4.1 Therapeutic indications

Applies to: CellCept 250 mg hard capsules · CellCept 500 mg film-coated tablets

CellCept is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult and paediatric (1 to 18 years of age) patients receiving allogeneic renal, cardiac or hepatic transplants.

Applies to: CellCept 500 mg powder for concentrate for solution for infusion

CellCept 500 mg powder for concentrate for solution for infusion is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal or hepatic transplants.

Applies to: CellCept 1 g/5 ml powder for oral suspension

CellCept 1 g/5 ml powder for oral suspension is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult and paediatric (1 to 18 years of age) patients receiving allogeneic renal, cardiac or hepatic transplants.

4.2 Posology and method of administration

Applies to: CellCept 250 mg hard capsules

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

Posology

Adults
Renal transplant
Treatment should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).

Cardiac transplant
Treatment should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).

Hepatic transplant
Treatment of intravenous mycophenolate mofetil should be administered for the first 4 days following hepatic transplant, with oral mycophenolate mofetil initiated as soon after this as it can be tolerated.
The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

Paediatric population (1 to 18 years)
The paediatric dosing information in this section applies to all oral formulations within the range of mycophenolate mofetil products, as appropriate. Different oral formulations should not be substituted without clinical supervision.

The recommended mycophenolate mofetil initial dose for paediatric renal, cardiac and hepatic transplant patients is 600 mg/m2 (of body surface area (BSA)), administered orally, twice daily (initial total daily dose not to exceed 2 g, or 10 ml of the oral suspension).

The dose and product form should be individualised based on clinical assessment. If the recommended initial dose is well tolerated but does not achieve clinically adequate immunosuppression in paediatric cardiac and hepatic transplant patients, the dose can be increased to 900 mg/m2 BSA twice daily (maximum total daily dose of 3 g, or 15 ml of the oral suspension). The recommended maintenance dose for paediatric renal transplant patients remains at 600 mg/m2 twice daily (maximum total daily dose of 2 g or 10 ml of the oral suspension).

The mycophenolate mofetil powder for oral suspension should be used in those patients unable to swallow capsules and tablets and/or with a BSA lower than 1.25 m2 due to the increased risk of choking. Patients with a BSA of 1.25 to 1.5 m2 may be prescribed mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a BSA greater than 1.5 m2 may be prescribed mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group (see section 4.8) compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.

Use in special populations
Elderly
The recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.

Renal impairment
In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 ml/min/1.73 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. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for cardiac or 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.
No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes
Adults
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. There is no basis for dose adjustment following cardiac transplant rejection.
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.

Method of administration

For oral use.

Precautions to be taken before handling or administering the medicinal product.
Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, capsules should not be opened or crushed to avoid inhalation or direct contact with skin or mucous membranes of the powder contained in the capsules. If such contact occurs, wash thoroughly with soap and water;
rinse eyes with plain water.

Applies to: CellCept 500 mg powder for concentrate for solution for infusion

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

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. The recommended oral dose in hepatic transplant patients is 1.5 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.

Renal impairment
In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 ml/min/1.73 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. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). 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
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.

Method of administration

Following reconstitution to a concentration of 6 mg/ml, mycophenolate mofetil 500 mg powder for concentrate for solution for infusion must be administered by slow intravenous infusion over a period of 2 hours by either a peripheral or a central vein (see section 6.6).

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.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

Applies to: CellCept 1 g/5 ml powder for oral suspension

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

Posology

Adults
Renal transplant
Treatment with 1 g/5 ml powder for oral suspension should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose), i.e. 5 ml oral suspension twice daily.

Cardiac transplant
Treatment should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).

Hepatic transplant
Treatment of intravenous mycophenolate mofetil should be administered for the first 4 days following hepatic transplant, with oral mycophenolate mofetil initiated as soon after this as it can be tolerated.
The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

Paediatric population (1 to 18 years)
The paediatric dosing information in this section applies to all oral formulations within the range of mycophenolate mofetil products, as appropriate. Different oral formulations should not be substituted without clinical supervision.

The recommended mycophenolate mofetil initial dose for paediatric renal, cardiac and hepatic transplant patients is 600 mg/m2 (of body surface area (BSA)) administered orally, twice daily (initial total daily dose not to exceed 2 g, or 10 ml of the oral suspension).

