CELLCEPT

Treatment should be initiated and maintained by appropriately qualified transplant specialists.

CAUTION:

CELLCEPT INTRAVENOUS SOLUTION MUST NOT BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION. Posology 2 CellCept 500 mg powder for concentrate for solution for infusion is an alternative dosage form to CellCept oral forms (capsules, tablets and powder for oral suspension) that may be administered for up to 14 days.

The initial dose of CellCept (mycophenolate mofetil) 500 mg powder for concentrate for solution for infusion should be given within 24 hours following transplantation. Adults Renal transplant The recommended dose of mycophenolate mofetil for infusion in renal transplant patients is 1 g administered twice daily (2 g daily dose).

Hepatic transplant The recommended dose of mycophenolate mofetil for infusion in hepatic transplant patients is 1 g administered twice daily (2 g daily dose). Intravenous mycophenolate mofetil should continue for the first 4 days following hepatic transplant, with oral mycophenolate mofetil initiated as soon after this as it can be tolerated.

5 g administered twice daily (3 g daily dose). Paediatric population The safety and efficacy of mycophenolate mofetil for infusion in paediatric patients have not been established. No pharmacokinetic data with mycophenolate mofetil for infusion are available for renal and hepatic transplant patients.

Paediatric indications are therefore only covered by the oral formulations of the mycophenolate mofetil product range. Use in special populations Elderly The recommended dose of 1 g administered twice a day for renal or hepatic transplant patients is appropriate for the elderly.

73 m2), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. 2). No data are available for hepatic transplant patients with severe chronic renal impairment.

Severe hepatic impairment No dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease. Treatment during rejection episodes Adults 3 Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil.

Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dose reduction or interruption of treatment is not required. No pharmacokinetic data are available during hepatic transplant rejection. Paediatric population No data are available for treatment of first or refractory rejection in paediatric transplant patients.

6). Precautions to be taken before handling or administering the medicinal product Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid direct contact of the dry powder or prepared solutions of mycophenolate mofetil 500 mg powder for concentrate for solution for infusion with skin or mucous membranes.

If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. 6.

1%) were among the most common and/or serious adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids. 4). Tabulated list of adverse reactions The adverse reactions from clinical trials and post-marketing experience are listed in Table 1, by MedDRA system organ class (SOC) along with their frequencies.

The corresponding frequency category for each adverse reaction is based on the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).

