Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Medical supervision
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 this medicinal product 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.

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.

A treatment regimen containing multiple immunosuppressants (including ciclosporin) should therefore 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, in particular those treated for psoriasis or atopic dermatitis, should be warned to avoid excess unprotected sun exposure and should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

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.

Renal toxicity
A frequent and potentially serious complication, an increase in serum creatinine and urea, may occur during Sandimmun Neoral therapy. These functional changes are dose-dependent and are initially reversible, usually responding to dose reduction. During long-term treatment, some patients may develop structural changes in the kidney (e.g., interstitial fibrosis) which, in renal transplant patients, must be differentiated from changes due to chronic rejection. Frequent monitoring of renal function is therefore required according to local guidelines for the indication in question (see sections 4.2 and 4.8).

Hepatotoxicity
Sandimmun Neoral may also cause dose-dependent, reversible increases in serum bilirubin and in liver enzymes (see section 4.8). There have been solicited and spontaneous 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 section 4.8). Close monitoring of parameters that assess hepatic function is required and abnormal values may necessitate dose reduction (see sections 4.2 and 5.2).

Elderly population (age 65 years and above)
In elderly patients, renal function should be monitored with particular care.

Monitoring ciclosporin levels (see section 4.2)
When Sandimmun Neoral is used in transplant patients, routine monitoring of ciclosporin blood levels is an important safety measure. For monitoring ciclosporin levels in whole blood, a specific monoclonal antibody (measurement of parent compound) is preferred; a high-performance liquid chromatography (HPLC) method, which also measures the parent compound, 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.

In non-transplant patients, occasional monitoring of ciclosporin blood levels is recommended, e.g., when Sandimmun Neoral is co-administered with substances that may interfere with the 

pharmacokinetics of ciclosporin, or in the event of unusual clinical response (e.g., lack of efficacy or increased drug intolerance such as renal dysfunction).
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 Neoral 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 (see section 4.5).

Blood lipids increased
Since Sandimmun Neoral 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.

Hyperkalaemia
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 (e.g., potassium- sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable.

Hypomagnesaemia
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.

Hyperuricaemia
Caution is required when treating patients with hyperuricaemia.

Live-attenuated vaccines
During treatment with ciclosporin, vaccination may be less effective. The use of live attenuated vaccines should be avoided (see section 4.5).

Interactions
Caution should be observed when co-administering ciclosporin with drugs that substantially increase or decrease ciclosporin plasma concentrations, through inhibition or induction of CYP3A4 and/or P-gp (see section 4.5).

Renal toxicity should be monitored when initiating ciclosporin use together with active substances that increase ciclosporin levels or with substances that exhibit nephrotoxic synergy (see section 4.5). The clinical condition of the patient should be monitored closely. Monitoring of ciclosporin blood levels and adjustment of the ciclosporin dose may be required.

Concomitant use of ciclosporin and tacrolimus should be avoided (see section 4.5).

Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-gp and organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter. Caution should be observed while co-administering ciclosporin with such drugs or concomitant use should be avoided (see section 4.5). Ciclosporin increases the exposure to HMG-CoA reductase inhibitors (statins). When concurrently administered with ciclosporin, the dosage of the statins should be reduced and concomitant use of certain statins should be avoided according to their 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 (see section 4.5).

Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased three-fold and the AUC of ciclosporin was increased 21%. Therefore the simultaneous combination of ciclosporin and lercanidipine should be avoided. Administration of ciclosporin 3 hours after lercanidipine yielded no change of the lercanidipine AUC, but the ciclosporin AUC was increased by 27%. This combination should therefore be given with caution with an interval of at least 3 hours.

Additional precautions in non-transplantation indications
Patients with impaired renal function (except nephrotic syndrome patients with a permissible degree of renal impairment), uncontrolled hypertension, uncontrolled infections, or any kind of malignancy should not receive ciclosporin.

Before initiation of treatment a reliable baseline assessment of renal function should be established by at least two measurements of eGFR. Renal function must be assessed frequently throughout therapy to allow dosage adjustment (see section 4.2).

Additional precautions in endogenous uveitis
Sandimmun Neoral should be administered with caution in patients with neurological Behcet`s syndrome. The neurological status of these patients 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
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 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
After 6 months of therapy, renal function needs to be assessed 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 an NSAID is initiated or its dosage increased. Discontinuation of Sandimmun Neoral may also become necessary if hypertension developing during treatment cannot be controlled by appropriate 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 due to nephrotoxic synergy.

Additional precautions in psoriasis
Discontinuation of Sandimmun Neoral therapy is recommended if hypertension developing during 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 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 Sandimmun Neoral, lymphoproliferative disorders have occurred. These were responsive to prompt discontinuation.

Patients on Sandimmun Neoral should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

Additional precautions in atopic dermatitis
Discontinuation of Sandimmun Neoral is recommended if hypertension developing during treatment cannot be controlled with appropriate therapy.

Experience with Sandimmun Neoral in children with atopic dermatitis is limited.

Elderly patients should be treated only in the presence of disabling atopic dermatitis and renal function should be monitored with particular care.

Benign lymphadenopathy is commonly associated with flares in atopic dermatitis and invariably disappears spontaneously or with general improvement in the disease.

Lymphadenopathy observed on treatment with ciclosporin should be regularly monitored.

Lymphadenopathy which persists despite improvement in disease activity should be examined by biopsy as a precautionary measure to ensure the absence of lymphoma.

Active herpes simplex infections should be allowed to clear before treatment with Sandimmun Neoral is initiated, but are not necessarily a reason for treatment withdrawal if they occur during therapy unless infection is severe.

Skin infections with Staphylococcus aureus are not an absolute contraindication for Sandimmun Neoral therapy, but should be controlled with appropriate antibacterial agents. Oral erythromycin, which is known to have the potential to increase the blood concentration of ciclosporin (see section 4.5), should be avoided. If there is no alternative, it is recommended to closely monitor blood levels of ciclosporin, renal function, and for side effects of ciclosporin.

Patients on Sandimmun Neoral should not receive concomitant ultraviolet B irradiation or PUVA photochemotherapy.

Paediatric use in non-transplantation indications
Except for the treatment of nephrotic syndrome, there is no adequate experience available with Sandimmun Neoral. Its use in children for non-transplantation indications other than nephrotic syndrome cannot be recommended.

Special excipients: Polyoxyl 40 hydrogenated castor oil
Sandimmun Neoral contains polyoxyl 40 hydrogenated castor oil, which may cause stomach upsets and diarrhoea.

Special excipients: Ethanol
Sandimmun Neoral contains 25, 50, 100 mg of alcohol (ethanol) in each 25, 50, 100 mg Sandimmun Neoral capsule respectively, which is equivalent to 11.8 % v/v. A 500 mg dose of Neoral contains 500 mg ethanol, equivalent to nearly 13 ml beer or 5 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.

Sandimmun Neoral 100mg/mL Oral Solution contains 94.70 mg of alcohol (ethanol) in each ml which is equivalent to 12 % v/v. A 500 mg dose of Neoral contains 500 mg ethanol, equivalent to nearly 13 ml beer or 5 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.

Special excipients: Sodium
This medicine contains less than 1 mmol Sodium (23 mg) in each 25, 50, 100 mg capsules i.e. to say essentially ‘sodium free’.

Effects on Driving

4.7   Effects on ability to drive and use machines

Sandimmun Neoral may cause neurological and visual disturbances (see section 4.8). Sandimmun Neoral may have a moderate influence on the ability to drive and use machines. 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.