sandimmun Neoral Solution: Raise the plastic cap. Tear off the sealing ring completely. Remove the black stopper and throw it away. Push the tube unit with the white stopper firmly into the neck of the bottle. Insert the syringe into the white stopper. Draw up prescribed volume of solution. Expel any large bubbles by depressing and withdrawing plunger a few times before removing syringe containing prescribed dose from bottle. The presence of a few tiny bubbles is of no importance and will not affect the dose in any way. Push the medicine out of the syringe into a small glass with some liquid, but no grapefruit juice. The medicine can be mixed just before it is taken. Stir and drink the entire mixture right away. Take the medicine immediately after preparation.
After use, wipe syringe on outside only with a dry tissue and replace in its case. White stopper and tube should remain in bottle. Close bottle with cap provided.

Sandimmun Neoral capsules may be stored at room temperature not exceeding 25°C. Occasional increases in temperature up to 30°C do not affect the quality of the product. Sandimmun Neoral capsules should be left in the blister pack until required for use. When a blister is opened, a characteristic smell is noticeable. This is normal and does not mean that there is anything wrong with the capsule.
Sandimmun Neoral oral solution should be used within 2 months of opening the bottle and be stored between 15° and 30°C, preferably not below 20°C for prolonged periods, as it contains oily components of natural origin which tend to solidify at low temperatures. A jelly-like formation may occur below 20°C, which is however reversible at temperatures up to 30°C. Minor flakes or a slight sediment may still be observed. These phenomena do not affect the efficacy and safety of the product, and the dosing by means of the pipette remains accurate.
Shelf-Life: Sandimmun Neoral Capsule/Oral Solution: 3 years.

Immunosuppressants

L04AD01 - ciclosporin ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.

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