Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Novartis Pharmaceuticals UK Limited, 2nd Floor, The WestWorks Building, White City Place, 195 Wood Lane, London, W12 7FQ, United Kingdom
Myfortic should not be used in patients with hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients (see section 6.1).
Myfortic should not be used in women of child bearing potential (WOCBP) who are not using highly effective contraception methods.
Myfortic should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).
Myfortic should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6).
Myfortic should not be given to women who are breastfeeding (see section 4.6).
Patients receiving immunosuppressive regimens involving combinations of drugs, including Myfortic, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Patients receiving Myfortic should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients treated with immunosuppressants, including Myfortic, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Among the opportunistic infections are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Myfortic in combination with other immunosuppressants. In some of these cases, switching MPA derivatives to an alternative immunosuppressant, resulted in serum IgG levels returning to normal. Patients on Myfortic 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 reports of bronchiectasis in patients who received Myfortic in combination with other immunosuppressants. In some of these cases, switching MPA derivatives 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 been also isolated reports of interstitial lung disease (see section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated for any evidence of underlying interstitial lung disease.
Reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with immunosuppressants, including the mycophenolic acid (MPA) derivatives Myfortic and mycophenolate mofetil (MMF). Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (which include mycophenolate mofetil and mycophenolate sodium) in combination with other immunosuppressants. The mechanism for MPA derivatives induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of therapy. Changes to Myfortic therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see Section 4.8).
Patients receiving Myfortic should be monitored for blood disorders (e.g. neutropenia or anemia – see section 4.8), which may be related to MPA itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Myfortic 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 blood disorders occur (e.g. neutropenia with absolute neutrophil count <1.5 × 103/µl or anemia) it may be appropriate to interrupt or discontinue Myfortic.
Patients should be advised that during treatment with MPA vaccinations may be less effective and the use of live attenuated vaccines should be avoided (see section 4.5).
Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Because MPA derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration and haemorrhage and perforation, Myfortic should be administered with caution in patients with active serious digestive system disease.
It is recommended that Myfortic not be administered concomitantly with azathioprine because concomitant administration of these drugs has not been evaluated.
Mycophenolic acid (as sodium salt) and mycophenolate mofetil should not be indiscriminately interchanged or substituted because of their different pharmacokinetic profiles.
Myfortic has been administered in combination with corticosteroids and ciclosporin.
There is limited experience with its concomitant use with induction therapies such as anti-T-lymphocyte globulin or basiliximab. The efficacy and safety of the use of Myfortic with other immunosuppressive agents (for example, tacrolimus) have not been studied.
Myfortic contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The concomitant administration of Myfortic and drugs which interfere with enterohepatic circulation, for example cholestyramine or activated charcoal, may result in sub-therapeutic systemic MPA exposure and reduced efficacy.
Myfortic 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.
Myfortic therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Myfortic therapy, during therapy and for six weeks following therapy discontinuation (see section 4.6).
Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45 to 49%) and congenital malformations (estimated rate of 23 to 27%) have been reported following mycophenolate mofetil exposure during pregnancy. Therefore Myfortic is contraindicated in pregnancy unless there are no suitable alternative treatments to prevent transplant rejection. Female patients of childbearing potential should be made aware of the risks and follow the recommendations provided in section 4.6. (e.g. contraceptive methods, pregnancy testing) prior to, during, and after therapy with Myfortic. 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.
Because of robust clinical evidence showing a high risk of abortion and congenital 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 (section 4.3) before starting Myfortic 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.
For contraception advice for men see section 4.6.
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.
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 at least 90 days following discontinuation of mycophenolate.
The following interactions have been reported between MPA and other medicinal products.
The potential for myelosuppression in patients receiving both Myfortic and aciclovir or ganciclovir has not been studied. Increased levels of mycophenolic acid glucuronide (MPAG) and aciclovir/ganciclovir may be expected when aciclovir/ganciclovir and Myfortic are administered concomitantly, possibly as a result of competition for the tubular secretion pathway.
The changes in MPAG pharmacokinetics are unlikely to be of clinical significance in patients with adequate renal function. In the presence of renal impairment, the potential exists for increases in plasma MPAG and aciclovir/ganciclovir concentrations; dose recommendations for aciclovir/ganciclovir should be followed and patients carefully observed.
MPA AUC and Cmax have been shown to decrease by approximately 37% and 25%, respectively, when a single dose of magnesium-aluminium containing antacids is given concomitantly with Myfortic. Magnesium aluminium-containing antacids may be used intermittently for the treatment of occasional dyspepsia. However the chronic, daily use of magnesium-aluminium containing antacids with Myfortic is not recommended due to the potential for decreased mycophenolic acid exposure and reduced efficacy.