Due to the large differences observed in the frequency of certain adverse reactions across the different transplant indications, the frequency is presented separately for renal and hepatic transplant patients. 13 Table 1 Adverse reactions in studies investigating mycophenolate mofetil treatment in adults and adolescents, or through post- marketing surveillance Adverse reaction (MedDRA) System Organ Class Renal transplant Hepatic transplant Frequency Frequency Infections and infestations Bacterial infections Very Common Very Common Fungal infections Common Very Common Protozoal infections Uncommon Uncommon Viral infections Very Common Very Common Neoplasms benign, malignant and unspecified (including cysts and polyps) Benign neoplasm of skin Common Common Lymphoma Uncommon Uncommon Lymphoproliferative disorder Uncommon Uncommon Neoplasm Common Common Skin cancer Common Uncommon Blood and lymphatic system disorders Anaemia Very Common Very Common Aplasia pure red cell Uncommon Uncommon Bone marrow failure Uncommon Uncommon Ecchymosis Common Common Leukocytosis Common Very Common Leukopenia Very Common Very Common Pancytopenia Common Common Pseudolymphoma Uncommon Uncommon Thrombocytopenia Common Very Common Metabolism and nutrition disorders Acidosis Common Common Hypercholesterolaemia Very Common Common Hyperglycaemia Common Very Common Hyperkalaemia Common Very Common Hyperlipidaemia Common Common Hypocalcaemia Common Very Common Hypokalaemia Common Very Common Hypomagnesaemia Common Very Common Hypophosphataemia Very Common Very Common Hyperuricaemia Common Common Gout Common Common Weight decreased Common Common 14 Adverse reaction (MedDRA) System Organ Class Renal transplant Hepatic transplant Psychiatric disorders Confusional state Common Very Common Depression Common Very Common Insomnia Common Very Common Agitation Uncommon Common Anxiety Common Very Common Thinking abnormal Uncommon Common Nervous system disorders Dizziness Common Very Common Headache Very Common Very Common Hypertonia Common Common Paraesthesia Common Very Common Somnolence Common Common Tremor Common Very Common Convulsion Common Common Dysgeusia Uncommon Uncommon Cardiac disorders Tachycardia Common Very Common Vascular disorders Hypertension Very Common Very Common Hypotension Common Very Common Lymphocele Uncommon Uncommon Venous thrombosis Common Common Vasodilatation Common Common Respiratory, thoracic and mediastinal disorders Bronchiectasis Uncommon Uncommon Cough Very Common Very Common Dyspnoea Very Common Very Common Interstitial lung disease Uncommon Very Rare Pleural effusion Common Very Common Pulmonary fibrosis Very Rare Uncommon Gastrointestinal disorders Abdominal distension Common Very Common Abdominal pain Very Common Very Common Colitis Common Common Constipation Very Common Very Common Decreased appetite Common Very Common Diarrhoea Very Common Very Common Dyspepsia Very Common Very Common Esophagitis Common Common 15 Adverse reaction (MedDRA) System Organ Class Renal transplant Hepatic transplant Eructation Uncommon Uncommon Flatulence Common Very Common Gastritis Common Common Gastrointestinal haemorrhage Common Common Gastrointestinal ulcer Common Common Gingival hyperplasia Common Common Ileus Common Common Mouth ulceration Common Common Nausea Very Common Very Common Pancreatitis Uncommon Common Stomatitis Common Common Vomiting Very Common Very Common Immune system disorders Hypersensitivity Uncommon Common Anaphylactic reactions Not known Not known Hypogammaglobulinaemia Uncommon Very Rare Hepatobiliary disorders Blood alkaline phosphatase increased Common Common Blood lactate dehydrogenase increased Common Uncommon Hepatic enzyme increased Common Very Common Hepatitis Common Very Common Hyperbilirubinaemia Common Very Common Jaundice Uncommon Common Skin and subcutaneous tissue disorders Acne Common Common Alopecia Common Common Rash Common Very Common Skin hypertrophy Common Common Musculoskeletal and connective tissue disorders Arthralgia Common Common Muscular weakness Common Common Renal and urinary disorders Blood creatinine increased Common Very Common Blood urea increased Uncommon Very Common Haematuria Very Common Common Renal impairment Common Very Common General disorders and administration site conditions Asthenia Very Common Very Common 16 Adverse reaction (MedDRA) System Organ Class Renal transplant Hepatic transplant Chills Common Very Common Oedema Very Common Very Common Hernia Common Very Common Malaise Common Common Pain Common Very Common Pyrexia Very Common Very Common De novo purine synthesis inhibitors associated acute inflammatory syndrome Uncommon Uncommon Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4% in patients treated with CellCept 500 mg powder for concentrate for solution for infusion.

Description of selected adverse reactions Malignancies Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate mofetil, are at increased risk of developing lymphomas […]

8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

8). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus-associated nephropathy, JC virus-associated progressive multifocal leukoencephalopathy PML).

Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. 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.

Mycophenolic acid has a cytostatic effect on B- and T-lymphocytes, therefore an increased severity of COVID- 19 may occur, and appropriate clinical action should be considered. There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving mycophenolate mofetil in combination with other immunosuppressants.

In some of these cases, switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on mycophenolate mofetil who develop recurrent infections should have their serum immunoglobulins measured.

In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B- lymphocytes. There have been published reports of bronchiectasis in adults and children who received mycophenolate mofetil in combination with other immunosuppressants.

In some of these cases, switching mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung.

8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated. Blood and immune system Patients receiving mycophenolate mofetil should be monitored for neutropenia, which may be related to the treatment itself, concomitant medications, viral infections, or some combination of these causes.

Patients taking mycophenolate mofetil should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. 3 x 103/μl) it may be appropriate to interrupt or discontinue mycophenolate mofetil.

5 Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of mycophenolate mofetil therapy.

8). Patients receiving mycophenolate mofetil should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow failure. 5). Influenza vaccination may be of value.

Prescribers should refer to national guidelines for influenza vaccination. Gastrointestinal Mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation.

Treatment should be administered with caution in patients with active serious digestive system disease. Mycophenolate is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.

g. g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure. g. 5). Some degree of enterohepatic recirculation is anticipated following intravenous administration of mycophenolate mofetil. It is recommended that mycophenolate mofetil should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.

The risk/benefit ratio of mycophenolate mofetil in combination with sirolimus has not been […]

1. 8). • Treatment should not be given to patients who are allergic to polysorbate 80. 6). 6). 6). 6).