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. If neutropenia develops, dosing with Micofenolato de Mofetil Generis should be interrupted or the dose reduced.
Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic re-circulation of the drug.
- Hypersensitivity reactions to Micofenolato de Mofetil Generis have been observed.
- Micofenolato de Mofetil Generis should not be given to women of childbearing potential who are not using highly effective contraception.
- Micofenolato de Mofetil Generis treatment should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy.
- Micofenolato de Mofetil Generis should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection.
- Micofenolato de Mofetil Generis should not be given to women who are breastfeeding.
The following undesirable effects cover adverse reactions from clinical trials:
The principal adverse reactions associated with the administration of Micofenolato de Mofetil Generis in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections.
Malignancies
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Micofenolato de Mofetil Generis, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. Lymphoproliferative disease or lymphoma developed in 0.6% of patients receiving Micofenolato de Mofetil Generis (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 3.6% of patients; other types of malignancy occurred in 1.1% of patients. 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.
Opportunistic infections
All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load. The most common opportunistic infections in patients receiving Micofenolato de Mofetil Generis (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal (2 g data), 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%.
Paediatric population
The type and frequency of adverse reactions in a clinical study, which recruited 92 paediatric patients aged 2 to 18 years who were given 600 mg/m2 mycophenolate mofetil orally twice daily, were generally similar to those observed in adult patients given 1 g Micofenolato de Mofetil Generis twice daily. However, the following treatment-related adverse events were more frequent in the paediatric population, particularly in children under 6 years of age, when compared to adults: diarrhoea, sepsis, leucopenia, anaemia and infection.
Elderly
Elderly patients (> 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving Micofenolato de Mofetil Generis 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.
Other adverse reactions
Adverse reactions, probably or possibly related to Micofenolato de Mofetil Generis, reported in >1/10 and in >1/100 to <1/10 of patients treated with Micofenolato de Mofetil Generis in the controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients are listed in the following table.
Adverse Reactions, Probably or Possibly Related to Micofenolato de Mofetil Generis, Reported in Patients Treated with Micofenolato de Mofetil Generis in Renal, Cardiac and Hepatic Clinical Trials when Used in Combination with Ciclosporin and Corticosteroids
Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System organ class | Adverse drug reactions | |
| Infections and infestations | Very common | Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster |
| Common | Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Very common | - |
| Common | Skin cancer, benign neoplasm of skin | |
| Blood and lymphatic system disorders | Very common | Leucopenia, thrombocytopenia, anaemia |
| Common | Pancytopenia, leukocytosis | |
| Metabolism and nutrition disorders | Very common | - |
| Common | Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, hyperuricaemia, gout, anorexia | |
| Psychiatric disorders | Very common | - |
| Common | Agitation, confusional state, depression, anxiety, thinking abnormal, insomnia | |
| Nervous system disorders | Very common | - |
| Common | Convulsion, hypertonia, tremor, somnolence, myasthenic syndrome, dizziness, headache, paraesthesia, dysgeusia | |
| Cardiac disorders | Very common | - |
| Common | Tachycardia | |
| Vascular disorders | Very common | - |
| Common | Hypotension, hypertension, vasodilatation | |
| Respiratory, thoracic and mediastinal disorders | Very common | - |
| Common | Pleural effusion, dyspnoea, cough | |
| Gastrointestinal disorders | Very common | Vomiting, abdominal pain, diarrhoea, nausea |
| Common | Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, oesophagitis, stomatitis, constipation, dyspepsia, flatulence, eructation | |
| Hepatobiliary disorders | Very common | - |
| Common | Hepatitis, jaundice, hyperbilirubinaemia | |
| Skin and subcutaneous tissue disorders | Very common | - |
| Common | Skin hypertrophy, rash, acne, alopecia, | |
| Musculoskeletal and connective Tissue disorders | Very common | - |
| Common | Arthralgia | |
| Renal and urinary disorders | Very common | - |
| Common | Renal impairment | |
| General disorders and administration site conditions | Very common | - |
| Common | Oedema, pyrexia, chills, pain, malaise, asthenia, | |
| Investigations | Very common | - |
| Common | Hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood urea increased, blood alkaline phosphatase increased, weight decreased | |
Note: 501 (2 g Micofenolato de Mofetil Generis daily), 289 (3 g Micofenolato de Mofetil Generis daily) and 277 (2 g IV / 3 g oral Micofenolato de Mofetil Generis daily) patients were treated in Phase III studies for the prevention of rejection in renal, cardiac and hepatic transplantation, respectively.