In healthy volunteers, no changes in the pharmacokinetics of MPA were observed following concomitant administration of Myfortic and pantoprazole given at 40 mg twice daily during the four previous days. No data are available with other proton pump inhibitors given at high doses.
Interaction studies between MMF and oral contraceptives indicate no interaction. Given the metabolic profile of MPA, no interactions would be expected for Myfortic and oral contraceptives.
Caution should be used when co-administering drugs or therapies that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to decrease MPA exposure and thus reduce the efficacy of Myfortic.
When studied in stable renal transplant patients, ciclosporin pharmacokinetics were unaffected by steady state dosing of Myfortic. When co-administered with mycophenolate mofetil, ciclosporin is known to decrease the exposure of MPA. When co-administered with Myfortic, ciclosporin may decrease the concentration of MPA as well (by approximately 20%, extrapolated from mycophenolate mofetil data), but the exact extent of this decrease is unknown because such an interaction has not been studied. However, as efficacy studies were conducted in combination with ciclosporin, this interaction does not modify the recommended posology of Myfortic. In case of interruption or discontinuation of ciclosporin, Myfortic dosage should be re-evaluated depending on the immunosuppressive regimen.
In a calcineurin cross-over study in stable renal transplant patients, steady-state Myfortic pharmacokinetics were measured during both Neoral and tacrolimus treatment. Mean MPA AUC was 19% higher (90% CI: -3, +47), whereas mean MPAG AUC was about 30% lower (90% CI: 16, 42) on tacrolimus compared to Neoral treatment. In addition, MPA AUC intra-subject variability was doubled when switching from Neoral to tacrolimus. Clinicians should note this increase both in MPA AUC and variability, and adjustments to Myfortic dosing should be dictated by the clinical situation. Close clinical monitoring should be performed when a switch from one calcineurin inhibitor to another is planned.
Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.
Pregnancy whilst taking mycophenolate must be avoided. Therefore women of childbearing potential must use at least one form of reliable contraception (section 4.3) before starting Myfortic 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.
Myfortic is contraindicated during pregnancy unless there is no suitable alternative treatment available to prevent transplant rejection.
Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy.
Female patients of reproductive potential must be made aware of the increased risk of pregnancy loss and congenital malformations at the beginning of the treatment and must be counseled regarding pregnancy prevention and planning.
Before starting Myfortic treatment, women of child bearing potential should have two negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL in order to exclude unintended exposure of the embryo to mycophenolate. It is recommended that the second test should be performed 8-10 days after the first test. For transplants from deceased donors, if it is not possible to perform two tests 8-10 days apart before treatment starts (because of the timing of transplant organ availability), a pregnancy test must be performed immediately before starting treatment and a further test performed 8-10 days later. Pregnancy tests should be repeated as clinically required (e.g. after any gap in contraception is reported). Results of all pregnancy tests should be discussed with the patient. Patients should be instructed to consult their physician immediately should pregnancy occur.
Mycophenolate is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy:
Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to Myfortic in combination with other immunosuppressants during pregnancy. The following malformations were most frequently reported:
In addition there have been isolated reports of the following malformations:
Studies in animals have shown reproductive toxicity (see section 5.3).
Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to mycophenolate mofetil.
MPA is a powerful teratogen. It is not known if MPA is present in semen. Calculations based on animal data show that the maximum amount of MPA that could potentially be transferred to woman is so low that it would be unlikely to have an effect. Mycophenolate has been shown to be genotoxic in animal studies at concentrations exceeding the human therapeutic exposures by small margins, such that the risk of genotoxic effects on sperm cells cannot completely be excluded.
Therefore, the following precautionary measures are recommended: sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 90 days after cessation of mycophenolate. Male patients of reproductive potential should be made aware of and discuss the potential risks of fathering a child with a qualified health-care professional.
MPA is excreted in milk in lactating rats. It is unknown whether Myfortic is excreted in human breast milk. Because of the potential for serious adverse reactions to MPA in breast-fed infants, Myfortic is contra-indicated in women who are breast-feeding (see section 4.3).
No specific studies with Myfortic in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen up to a dose of 40 mg/kg and 20 mg/kg respectively (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed. The mechanism of action and pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.