The dose and product form should be individualised based on clinical assessment. If the recommended initial dose is well tolerated but does not achieve clinically adequate immunosuppression in paediatric cardiac and hepatic transplant patients, the dose can be increased to 900 mg/m2 BSA twice daily (maximum total daily dose of 3 g, or 15 ml of the oral suspension). The recommended maintenance dose for paediatric renal transplant patients remains at 600 mg/m2 twice daily (maximum total daily dose of 2 g or 10 ml of the oral suspension).

The mycophenolate mofetil powder for oral suspension should be used in those patients unable to swallow capsules and tablets and/or with a BSA lower than 1.25 m2 due to the increased risk of choking. Patients with a BSA of 1.25 to 1.5 m2 may be prescribed mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a BSA greater than 1.5 m2 may be prescribed mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group (see section 4.8) compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.
The table below shows, for a range of BSA, the dose (mg) to volume (ml) conversion using the oral dispenser.

Table 1 Dose (mg) to volume (ml) conversion of suspension (1 g/ 5 ml) using the oral dispenser

600 mg/m2 dose level

900 mg/m2 dose level
Child’s Body
Surface Area
(m2)A

Total dose to be administered twice a day
Child’s Body
Surface Area
(m2)A

Total dose to be administered twice a day mg ml
(with oral dispenser) mg ml
(with oral dispenser)

Applies to: CellCept 500 mg film-coated tablets

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

Posology

Adults
Renal transplant
Treatment should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).

Cardiac transplant
Treatment should be initiated within 5 days following transplantation. The recommended dose in cardiac transplant patients is 1.5 g administered twice daily (3 g daily dose).

Hepatic transplant
Treatment of intravenous mycophenolate mofetil should be administered for the first 4 days following hepatic transplant, with oral mycophenolate mofetil initiated as soon after this as it can be tolerated.
The recommended oral dose in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).

Paediatric population (1 to 18 years)
The paediatric dosing information in this section applies to all oral formulations within the range of mycophenolate mofetil products, as appropriate. Different oral formulations should not be substituted without clinical supervision.

The recommended mycophenolate mofetil initial dose for paediatric renal, cardiac and hepatic transplant patients is 600 mg/m2 (of body surface area (BSA)), administered orally, twice daily (initial total daily dose not to exceed 2 g, or 10 ml of the oral suspension).

The dose and product form should be individualised based on clinical assessment. If the recommended initial dose is well tolerated but does not achieve clinically adequate immunosuppression in paediatric cardiac and hepatic transplant patients, the dose can be increased to 900 mg/m2 BSA twice daily (maximum total daily dose of 3 g, or 15 ml of the oral suspension). The recommended maintenance dose for paediatric renal transplant patients remains at 600 mg/m2 twice daily (maximum total daily dose of 2 g or 10 ml of the oral suspension).

The mycophenolate mofetil powder for oral suspension should be used in those patients unable to swallow capsules and tablets and/or with BSA lower than 1.25 m2 due to the increased risk of choking.
Patients with a BSA of 1.25 to 1.5 m2 may be prescribed mycophenolate mofetil capsules at a dose of 750 mg twice daily (1.5 g daily dose). Patients with a BSA greater than 1.5 m2 may be prescribed mycophenolate mofetil capsules or tablets at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group (see section 4.8) compared with adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.

Use in special populations
Elderly
The recommended dose of 1 g administered twice a day for renal transplant patients and 1.5 g twice a day for cardiac or hepatic transplant patients is appropriate for the elderly.

Renal impairment
In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 ml/min/1.73 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. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for cardiac or 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.
No data are available for cardiac transplant patients with severe hepatic parenchymal disease.

Treatment during rejection episodes
Adults
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. There is no basis for dose adjustment following cardiac transplant rejection.
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.

Method of administration

For oral use.

Precautions to be taken before handling or administering the medicinal product.
Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, tablets should not be crushed to avoid inhalation or direct contact with skin or mucous membranes with powder. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

4.3 Contraindications

Applies to: CellCept 250 mg hard capsules · CellCept 1 g/5 ml powder for oral suspension

CellCept should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions to this medicinal product have been observed (see section 4.8).

Treatment should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6).

Treatment should not be initiated in women of childbearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).

Treatment should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6).

Treatment should not be given to women who are breastfeeding (see section 4.6).