The following undesirable effects cover adverse reactions from post-marketing experience
The types of adverse reactions reported during post-marketing with Micofenolato de Mofetil Generis are similar to those seen in the controlled renal, cardiac and hepatic transplant studies. Additional adverse reactions reported during post-marketing are described below with the frequencies reported within brackets if known.
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.
Infections
Serious life-threatening infections including meningitis, endocarditis, tuberculosis and atypical mycobacterial infection. 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 Micofenolato de Mofetil Generis.
Agranulocytosis (>1/1000 to <1/100) and neutropenia have been reported; therefore regular monitoring of patients taking Micofenolato de Mofetil Generis is advised. There have been reports of aplastic anaemia and bone marrow depression in patients treated with Micofenolato de Mofetil Generis, some of which have been fatal.
Blood and lymphatic system disorder
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Micofenolato de Mofetil Generis.
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with Micofenolato de Mofetil Generis. 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 Micofenolato de Mofetil Generis.
Hypersensitivity
Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction have been reported.
Pregnancy, puerperium and perinatal conditions
Congenital disorders
Respiratory, thoracic and mediastinal disorders
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with Micofenolato de Mofetil Generis in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults (frequency not known).
Immune system disorders
Hypogammaglobulinaemia has been reported in patients receiving Micofenolato de Mofetil Generis in combination with other immunosuppressants (frequency not known).
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 (see details below).
Ireland
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In experimental models, mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2 - 3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day and 1.3 - 2 times the systemic exposure (AUC or Cmax) observed in cardiac transplant patients at the recommended clinical dose of 3 g/day.
Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.
Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg/kg/day. The systemic exposure at this dose represents 2 - 3 times the clinical exposure at the recommended clinical dose of 2 g/day in renal transplant patients and 1.3 - 2 times the clinical exposure at the recommended clinical dose of 3 g/day in cardiac transplant patients. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg/kg-/day caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.
In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg/kg/day (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg/kg/day (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day for renal transplant patients and approximately 0.3 times the clinical exposure at the recommended clinical dose of 3 g/day for cardiac transplant patients.
The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day for renal transplant recipients. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population.
Micofenolato de Mofetil Generis 1 g/5 ml powder for oral suspension is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants.
Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06
Mechanism of action
Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.
Absorption
Following oral administration, mycophenolate mofetil undergoes rapid and extensive absorption and complete presystemic metabolism to the active metabolite, MPA. As evidenced by suppression of acute rejection following renal transplantation, the immunosuppressant activity of Micofenolato de Mofetil Generis is correlated with MPA concentration. The mean bioavailability of oral mycophenolate mofetil, based on MPA AUC, is 94% relative to IV mycophenolate mofetil. Food had no effect on the extent of absorption (MPA AUC) of mycophenolate mofetil when administered at doses of 1.5 g BID to renal transplant patients. However, MPA Cmax was decreased by 40% in the presence of food. Mycophenolate mofetil is not measurable systemically in plasma following oral administration.
Distribution
As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA of approximately 40% is associated with the co-administration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation.
MPA at clinically relevant concentrations is 97% bound to plasma albumin.
Biotransformation
MPA is metabolised principally by glucuronyl transferase (isoform UGT1A9) to form the inactive phenolic glucuronide of MPA (MPAG). In vivo, MPAG is converted back to free MPA via enterohepatic recirculation. A minor acylglucuronide (AcMPAG) is also formed. AcMPAG is pharmacologically active and is suspected to be responsible for some of MMF´s side effects (diarrhoea, leucopenia).
Elimination
A negligible amount of substance is excreted as MPA (< 1% of dose) in the urine. Oral administration of radiolabelled mycophenolate mofetil results in complete recovery of the administered dose, with 93% of the administered dose recovered in the urine and 6% recovered in the faeces. Most (about 87%) of the administered dose is excreted in the urine as MPAG.
