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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 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.
Polyoxyl castor oil in the i.v. formulation and anaphylactoid reactions: Sandimmun concentrate for solution for infusion contains polyoxyl castor oil (see Description), 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 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 (see Adverse Reactions).
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 (see Adverse Reactions).
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 ciclosporin 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. arteriolar hyalinosis, tubular atrophy and interstitial fibrosis) which, in renal transplant patients, must be differentiated from changes due to chronic rejection (see Adverse Reactions). Close monitoring of parameters that assess renal function is required. Abnormal values may necessitate dose reduction (see Dosage & Administration and Pharmacology under Actions).
Hepatotoxicity and liver injury: Ciclosporin may also cause dose-dependent, reversible increases in serum bilirubin and in liver enzymes (see Adverse Reactions). There have been solicited and spontaneous postmarketing 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 Adverse Reactions). Close monitoring of parameters that assess hepatic function is required. Abnormal values may necessitate dose reduction (see Dosage & Administration and Pharmacology under Actions).
Monitoring ciclosporin levels in transplant patients: When ciclosporin is used in transplant patients, routine monitoring of ciclosporin blood levels is an important safety measure (see Dosage & Administration). For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent drug) is preferred; a HPLC method, which also measures the parent drug, can be used as well. If plasma or serum is used, a standard separation protocol (time and temperature) should be followed. For the initial monitoring of liver transplant patients, either the specific monoclonal antibody should be used, or parallel measurements using both the specific monoclonal antibody and the nonspecific monoclonal antibody should be performed, to ensure a dosage that provides adequate immunosuppression.
It must be remembered that the ciclosporin concentration in blood, plasma, or serum is only one of many factors contributing to the clinical status of the patient. Results should therefore serve only as a guide to dosage in relationship to other clinical and laboratory parameters (see Dosage & Administration).
Hypertension: Regular monitoring of blood pressure is required during ciclosporin therapy; if hypertension develops, appropriate antihypertensive treatment must be instituted (see Adverse Reactions). Preference should be given to an antihypertensive agent that does not interfere with the pharmacokinetics of ciclosporin, e.g. isradipine (see Interactions).
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 (see Adverse Reactions).
Hyperkalemia: Ciclosporin enhances the risk of hyperkalemia, especially in patients with renal dysfunction (see Adverse Reactions). Caution is also required when ciclosporin is co-administered with potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) and potassium containing drugs as well as in patients on a potassium rich diet (see Interactions). 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 (see Adverse Reactions). 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.
Hyperuricemia: Caution is required in treating patients with hyperuricemia (see Adverse Reactions).
Live-attenuated vaccines: During treatment with ciclosporin, vaccination may be less effective; the use of live-attenuated vaccines should be avoided (see Interactions).
Interactions: Caution should be observed while co-administering lercanidipine with ciclosporin (see Interactions).
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 Interactions).
Special Excipients: Ethanol: The ethanol content (see Description) 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 Neoral or Sandimmun concentrate for solution for infusion is being given to a child.
Driving and using machines: Sandimmun Neoral may cause neurological and visual disturbances (see Adverse Reactions). 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.
Additional precautions in non-transplant 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.
Additional precautions in endogenous uveitis: Since Sandimmun Neoral can impair renal function, it is necessary to assess renal function frequently, and if serum creatinine remains increased to more than 30% above baseline at more than one measurement, to reduce the dosage of Sandimmun Neoral by 25 to 50%. If the increase from baseline exceeds 50%, further reduction should be considered. These recommendations apply even if the patient's values still lie within the laboratory's normal range.
Sandimmun Neoral should be administered with caution in patients with neurological Behcet's syndrome. The neurological status of patients with neurological Behcet's syndrome should be carefully monitored.
There is only limited experience with the use of Sandimmun Neoral in children with endogenous uveitis.
Additional precautions in 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 more than 30% above baseline at more than one measurement, to reduce the dosage of Sandimmun Neoral by 25 to 50%. If the increase from baseline exceeds 50%, further reduction should be considered. Patients with abnormal baseline renal function should initially be treated with 2.5 mg/kg per 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. Therefore, renal biopsy should be considered for patients with steroid-dependent minimal-change nephropathy, in whom Sandimmun Neoral therapy has been maintained for more than 1 year.
In patients with nephrotic syndrome treated with immunosuppressants (including ciclosporin), the occurrence of malignancies (including Hodgkin's lymphoma) has occasionally been reported.
Additional precautions in rheumatoid arthritis: Since Sandimmun Neoral can impair renal function, a reliable baseline level of serum creatinine should be established by at least two measurements prior to treatment, and serum creatinine should be monitored at 2-weekly intervals for the first 3 months of therapy and thereafter once a month. After 6 months of therapy, serum creatinine needs to be measured every 4 to 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 non-steroidal anti-inflammatory drug is initiated or its dosage increased (see Interactions).
If the serum creatinine remains increased to more than 30% above baseline at more than one measurement, the dosage of Sandimmun Neoral should be reduced. If the serum creatinine increases by more than 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 one month, Sandimmun Neoral treatment should be discontinued.
Discontinuation of the drug may also become necessary if hypertension developing during Sandimmun Neoral therapy cannot be controlled by appropriate antihypertensive therapy (see Interactions).
As with other long-term immunosuppressive treatments (including ciclosporin), 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 (see Interactions).
Additional precautions in psoriasis: Since Sandimmun Neoral can impair renal function, a reliable baseline level of serum creatinine should be established by at least two 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 more than 30% above baseline at more than one measurement, the dosage of Sandimmun Neoral must be reduced by 25 to 50%. If the increase from baseline exceeds 50%, further reduction should be considered. These recommendations apply even if the patient's creatinine values still lie within the laboratory's normal range. If dose reduction is not successful in reducing creatinine levels within one 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 (see Interactions).
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 pre-malignant should be biopsied before Sandimmun Neoral treatment is started. Patients with malignant or pre-malignant 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 ciclosporin, 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.
Use in the Elderly: In elderly patients, renal function should be monitored with particular care.
