Sandimmun/Sandimmun Neoral Special Precautions

Sandimmun: Only physicians with experience of immunosuppressive therapy who are able to perform the necessary investigations (regular full physical examinations, blood pressure checks, monitoring of laboratory safety parameters) should prescribe Sandimmun. Transplant patients receiving Sandimmun should be treated at centres with the requisite laboratory and medical equipment. The physician responsible for maintenance therapy must be given all information necessary for the patient's proper care.
The concentrate for i.v. infusion contains polyoxyethylated castor oil, which has been reported to cause anaphylactoid reactions such as flushing of the face and upper thorax, non-cardiogenic pulmonary oedema with acute respiratory distress, dyspnoea and wheezing, blood pressure changes and tachycardia.
Particular caution is therefore required both in patients who have previously received i.v. injection or infusion of preparations containing polyoxyethylated castor oil (e.g. medications containing Cremophor EL) and in those with an allergic predisposition. All patients receiving Sandimmun i.v. should therefore be kept under constant observation for at least the first 30 minutes of the infusion and at frequent intervals thereafter. Infusion should be discontinued at the first sign of anaphylaxis. Adrenaline (aqueous solution 1:1000) and oxygen should be available at the bedside.
Because of the risk of anaphylaxis, Sandimmun concentrate for i.v. infusion should only be used in cases where oral ingestion is not feasible. In such cases, patients should be switched to oral therapy with Sandimmun Neoral as soon as possible.
It has been possible to prevent anaphylactoid reactions through prophylactic administration of an antihistamine (H₁ and H₂ blocker) prior to i.v. infusion of Sandimmun.
Like other immunosuppressive agents, ciclosporin increases the risk of developing lymphomas and other malignancies, particularly of the skin.
This increased risk seems to be related more to the degree and duration of immunosuppression than to the use of specific medicines.
In addition, a treatment regimen containing several immunosuppressive agents (including ciclosporin) must be used with caution, since it may lead to lymphoproliferative disorders and solid tumours of other organs that may be fatal.
Due to the potential risk of malignant skin changes, patients receiving Sandimmun, in particular those being treated for psoriasis or atopic dermatitis, should be warned against excessive exposure to the sun without adequate protection and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy (see Interactions).
As is the case in patients using other immunosuppressive agents, those using ciclosporin are susceptible to a number 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 BK virus nephropathy (BKVN) or JC-virus-associated progressive multifocal leucoencephalopathy (PML) - have been observed in patients receiving ciclosporin. These conditions are often secondary to high immunosuppression and should be considered in the differential diagnosis of immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. BKVN can cause graft loss. Effective preventive and therapeutic strategies should be employed, particularly in patients on multiple long-term immunosuppressive therapy. A reduction in total immunosuppression should be considered in patients with PVAN or PML, but reduced immunosuppression may also jeopardise the graft.
A frequent and potentially serious complication during the first few weeks of Sandimmun treatment is a rise in serum creatinine and urea levels. These functional changes are dose-dependent and reversible and usually return to normal when the dose is reduced. In some patients, long-term use may lead to structural changes in the kidneys (e.g. interstitial fibrosis), which must be distinguished from signs of chronic rejection in kidney transplant patients.
Sandimmun may also cause a dose-dependent and reversible increase in serum bilirubin and liver enzyme levels (see Adverse Reactions).
Regular monitoring of the appropriate hepatic and renal parameters is required. Dose reduction may be necessary should results be abnormal.
Renal function should be monitored particularly closely in elderly patients.
Ciclosporin blood levels should preferably be monitored by measuring the proportion of parent drug using a specific monoclonal antibody or a HPLC-based analysis method. If plasma or serum is used, a standard separation protocol should be followed, with defined values for time and temperature. 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. The results should therefore only be viewed as a guideline for treatment in the context of a whole range of other clinical and biochemical parameters (see Organ transplantation under Dosage & Administration).