At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (> 100µg/mL), small amounts of MPAG are removed. By interfering with enterohepatic circulation of the drug, bile acid sequestrants such as cholestyramine, reduce MPA AUC.
MPA's disposition depends on several transporters. Organic anion-transporting polypeptides (OATPs) and multidrug resistance-associated protein 2 (MRP2) are involved in MPA's disposition; OATP isoforms, MRP2 and breast cancer resistance protein (BCRP) are transporters associated with the glucuronides' biliary excretion. Multidrug resistance protein 1 (MDR1) is also able to transport MPA, but its contribution seems to be confined to the absorption process. In the kidney MPA and its metabolites potently interact with renal organic anion transporters.
In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30% lower and Cmax approximately 40% lower compared to the late post-transplant period (3 - 6 months post-transplant).
Special populations
Renal impairment
In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25mL/min/1.73 m2) were 28 - 75% higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. The mean single dose MPAG AUC was 3 - 6-fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for cardiac or hepatic transplant patients with severe chronic renal impairment.
Delayed renal graft function
In patients with delayed renal graft function post-transplant, mean MPA AUC (0-12h) was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC (0-12h) was 2 - 3-fold higher than in post-transplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of Micofenolato de Mofetil Generis does not appear to be necessary.
Hepatic impairment
In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.
Paediatric population
Pharmacokinetic parameters were evaluated in 49 paediatric renal transplant patients (aged 2 to 18 years) given 600 mg/m2 mycophenolate mofetil orally twice daily. This dose achieved MPA AUC values similar to those seen in adult renal transplant patients receiving Micofenolato de Mofetil Generis at a dose of 1 g bid in the early and late post-transplant period. MPA AUC values across age groups were similar in the early and late post-transplant period.
Elderly
Pharmacokinetic behaviour of Micofenolato de Mofetil Generis in the elderly (> 65 years) has not been formally evaluated.
Patients taking oral contraceptives
A study of the co-administration of Micofenolato de Mofetil Generis (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 non-transplant women (not taking other immunosupressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of Micofenolato de Mofetil Generis on the ovulation suppressing action of the oral contraceptives.).
Neoplasms
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Micofenolato de Mofetil Generis, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. 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.
Infections
Patients treated with immunosuppressants, including Micofenolato de Mofetil Generis, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis. 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.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Micofenolato de Mofetil Generis in combination with other immunosuppressants. In some of these cases switching Micofenolato de Mofetil Generis to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on Micofenolato de Mofetil Generis 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 Micofenolato de Mofetil Generis in combination with other immunosuppressants. In some of these cases switching Micofenolato de Mofetil Generis 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. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal. It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
Blood and immune system
Patients receiving Micofenolato de Mofetil Generis should be monitored for neutropenia, which may be related to Micofenolato de Mofetil Generis itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Micofenolato de Mofetil Generis 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. If neutropenia develops (absolute neutrophil count < 1.3 x 103/µl), it may be appropriate to interrupt or discontinue Micofenolato de Mofetil Generis.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Micofenolato de Mofetil Generis in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of Micofenolato de Mofetil Generis therapy. Changes to Micofenolato de Mofetil Generis therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection.
Patients receiving Micofenolato de Mofetil Generis should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients should be advised that during treatment with Micofenolato de Mofetil Generis, vaccinations may be less effective, and the use of live attenuated vaccines should be avoided. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Gastro-intestinal
Micofenolato de Mofetil Generis has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation. Micofenolato de Mofetil Generis should be administered with caution in patients with active serious digestive system disease.
Micofenolato de Mofetil Generis is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. Therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
Interactions
Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with MPA enterohepatic recirculation, e.g. ciclosporin, to others devoid of this effect, e.g. tacrolimus, sirolimus, belatacept, or vice versa, as this might result in changes of MPA exposure.). Therapeutic drug monitoring of MPA may be appropriate when switching combination therapy (e.g. from ciclosporin to tacrolimus or vice versa) or to ensure adequate immunosuppression in patients with high immunological risk (e.g. risk of rejection, treatment with antibiotics).
It is recommended that Micofenolato de Mofetil Generis should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.
