Sandimmun Neoral Special Precautions

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.