Applies to: CellCept 500 mg powder for concentrate for solution for infusion

CellCept should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions to this medicinal product have been observed (see section 4.8).

Treatment should not be given to patients who are allergic to polysorbate 80.

Treatment should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6).

Treatment should not be initiated in women of childbearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).

Treatment should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6).

Treatment should not be given to women who are breastfeeding (see section 4.6).

Applies to: CellCept 500 mg film-coated tablets

CellCept should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions to this medicinal product have been observed (see section 4.8).

Treatment should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6).

Treatment should not be initiated in women of childbearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).

Treatment should not be used during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6).

Treatment should not be given to women who are breastfeeding (see section 4.6).

4.8 Undesirable effects

Applies to: CellCept 250 mg hard capsules

Summary of the safety profile

Diarrhoea (up to 52.6%), leukopenia (up to 45.8%), bacterial infections (up to 39.9%) and vomiting (up to 39.1%) were among the most common and/or serious adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4).

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, hepatic and cardiac transplant patients.

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

Cardiac transplant

Frequency
Frequency
Frequency
Infections and infestations
Bacterial infections
Very Common
Very Common
Very Common
Fungal infections
Common
Very Common
Very Common

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

Cardiac transplant

Protozoal infections
Uncommon
Uncommon
Uncommon
Viral infections
Very Common
Very Common
Very Common
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Benign neoplasm of skin
Common
Common
Common
Lymphoma
Uncommon
Uncommon
Uncommon
Lymphoproliferative disorder
Uncommon
Uncommon
Uncommon
Neoplasm
Common
Common
Common
Skin cancer
Common
Uncommon
Common
Blood and lymphatic system disorders
Anaemia
Very Common
Very Common
Very Common
Aplasia pure red cell
Uncommon
Uncommon
Uncommon
Bone marrow failure
Uncommon
Uncommon
Uncommon
Ecchymosis
Common
Common
Very Common
Leukocytosis
Common
Very Common
Very Common
Leukopenia
Very Common
Very Common
Very Common
Pancytopenia
Common
Common
Uncommon
Pseudolymphoma
Uncommon
Uncommon
Common
Thrombocytopenia
Common
Very Common
Very Common
Metabolism and nutrition disorders
Acidosis
Common
Common
Very Common
Hypercholesterolaemia
Very Common
Common
Very Common
Hyperglycaemia
Common
Very Common
Very Common
Hyperkalaemia
Common
Very Common
Very Common
Hyperlipidaemia
Common
Common
Very Common
Hypocalcaemia
Common
Very Common
Common
Hypokalaemia
Common
Very Common
Very Common
Hypomagnesaemia
Common
Very Common
Very Common
Hypophosphataemia
Very Common
Very Common
Common
Hyperuricaemia
Common
Common
Very Common
Gout
Common
Common
Very Common
Weight decreased
Common
Common
Common
Psychiatric disorders
Confusional state
Common
Very Common
Very Common
Depression
Common
Very Common
Very Common
Insomnia
Common
Very Common
Very Common
Agitation
Uncommon
Common
Very Common
Anxiety
Common
Very Common
Very Common
Thinking abnormal
Uncommon
Common
Common
Nervous system disorders
Dizziness
Common
Very Common
Very Common
Headache
Very Common
Very Common
Very Common
Hypertonia
Common
Common
Very Common