Micofenolato de Mofetil Generis 1 g/5 ml powder for oral suspension contains aspartame. Therefore, care should be taken if Micofenolato de Mofetil Generis 1 g/5 ml powder for oral suspension is administered to patients with phenylketonuria
This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Special populations
Elderly patients may be at an increased risk of adverse events such as certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared with younger individuals.
Teratogenic effects
Mycophenolate is a powerful human teratogen.(e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with Micofenolato de Mofetil Generis. Physicians should ensure that women taking mycophenolate understand the risk of harm to the baby, the need for effective contraception, and the need to immediately consult their physician if there is a possibility of pregnancy.
Contraception
Because of robust clinical evidence showing a high risk of abortion and congential malformations when mycophenolate mofetil is used in pregnancy every effort to avoid pregnancy during treatment should be taken. Therefore women with childbearing potential must use at least one form of reliable contraception before starting Micofenolato de Mofetil Generis therapy, during therapy, and for six weeks after stopping the therapy, unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preferred to minimise the potential for contraceptive failure and unintended pregnancy.
Educational materials
In order to assist patients in avoiding foetal exposure to mycophenolate and to provide additional important safety information, the Marketing Authorisation holder will provide educational materials to healthcare professionals. The educational materials will reinforce the warnings about the teratogenicity of mycophenolate, provide advice on contraception before therapy is started and guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures should be given by the physician to women of childbearing potential and, as appropriate, to male patients.
Additional precautions
Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate. Men should not donate semen during therapy or for 90 days following discontinuation of mycophenolate.
No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.
Treatment with Micofenolato de Mofetil Generis should be initiated and maintained by appropriately qualified transplant specialists.
Posology
Use in renal transplant
Adults
Oral Micofenolato de Mofetil Generis 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.
Paediatric population aged 2 to 18 years
The recommended dose of Micofenolato de Mofetil Generis 1 g/5 ml powder for oral suspension is 600 mg/m2 administered twice daily (up to a maximum of 2 g/10 mL oral suspension daily). As some adverse reactions occur with greater frequency in this age group 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.
Paediatric population < 2 years
There are limited safety and efficacy data in children below the age of 2 years. These are insufficient to make dosage recommendations, and therefore use in this age group is not recommended.
Use in cardiac transplant
Adults
Oral Micofenolato de Mofetil Generis 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).
Paediatric population
No data are available for paediatric cardiac transplant patients.
Use in hepatic transplant
Adults
IV Micofenolato de Mofetil Generis should be administered for the first 4 days following hepatic transplant, with oral Micofenolato de Mofetil Generis 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
No data are available for paediatric hepatic transplant patients.
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.. 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
Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of Micofenolato de Mofetil Generis is not required. There is no basis for Micofenolato de Mofetil Generis dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.
Method of administration
Oral administration.
Note: If required, Micofenolato de Mofetil Generis 1 g/5 ml powder for oral suspension can be administered via a nasogastric tube with a minimum size of 8 French (minimum 1.7 mm interior diameter).
Precautions to be taken before handling or administering the medicinal product.
Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid inhalation or direct contact with skin or mucous membranes of the dry powder as well as direct contact of the reconstituted suspension with the skin. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.
It is recommended that Micofenolato de Mofetil Generis 1 g/5 ml powder for oral suspension be reconstituted by the pharmacist prior to dispensing to the patient. Wearing disposable gloves is recommended during reconstitution and when wiping the outer surface of the bottle/cap and the table after reconstitution.
Preparation of suspension
1. Tap the closed bottle several times to loosen the powder.
2. Measure 94 mL of purified water in a graduated cylinder.
3. Add approximately half of the total amount of purified water to the bottle and shake the closed bottle well for about 1 minute.
4. Add the remainder of water and shake the closed bottle well for about 1 minute.
5. Remove child-resistant cap and push bottle adapter into neck of bottle.
6. Close bottle with child-resistant cap tightly. This will assure the proper seating of the bottle adapter in the bottle and child-resistant status of the cap.
7. Write the date of expiration of the reconstituted suspension on the bottle label. (The shelf-life of the reconstituted suspension is two months.)
Any unused product or waste material should be disposed of in accordance with local requirements.