Blood pressure should be checked regularly during Sandimmun therapy. In the event of hypertension, appropriate treatment should be given to lower blood pressure. Preference should be given to an antihypertensive agent that has no pharmacokinetic interactions with ciclosporin (see Interactions).
Since there have been reports of treatment with Sandimmun being associated with a slight, reversible increase in blood lipids, lipid levels should therefore be measured prior to and one month after the start of treatment. In the event of an increase in lipid levels, a reduction in dietary fat intake and possibly a dose reduction should be considered.
Ciclosporin increases the risk of hyperkalaemia, particularly in patients with renal dysfunction. Caution is called for when co-administering ciclosporin with potassium-sparing drugs (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or medicines containing potassium or when using it in patients on a potassium-rich diet (see Interactions). In such situations, it is advisable to check potassium levels.
Caution is required when giving ciclosporin concomitantly with lercanidipine (see Interactions).
Ciclosporin may increase the plasma concentrations and the dose-dependent risk of side effects of co-administered medicines which are substrates of the multidrug efflux transporter p-glycoprotein, or of the organic anion transporter proteins (OAPTs), such as aliskiren, dabigatran or bosentan. Co-administration of ciclosporin and aliskiren or dabigatran or bosentan should be avoided (see Interactions).
Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplantation period. Moreover, monitoring of serum magnesium levels is recommended during the peri-transplantation period, particularly in the presence of neurological symptoms. If considered necessary, magnesium supplementation should be given.
Caution is required in treating patients with hyperuricaemia.
Vaccination may be less effective during treatment with ciclosporin, and the use of live vaccines should be avoided.
Effects on the ability to drive and to use machines: No data are available on the effect of Sandimmun on the ability to drive or to use machines.
Sandimmun Neoral: General: Only physicians with experience of immunosuppressive therapy who are able to perform the necessary follow-up examinations (regular full physical examinations, blood pressure checks, laboratory tests) should prescribe Sandimmun Neoral. Transplant patients receiving Sandimmun Neoral should be treated at centres with the requisite laboratory and medical equipment. The physician responsible for maintenance therapy must be given all information necessary for the patient's proper care.
Absorption of calcineurin inhibitors may be impaired in patients with cystic fibrosis.
Due to the potential risk of malignant skin changes, patients receiving Sandimmun Neoral should be warned against excessive exposure to the sun without appropriate protection.
Paediatric use: Owing to insufficient data, the use of Sandimmun Neoral in patients under 16 years of age cannot be recommended in non-transplantation indications other than nephrotic syndrome.
Switching to other ciclosporin formulations: Once treatment with Sandimmun Neoral has started, appropriate monitoring of blood ciclosporin levels, serum creatinine levels and blood pressure is necessary before a switch to another oral formulation of ciclosporin can be attempted, as differences in bioavailability may occur.
Combination with other immunosuppressive agents: Like other immunosuppressive agents, ciclosporin increases the risk of developing lymphomas and other malignancies, particularly of the skin.
This increased risk seems to be related more to the degree and duration of immunosuppression than to the use of specific medicines.
In addition, a treatment regimen containing several immunosuppressive agents (including ciclosporin) must be used with caution, since it may lead to lymphoproliferative disorders and solid tumours of other organs that may be fatal.
As is the case in patients using other immunosuppressive agents, those using ciclosporin are susceptible to a number 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 BK virus nephropathy (BKVN) or JC-virus-associated progressive multifocal leucoencephalopathy (PML) - have been observed in patients receiving ciclosporin. These conditions are often secondary to high immunosuppression and should be considered in the differential diagnosis of immunosuppressed patients with deteriorating renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. BKVN can cause graft loss. Effective preventive and therapeutic strategies should be employed, particularly in patients on multiple long-term immunosuppressive therapy. A reduction in total immunosuppression should be considered in patients with PVAN or PML, but reduced immunosuppression may also jeopardize the graft.