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

Cardiac transplant

Paresthesia
Common
Very Common
Very Common
Somnolence
Common
Common
Very Common
Tremor
Common
Very Common
Very Common
Convulsion
Common
Common
Common
Dysgeusia
Uncommon
Uncommon
Common
Cardiac disorders
Tachycardia
Common
Very Common
Very Common
Vascular disorders
Hypertension
Very Common
Very Common
Very Common
Hypotension
Common
Very Common
Very Common
Lymphocele
Uncommon
Uncommon
Uncommon
Venous thrombosis
Common
Common
Common
Vasodilatation
Common
Common
Very Common
Respiratory, thoracic and mediastinal disorders
Bronchiectasis
Uncommon
Uncommon
Uncommon
Cough
Very Common
Very Common
Very Common
Dyspnoea
Very Common
Very Common
Very Common
Interstitial lung disease
Uncommon
Very Rare
Very Rare
Pleural effusion
Common
Very Common
Very Common
Pulmonary fibrosis
Very Rare
Uncommon
Uncommon
Gastrointestinal disorders
Abdominal distension
Common
Very Common
Common
Abdominal pain
Very Common
Very Common
Very Common
Colitis
Common
Common
Common
Constipation
Very Common
Very Common
Very Common
Decreased appetite
Common
Very Common
Very Common
Diarrhoea
Very Common
Very Common
Very Common
Dyspepsia
Very Common
Very Common
Very Common
Esophagitis
Common
Common
Common
Eructation
Uncommon
Uncommon
Common
Flatulence
Common
Very Common
Very Common
Gastritis
Common
Common
Common
Gastrointestinal haemorrhage
Common
Common
Common
Gastrointestinal ulcer
Common
Common
Common
Gingival hyperplasia
Common
Common
Common
Ileus
Common
Common
Common
Mouth ulceration
Common
Common
Common
Nausea
Very Common
Very Common
Very Common
Pancreatitis
Uncommon
Common
Uncommon
Stomatitis
Common
Common
Common
Vomiting
Very Common
Very Common
Very Common
Immune system disorders
Hypersenstivity
Uncommon
Common
Common

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

Cardiac transplant

Anaphylactic reactions
Not known
Not known
Not known
Hypogammaglobulinaemia
Uncommon
Very Rare
Very Rare
Hepatobiliary disorders
Blood alkaline phosphatase increased
Common
Common
Common
Blood lactate dehydrogenase increased
Common
Uncommon
Very Common
Hepatic enzyme increased
Common
Very Common
Very Common
Hepatitis
Common
Very Common
Uncommon
Hyperbilirubinaemia
Common
Very Common
Very Common
Jaundice
Uncommon
Common
Common
Skin and subcutaneous tissue disorders
Acne
Common
Common
Very Common
Alopecia
Common
Common
Common
Rash
Common
Very Common
Very Common
Skin hypertrophy
Common
Common
Very Common
Musculoskeletal and connective tissue disorders
Arthralgia
Common
Common
Very Common
Muscular weakness
Common
Common
Very Common
Renal and urinary disorders
Blood creatinine increased
Common
Very Common
Very Common
Blood urea increased
Uncommon
Very Common
Very Common
Haematuria
Very Common
Common
Common
Renal impairment
Common
Very Common
Very Common
General disorders and administration site conditions
Asthenia
Very Common
Very Common
Very Common
Chills
Common
Very Common
Very Common
Oedema
Very Common
Very Common
Very Common
Hernia
Common
Very Common
Very Common
Malaise
Common
Common
Common
Pain
Common
Very Common
Very Common
Pyrexia
Very Common
Very Common
Very Common
De novo purine synthesis inhibitors associated acute inflammatory syndrome
Uncommon
Uncommon
Uncommon

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 and other malignancies, particularly of the skin (see section 4.4). Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Infections

All patients treated with immunosuppressants are at increased risk of bacterial, viral and fungal infections (some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral reactivation. The risk increases with total immunosuppressive load (see section 4.4). The most serious infections were sepsis, peritonitis, meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. The most common opportunistic infections in patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal, cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate mofetil.

Blood and lymphatic disorders
Cytopenias, including leukopenia, anaemia, thrombocytopenia and pancytopenia, are known risks associated with mycophenolate mofetil and may lead or contribute to the occurrence of infections and haemorrhages (see section 4.4). Agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients taking mycophenolate mofetil is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow failure in patients treated with mycophenolate mofetil, some of which have been fatal.

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

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with mycophenolate mofetil. 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 mycophenolate mofetil.

Gastrointestinal disorders
The most serious gastrointestinal disorders were ulceration and haemorrhage which are known risks associated with mycophenolate mofetil. Mouth, oesophageal, gastric, duodenal, and intestinal ulcers often complicated by haemorrhage, as well as haematemesis, melena, and haemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials. The most common gastrointestinal disorders, however, were diarrhoea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate mofetil-related diarrhoea have revealed isolated cases of intestinal villous atrophy (see section 4.4).

Hypersensitivity
Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported.

Pregnancy, puerperium and perinatal conditions
Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester, see section 4.6.

Congenital disorders
Congenital malformations have been observed post-marketing in children of patients exposed to mycophenolate in combination with other immunosuppressants, see section 4.6.

