Roche Products Limited

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4.8 Undesirable effects

Respiratory, thoracic and mediastinal disorders:

There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with CellCept in combination with other immunosuppressants, some of which have been fatal.

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4.4       Special warnings and precautions for use

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of CellCept therapy. Changes to CellCept therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see section 4.8).

4.5     Interaction with other medicinal products and other forms of interaction

Ciprofloxacin and amoxicillin plus clavulanic acid: Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of their discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of CellCept should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

4.8     Undesirable effects

Gastrointestinal: gingival hyperplasia (≥1/100 to <1/10), colitis including cytomegaloviruscolitis, (≥1/100 to <1/10), pancreatitis (≥1/100 to <1/10) and intestinal villous atrophy.

Blood and lymphatic system disorder:

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with CellCept (see section 4.4).

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with CellCept. These changes are not associated with impaired neutrophil function. These changes may suggest a ‘left shift’ in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive CellCept.

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4.4     Special warnings and precautions for use

Oversuppression of the immune system increases the susceptibility to infection including opportunistic infections, fatal infections and sepsis (see section 4.8).

Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a Neurologist should be considered as clinically indicated. Consideration should be given to reducing the total immunosuppression in patients who develop PML. In transplant patients, however, reduced immunosuppression may place the graft at risk.Patients treated with immunosuppressants, including CellCept, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Among the opportunistic infections are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.8     Undesirable effects

Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including CellCept.

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4.4       Special warnings and precautions for use

Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a Neurologist should be considered as clinically indicated.

Consideration should be given to reducing the total immunosuppression in patients who develop PML. In transplant patients, however, reduced immunosuppression may place the graft at risk.

4.6     Pregnancy and lactation

Cases of spontaneous abortions have been reported in patients exposed to CellCept.

4.8     Undesirable effects

Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. Cases of Progressive Multifocal Leukoencephalopathy (PML), sometimes fatal, have been reported in CellCept treated patients. The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune function.

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4.6       Pregnancy and lactation

The use of CellCept is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. CellCept should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. There are no adequateis limited data from the use of CellCept in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, have been reported in children of patients exposed to CellCept in combination with other immunosuppressants during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

4.8     Undesirable effects

Congenital disorders: see further details in section 4.6.

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4.5              Interaction with other medicinal products and other forms of interaction

In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.

Several studies have demonstrated that ciclosporin A reduces MPA plasma AUC levels by 19 - 38 %, possibly as a result of inhibiting biliary secretion with consequent reduction of the entero-hepatic recirculation. However, as efficacy studies were carried out using CellCept combined with ciclosporin A and corticosteroids, these findings do not affect the recommended dose requirements (see section 4.2).

Rifampicin: in patients not also taking ciclosporin, concomitant administration of CellCept and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust CellCept doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.

Sirolimus: in renal transplant patients, concomitant administration of CellCept and CsA resulted in reduced MPA exposures by 30‑50% compared with patients receiving the combination of sirolimus and similar doses of CellCept (see also section 4.4).

Sevelamer: decrease in MPA Cmax and AUC0-12 by 30% and 25%, respectively, were observed when CellCept was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer CellCept at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There is no data on CellCept with phosphate binders other than sevelamer.

Trimethoprim/sulfamethoxazole: no effect on the bioavailability of MPA was observed.

Norfloxacin and metronidazole: in healthy volunteers, no significant interaction was observed when CellCept was concomitantly administered with norfloxacin and metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30 % following a single dose of CellCept.

Tacrolimus:  in renal transplant patients: stable renal transplant patients receiving ciclosporin and CellCept (1 g BID) showed about a 30 % increase in MPA plasma AUC and about a 20 % decrease in MPAG plasma AUC when ciclosporin was replaced with tacrolimus. MPA C_max was not affected, while MPAG C_max was reduced by approximately 20 %. The mechanism of this finding is not well understood. Increased biliary secretion of MPAG accompanied with increased enterohepatic recirculation of MPA may be partly responsible for the finding, since the elevation of MPA concentrations associated with tacrolimus administration was more pronounced in the later portions of the concentration-time profile (4 – 12 hours after dosing). In another study in renal transplant patients it was shown that the tacrolimus concentration did not appear to be altered by CellCept.

In hepatic transplant patients: very limited pharmacokinetic data on MPA AUC are available in hepaticliver transplant patientsrecipients treated withinitiated on CellCept in combination with and tacrolimus, the AUC and Cmax of MPA, the active metabolite of CellCept, were not significantly affected by coadministration withtrough tacrolimus level. In renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept. In a study designed to evaluate the effect of CellCept on the pharmacokinetics of tacrolimus in stable hepatic transplant patients contrastHowever, in hepatic transplant patients, there was an increase of approximately 20 % in tacrolimus AUC when multiple doses of CellCept (1.5 g BID) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by CellCept (see also section 4.4).

4.9              Overdose

The experience with overdose of CellCept in humans is very limited. The events received from reports of overdose Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.

It is expected that an overdose of mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, dosing with CellCept should be interrupted or the dose reduced (see section 4.4).

Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. By interfering with enterohepatic circulation of the medicinal product, bBile acid sequestrants, such as cholestyramine, reduce thecan remove MPA AUC by decreasing the enterohepatic re-circulation of the drug (see section 5.2).