Renal and hepatic function: A frequent and potentially serious complication during the first few weeks of Sandimmun Neoral treatment is a rise in serum levels of creatinine and urea. These functional changes are dose-dependent and reversible and usually return to normal when the dose is reduced. In some patients, long-term use may lead to structural changes in the kidneys (e.g. interstitial fibrosis), which must be distinguished from signs of chronic rejection in kidney transplant patients.
Sandimmun Neoral may also cause a dose-dependent and reversible increase in serum bilirubin and liver enzyme levels (see Adverse Reactions).
Regular monitoring of the appropriate hepatic and renal parameters is required. Dose reduction may be necessary should results be abnormal.
Renal function should be monitored particularly closely in elderly patients.
Determination of blood ciclosporin levels: Ciclosporin blood levels should preferably be monitored by measuring the proportion of parent drug using a specific monoclonal antibody or a HPLC-based analysis method. If plasma or serum is used, a standard separation protocol should be followed, with defined values for time and temperature.
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 also 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. The results should therefore only be viewed as a guideline for treatment in the context of a whole range of other clinical and biochemical parameters (see Organ transplantation under Dosage & Administration).
Blood pressure monitoring: Blood pressure should be checked regularly during Sandimmun Neoral therapy. In the event of hypertension, appropriate treatment should be given to lower blood pressure. Preference should be given to an antihypertensive agent that has no pharmacokinetic interactions with ciclosporin (see Interactions).
Biochemical changes: There have been reports of treatment with Sandimmun Neoral being associated with a slight, reversible increase in blood lipids; blood lipid levels should therefore be measured prior to and one month after, the start of treatment. In the event of an increase in lipid levels, a reduction in dietary fat intake and possibly a dose reduction should be considered.
Ciclosporin increases the risk of hyperkalaemia, particularly in patients with renal dysfunction. Caution is required when administering ciclosporin concomitantly with potassium-sparing drugs (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or medicines containing potassium or in patients with a potassium-rich diet (see Interactions). In such situations, it is advisable to monitor potassium levels.
Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplantation period. Moreover, monitoring of serum magnesium levels is recommended during the peri-transplantation period, particularly in the presence of neurological symptoms. If considered necessary, magnesium supplementation should be given.
Caution is required in treating patients with hyperuricaemia.
Concomitant medication (see Interactions): Vaccination may be less effective during treatment with ciclosporin and the use of live vaccines should be avoided.
Caution is required when giving ciclosporin concomitantly with lercanidipine (see Interactions).
Ciclosporin may increase the plasma concentrations and the dose-dependent risk of side effects of co-administered medicines which are substrates of the multidrug efflux transporter, p-glycoprotein or of the organic anion transporter proteins (OAPTs), such as aliskiren, dabigatran or bosentan. Co-administration of ciclosporin and aliskiren or dabigatran or bosentan should be avoided (see Interactions).
Psoriasis patients should not be given concomitant treatment with beta blockers or diuretics.
Early detection of lymphoproliferative disorders and solid malignant tumours: As with other immunosuppressive therapies (including ciclosporin), the increased risk of lymphoproliferative disorders and solid tumours (particularly of the skin) should be borne in mind. Patients receiving long-term Sandimmun Neoral therapy should be monitored closely in order to ensure early detection. Treatment must be withdrawn if premalignancy or malignancy is determined.
Exposure to UV light: Due to the potential risk of malignant skin changes, patients receiving Sandimmun Neoral, in particular those being treated for psoriasis or atopic dermatitis, should be warned against excessive exposure to the sun without adequate protection and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy (see Interactions).
Ethanol: The ethanol content of the oral solution should be taken into account when using Sandimmun Neoral in patients at risk, particularly pregnant or breast-feeding women, patients with liver disease or epilepsy, alcoholic patients or children.
Endogenous uveitis: A possible connection between ciclosporin and neurological manifestations of Behcet's syndrome has been reported. Sandimmun Neoral should therefore be administered with caution in such patients and patients' neurological status should be carefully monitored.
Effects on the ability to drive and to use machines: No data are available on the effect of Sandimmun Neoral on the ability to drive or to use machines.