Respiratory, thoracic and mediastinal disorders
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with mycophenolate mofetil in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults.

Immune system disorders

Hypogammaglobulinaemia has been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants.

General disorders and administration site conditions
Oedema, including peripheral, face and scrotal oedema, was reported very commonly during the pivotal trials. Musculoskeletal pain such as myalgia, and neck and back pain were also very commonly reported.

De novo purine synthesis inhibitors associated acute inflammatory syndrome has been described from post-marketing experience as a paradoxical proinflammatory reaction associated with mycophenolate mofetil and mycophenolic acid, characterised by fever, arthralgia, arthritis, muscle pain and elevated inflammatory markers. Literature case reports showed rapid improvement following discontinuation of the medicinal product.

Special populations

Paediatric population
The type and frequency of adverse reactions were assessed in a long-term clinical trial, which recruited 33 paediatric renal transplant patients, aged 3 years to 18 years, who were given 23 mg/kg of mycophenolate mofetil orally, twice daily. Overall, the safety profile in these 33 children and adolescents was similar to that observed in adult recipients of solid organ allografts.

Similar observations were made in another clinical trial, which recruited 100 paediatric renal transplant patients aged 1 to 18 years. The type and frequency of adverse reactions in patients who were given 600 mg/m2, up to 1 g/m2 of mycophenolate mofetil orally, twice daily, were comparable to those observed in adult patients given 1 g mycophenolate mofetil twice daily. A summary of the more frequently occurring adverse reactions is shown in table 2 below:

Table 2
Summary of adverse reactions observed more frequently in a trial investigating mycophenolate mofetil in 100 paediatric renal transplant patients (age/surface area-based dosing [600 mg/m2, up to 1 g/m2 BID.])

Adverse reaction

(MedDRA)

System Organ Class
<6 years
(n=33)
6-11 years
(n=34)
12-18 years
(n=33)
Infections and infestations
Very common
(48.5%)
Very common
(44.1%)
Very common
(51.5%)
Blood and lymphatic system disorders

Leukopenia
Very common
(30.3%)
Very common
(29.4%)
Very common
(12.1%)
Anaemia
Very common
(51.5%)
Very common
(32.4%)
Very common
(27.3%)
Gastrointestinal disorders

Diarrhoea
Very common
(87.9%)
Very common
(67.6%)
Very common
(30.3%)
Vomitting
Very common
(69.7%)
Very common
(44.1%)
Very common
(36.4%)

Based on limited sub-set data (i.e. 33 of the 100 patients) there was a higher frequency of severe diarrhoea (common, 9.1%), and candida mucocutaneous (very common, 21.2%) in children under 6 years of age, compared to the older paediatric cohort in which no cases of severe diarrhoea were reported (0.0%) and candida mucocutaneous was common (7.5%).

Review of the available medical literature on paediatric hepatic and cardiac transplant patients shows the type and frequency of the reported adverse reactions are consistent with those observed in paediatric and adult patients following renal transplant.

Very limited post-marketing data indicates a higher frequency of the following adverse reactions in patients under 6 years of age compared to older patients (see section 4.4):
- lymphomas and other malignancies particularly of post-transplant lymphoproliferative disorder in cardiac transplant patients
- blood and lymphatic system disorders including anaemia and neutropenia in cardiac transplant patients under 6 years of age compared to older patients, and compared to paediatric hepatic/renal transplant recipients
- gastrointestinal disorders including diarrhoea and vomiting.

Renal transplant patients under 2 years of age might be at a higher risk of infections and respiratory events compared to older patients. However, these data should be interpreted with caution due to a very limited number of post-marketing reports concerning the same patients suffering from multiple infections.

In case of undesirable effects, temporary dose reduction or interruption may be considered as deemed clinically necessary.

Elderly
Elderly patients (≥ 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving mycophenolate mofetil as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Applies to: CellCept 500 mg powder for concentrate for solution for infusion

Summary of the safety profile

Diarrhoea (up to 52.6%), leukopenia (up to 45.8%), bacterial infections (up to 39.9%) and vomiting (up to 39.1%) were among the most common and/or serious adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4).

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.