The following undesirable effects cover adverse drug reactions from clinical trials:
Patients receiving immunosuppressive regimens involving combinations of drugs, including MPA, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 2 de novo (0.9%) patients and in 2 maintenance patients (1.3%) receiving Myfortic for up to 1 year. Non-melanoma skin carcinomas occurred in 0.9% of de novo and 1.8% of maintenance patients receiving Myfortic for up to 1 year; other types of malignancy occurred in 0.5% of de novo and 0.6% of maintenance patients.
All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see section 4.4). The most common opportunistic infections in de novo renal transplant patients receiving Myfortic with other immunosuppressants in controlled clinical trials of renal transplant patients followed for 1 year were cytomegalovirus (CMV), candidiasis and herpes simplex. CMV infection (serology, viraemia or disease) was reported in 21.6% of de novo and in 1.9% of maintenance renal transplant patients.
Elderly patients may generally be at increased risk of adverse drug reactions due to immunosuppression.
Table 1 below contains adverse drug reactions possibly or probably related to Myfortic reported in the controlled clinical trials in renal transplant patients, in which Myfortic was administered together with ciclosporin microemulsion and corticosteroids at a dose of 1,440 mg/day for 12 months. It is compiled according to MedDRA system organ class.
Adverse reactions are listed according to 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)
Table 1:
Very common: Viral, bacterial and fungal infections
Common: Upper respiratory tract infections, pneumonia
Uncommon: Wound infection, sepsis*, osteomyelitis*
Uncommon: Skin papilloma*, basal cell carcinoma*, Kaposi´s sarcoma*, lymphoproliferative disorder, squamous cell carcinoma*
Very common: Leukopenia
Common: Anaemia, thrombocytopenia
Uncommon: Lymphopenia*, neutropenia*, lymphadenopathy*
Very common: Hypocalcemia, hypokalemia, hyperuricemia
Common: Hyperkalemia, hypomagnesemia
Uncommon: Anorexia, hyperlipidaemia, diabetes mellitus*, hypercholesterolaemia*, hypophosphataemia
Very common: Anxiety
Uncommon: Abnormal dreams*, delusional perception*, insomnia*
Common: Dizziness, headache
Uncommon: Tremor
Uncommon: Conjunctivitis*, vision blurred*
Uncommon: Tachycardia, ventricular extrasystoles
Very common: Hypertension
Common: Hypotension
Uncommon: Lymphocele*
Common: Cough, dyspnoea
Uncommon: Interstitial lung disease, pulmonary congestion*, wheezing*, pulmonary oedema*
Very common: Diarrhoea
Common: Abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, nausea, vomiting
Uncommon: Abdominal tenderness, gastrointestinal haemorrhage, eructation, halitosis*, ileus*, lip ulceration*, oesophagitis*, subileus*, tongue discolouration*, dry mouth*, gastro-oesophageal reflux disease*, gingival hyperplasia*, pancreatitis, parotid duct obstruction*, peptic ulcer*, peritonitis*
Common: Liver function tests abnormal
Common: Acne, pruritus
Uncommon: Alopecia
Very common: Arthralgia
Common: Myalgia
Uncommon: Arthritis*, back pain*, muscle cramps
Common: Blood creatinine increased
Uncommon: Haematuria*, renal tubular necrosis*, urethral stricture
Uncommon: Impotence*
Common: Asthenia, Fatigue, oedema peripheral, pyrexia
Uncommon: Influenza like illness, oedema lower limb*, pain, rigors*, thirst*, weakness*
Uncommon: Contusion*
* event reported in a single patient (out of 372) only.
Note: renal transplant patients were treated with 1,440 mg Myfortic daily up to one year. A similar profile was seen in the de novo and maintenance transplant population although the incidence tended to be lower in the maintenance patients.
Rash and agranulocytosis have been identified as adverse drug reactions from post marketing experience.
The following additional adverse reactions are attributed to MPA derivatives as a class effect:
Infections and infestations: Serious, life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. 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 Myfortic (see section 4.4).
Blood and lymphatic system disorders: Neutropenia, pancytopenia.
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MPA derivatives (see section 4.4).
Immune system disorders: Hypogammaglobulinaemia has been reported in patients receiving Myfortic in combination with other immunosuppressants.
Respiratory, thoracic and mediastinal disorders: There have been isolated reports of interstitial lung disease in patients treated with Myfortic in combination with other immunosuppressants. There have also been reports of bronchiectasis in combination with other immunosuppressants.
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with MPA derivatives. 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 Myfortic.
Gastrointestinal disorders: Colitis, CMV gastritis, intestinal perforation, gastric ulcers, duodenal ulcers.
Pregnancy, puerperium and perinatal conditions: Cases of spontaneous abortion have been reported in patients exposed to mycophenolate 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).
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Not applicable.
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