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

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

Hyperuricaemia
Common
Common
Gout
Common
Common
Weight decreased
Common
Common
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
Paresthesia
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

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

Esophagitis
Common
Common
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
Hypersenstivity
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
Chills
Common
Very Common
Oedema
Very Common
Very Common
Hernia
Common
Very Common
Malaise
Common
Common

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

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 and other malignancies, particularly of the skin (see section 4.4). Three-year safety data in renal transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Infections
All patients treated with immunosuppressants are at increased risk of bacterial, viral and fungal infections (some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral reactivation. The risk increases with total immunosuppressive load (see section 4.4). The most serious infections were sepsis, peritonitis, meningitis, endocarditis tuberculosis and atypical mycobacterial infection. The most common opportunistic infections in patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate mofetil.

Blood and lymphatic disorders
Cytopenias, including leukopenia, anaemia, thrombocytopenia and pancytopenia, are known risks associated with mycophenolate mofetil and may lead or contribute to the occurrence of infections and haemorrhages (see section 4.4). Agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients taking mycophenolate mofetil is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow failure in patients treated with mycophenolate mofetil, some of which have been fatal.

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

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with mycophenolate mofetil. 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 mycophenolate mofetil.

Gastrointestinal disorders
The most serious gastrointestinal disorders were ulceration and haemorrhage which are known risks associated with mycophenolate mofetil. Mouth, oesophageal, gastric, duodenal, and intestinal ulcers often complicated by haemorrhage, as well as haematemesis, melena, and haemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials. The most common

gastrointestinal disorders, however, were diarrhoea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate mofetil-related diarrhoea have revealed isolated cases of intestinal villous atrophy (see section 4.4).

Hypersensitivity
Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported.

Pregnancy, puerperium and perinatal conditions
Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester, see section 4.6.

Congenital disorders
Congenital malformations have been observed post-marketing in children of patients exposed to mycophenolate in combination with other immunosuppressants, see section 4.6.

Respiratory, thoracic and mediastinal disorders
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with mycophenolate mofetil in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults.

Immune system disorders
Hypogammaglobulinaemia has been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants.

General disorders and administration site conditions
Oedema, including peripheral, face and scrotal oedema, was reported very commonly during the pivotal trials. Musculoskeletal pain such as myalgia, and neck and back pain were also very commonly reported.

De novo purine synthesis inhibitors associated acute inflammatory syndrome has been described from post-marketing experience as a paradoxical proinflammatory reaction associated with mycophenolate mofetil and mycophenolic acid, characterised by fever, arthralgia, arthritis, muscle pain and elevated inflammatory markers. Literature case reports showed rapid improvement following discontinuation of the medicinal product.

Special populations

Elderly
Elderly patients (≥ 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving mycophenolate mofetil as part of a combination immunosuppressive regimen may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Applies to: CellCept 1 g/5 ml powder for oral suspension

Summary of the safety profile

Diarrhoea (up to 52.6%), leukopenia (up to 45.8%), bacterial infections (up to 39.9%) and vomiting (up to 39.1%) were among the most common and/or serious adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids. There is evidence of a higher frequency of certain types of infections (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions from clinical trials and post-marketing experience are listed in Table 2, 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, hepatic and cardiac transplant patients.

Table 2
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

Cardiac transplant

Frequency
Frequency
Frequency
Infections and infestations
Bacterial infections
Very Common
Very Common
Very Common
Fungal infections
Common
Very Common
Very Common
Protozoal infections
Uncommon
Uncommon
Uncommon
Viral infections
Very Common
Very Common
Very Common
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Benign neoplasm of skin
Common
Common
Common
Lymphoma
Uncommon
Uncommon
Uncommon
Lymphoproliferative disorder
Uncommon
Uncommon
Uncommon
Neoplasm
Common
Common
Common
Skin cancer
Common
Uncommon
Common
Blood and lymphatic system disorders
Anaemia
Very Common
Very Common
Very Common
Aplasia pure red cell
Uncommon
Uncommon
Uncommon
Bone marrow failure
Uncommon
Uncommon
Uncommon
Ecchymosis
Common
Common
Very Common
Leukocytosis
Common
Very Common
Very Common
Leukopenia
Very Common
Very Common
Very Common
Pancytopenia
Common
Common
Uncommon
Pseudolymphoma
Uncommon
Uncommon
Common
Thrombocytopenia
Common
Very Common
Very Common
Metabolism and nutrition disorders
Acidosis
Common
Common
Very Common
Hypercholesterolaemia
Very Common
Common
Very Common
Hyperglycaemia
Common
Very Common
Very Common
Hyperkalaemia
Common
Very Common
Very Common
Hyperlipidaemia
Common
Common
Very Common
Hypocalcaemia
Common
Very Common
Common
Hypokalaemia
Common
Very Common
Very Common
Hypomagnesaemia
Common
Very Common
Very Common
Hypophosphataemia
Very Common
Very Common
Common
Hyperuricaemia
Common
Common
Very Common
Gout
Common
Common
Very Common
Weight decreased
Common
Common
Common
Psychiatric disorders
Confusional state
Common
Very Common
Very Common
Depression
Common
Very Common
Very Common
Insomnia
Common
Very Common
Very Common
Agitation
Uncommon
Common
Very Common

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

Cardiac transplant

Anxiety
Common
Very Common
Very Common
Thinking abnormal
Uncommon
Common
Common
Nervous system disorders
Dizziness
Common
Very Common
Very Common
Headache
Very Common
Very Common
Very Common
Hypertonia
Common
Common
Very Common
Paresthesia
Common
Very Common
Very Common
Somnolence
Common
Common
Very Common
Tremor
Common
Very Common
Very Common
Convulsion
Common
Common
Common
Dysgeusia
Uncommon
Uncommon
Common
Cardiac disorders
Tachycardia
Common
Very Common
Very Common
Vascular disorders
Hypertension
Very Common
Very Common
Very Common
Hypotension
Common
Very Common
Very Common
Lymphocele
Uncommon
Uncommon
Uncommon
Venous thrombosis
Common
Common
Common
Vasodilatation
Common
Common
Very Common
Respiratory, thoracic and mediastinal disorders
Bronchiectasis
Uncommon
Uncommon
Uncommon
Cough
Very Common
Very Common
Very Common
Dyspnoea
Very Common
Very Common
Very Common
Interstitial lung disease
Uncommon
Very Rare
Very Rare
Pleural effusion
Common
Very Common
Very Common
Pulmonary fibrosis
Very Rare
Uncommon
Uncommon
Gastrointestinal disorders
Abdominal distension
Common
Very Common
Common
Abdominal pain
Very Common
Very Common
Very Common
Colitis
Common
Common
Common
Constipation
Very Common
Very Common
Very Common
Decreased appetite
Common
Very Common
Very Common
Diarrhoea
Very Common
Very Common
Very Common
Dyspepsia
Very Common
Very Common
Very Common
Esophagitis
Common
Common
Common
Eructation
Uncommon
Uncommon
Common
Flatulence
Common
Very Common
Very Common
Gastritis
Common
Common
Common
Gastrointestinal haemorrhage
Common
Common
Common
Gastrointestinal ulcer
Common
Common
Common
Gingival hyperplasia
Common
Common
Common
Ileus
Common
Common
Common

Adverse reaction

(MedDRA)

System Organ Class
Renal transplant

Hepatic transplant

Cardiac transplant

Mouth ulceration
Common
Common
Common
Nausea
Very Common
Very Common
Very Common
Pancreatitis
Uncommon
Common
Uncommon
Stomatitis
Common
Common
Common
Vomiting
Very Common
Very Common
Very Common
Immune system disorders
Hypersenstivity
Uncommon
Common
Common
Anaphylactic reactions
Not known
Not known
Not known
Hypogammaglobulinaemia
Uncommon
Very Rare
Very Rare
Hepatobiliary disorders
Blood alkaline phosphatase increased
Common
Common
Common
Blood lactate dehydrogenase increased
Common
Uncommon
Very Common
Hepatic enzyme increased
Common
Very Common
Very Common
Hepatitis
Common
Very Common
Uncommon
Hyperbilirubinaemia
Common
Very Common
Very Common
Jaundice
Uncommon
Common
Common
Skin and subcutaneous tissue disorders
Acne
Common
Common
Very Common
Alopecia
Common
Common
Common
Rash
Common
Very Common
Very Common
Skin hypertrophy
Common
Common
Very Common
Musculoskeletal and connective tissue disorders
Arthralgia
Common
Common
Very Common
Muscular weakness
Common
Common
Very Common
Renal and urinary disorders
Blood creatinine increased
Common
Very Common
Very Common
Blood urea increased
Uncommon
Very Common
Very Common
Haematuria
Very Common
Common
Common
Renal impairment
Common
Very Common
Very Common
General disorders and administration site conditions
Asthenia
Very Common
Very Common
Very Common
Chills
Common
Very Common
Very Common
Oedema
Very Common
Very Common
Very Common
Hernia
Common
Very Common
Very Common
Malaise
Common
Common
Common
Pain
Common
Very Common
Very Common
Pyrexia
Very Common
Very Common
Very Common
De novo purine synthesis inhibitors associated acute inflammatory syndrome
Uncommon
Uncommon
Uncommon

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 and other malignancies, particularly of the skin (see section 4.4). Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.

Infections
All patients treated with immunosuppressants are at increased risk of bacterial, viral and fungal infections (some of which may lead to a fatal outcome), including those caused by opportunistic agents and latent viral reactivation. The risk increases with total immunosuppressive load (see section 4.4). The most serious infections were sepsis, peritonitis, meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. The most common opportunistic infections in patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal, cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5%. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate mofetil.

Blood and lymphatic disorders
Cytopenias, including leukopenia, anaemia, thrombocytopenia and pancytopenia, are known risks associated with mycophenolate mofetil and may lead or contribute to the occurrence of infections and haemorrhages (see section 4.4). Agranulocytosis and neutropenia have been reported; therefore, regular monitoring of patients taking mycophenolate mofetil is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow failure in patients treated with mycophenolate mofetil, some of which have been fatal.

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

Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with mycophenolate mofetil. 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 mycophenolate mofetil.

Gastrointestinal disorders
The most serious gastrointestinal disorders were ulceration and haemorrhage which are known risks associated with mycophenolate mofetil. Mouth, oesophageal, gastric, duodenal, and intestinal ulcers often complicated by haemorrhage, as well as haematemesis, melena, and haemorrhagic forms of gastritis and colitis were commonly reported during the pivotal clinical trials. The most common gastrointestinal disorders, however, were diarrhoea, nausea and vomiting. Endoscopic investigation of patients with mycophenolate mofetil-related diarrhoea have revealed isolated cases of intestinal villous atrophy (see section 4.4).

Hypersensitivity
Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction have been reported.

Pregnancy, puerperium and perinatal conditions
Cases of spontaneous abortion have been reported in patients exposed to mycophenolate mofetil, mainly in the first trimester, see section 4.6.

Congenital disorders
Congenital malformations have been observed post-marketing in children of patients exposed to mycophenolate in combination with other immunosuppressants, see section 4.6.

Respiratory, thoracic and mediastinal disorders
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with mycophenolate mofetil in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults.

Immune system disorders
Hypogammaglobulinaemia has been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants.

General disorders and administration site conditions
Oedema, including peripheral, face and scrotal oedema, was reported very commonly during the pivotal trials. Musculoskeletal pain such as myalgia, and neck and back pain were also very commonly reported.

De novo purine synthesis inhibitors associated acute inflammatory syndrome has been described from post-marketing experience as a paradoxical proinflammatory reaction associated with mycophenolate mofetil and mycophenolic acid, characterised by fever, arthralgia, arthritis, muscle pain and elevated inflammatory markers. Literature case reports showed rapid improvement following discontinuation of the medicinal product.

Special populations

Paediatric population
The type and frequency of adverse reactions were assessed in a long-term clinical trial, which recruited 33 paediatric renal transplant patients, aged 3 years to 18 years, who were given 23 mg/kg of mycophenolate mofetil orally, twice daily. Overall, the safety profile in these 33 children and adolescents was similar to that observed in adult recipients of solid organ allografts.

Similar observations were made in another clinical trial, which recruited 100 paediatric renal transplant patients aged 1 to 18 years. The type and frequency of adverse reactions in patients who were given 600 mg/m2, up to 1 g/m2 of mycophenolate mofetil orally, twice daily, were comparable to those observed in adult patients given 1 g mycophenolate mofetil twice daily. A summary of the more frequently occurring adverse reactions is shown in table 3 below:

Table 3
Summary of adverse reactions observed more frequently in a trialinvestigating mycophenolate mofetil in 100 paediatric renal transplant patients (age/surface area-based dosing [600 mg/m2, up to 1 g/m2 BID.])