Myfortic

/ Novartis

Treatment with Mycophenolic Acid should be initiated and maintained by appropriately qualified transplant specialists. The recommended dose is 720 mg (four 180 mg or two 360 mg Myfortic film coated tablets) administered twice daily (1,440 mg daily dose). In patients receiving mycophenolate mofetil (MMF) 2 g, treatment can be replaced by 720 mg administered twice daily (1,440 mg daily dose) of Mycophenolic Acid.
In de novo patients, Mycophenolic Acid should be initiated within 48 hours following transplantation.
Mycophenolic Acid can be taken with or without food. Patients may select either option but must adhere to their selected option. In order to retain the integrity of the enteric coating, Mycophenolic Acid tablets should not be crushed. Where crushing of Mycophenolic Acid tablets is necessary, avoid inhalation of the powder or direct contact of the powder with skin or mucous membrane. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water. This is due to the teratogenic effects of mycophenolate.
Paediatric population and adolescents: Insufficient data are available to support the efficacy and safety of Mycophenolic Acid in children and adolescents. Limited pharmacokinetic data are available for paediatric renal transplant patients.
Geriatric patients: No dose adjustment is required in this patient population.
Patients with renal impairment: In patients experiencing delayed renal graft function post-operatively, no dose adjustments are needed. Patients with severe renal impairment (glomerular filtration rate <25 ml·min-¹·1.73 m-²) should be carefully followed up.
Patients with hepatic impairment: No dose adjustments are needed for renal transplant patients with severe hepatic impairment.
Treatment during rejection episodes: Renal transplant rejection does not lead to changes in mycophenolic acid (MPA) pharmacokinetics; dosage reduction or interruption of mycophenolic acid is not required.

Indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult patients receiving allogeneic renal transplants.

Patients with hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients. Women of child bearing potential (WOCBP) who are not using highly effective contraception methods. The drug should not be initiated in women of child bearing potential without providing a pregnancy test result to rule out unintended use in pregnancy. Mycophenolic Acid should not be used in pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Breastfeeding. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Patients receiving immunosuppressive regimens involving combinations of drugs, including Myfortic, 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. 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. 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 ombination 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 ombination 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. 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.
Patients receiving Myfortic should be monitored for blood disorders (e.g neutropenia or anemia), 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 x 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. 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.
Teratogenic effects: Mycophenolate is a powerful human teratogen. Spontaneous abortion (rate of 45-49%) and congenital malformations (estimated rate of 23-27%) have been reported following mycophenolate mofetil exposure during pregnancy.
Contraception: For patients who are considering pregnancy, consider alternative immunosuppressants with less potential for embryofetal toxicity. Risks and benefits of Mycophenolic Acid should be discussed with the patient Because of the genotoxic and teratogenic potential of Mycophenolic Acid, women with childbearing potential should use two reliable forms of contraception simultaneously before starting Mycophenolic Acid therapy, during therapy, and for six weeks after stopping the therapy; unless abstinence is the chosen method of contraception.
Additional precautions: Patients should not donate blood during therapy or for at least 6 weeks following discontinuation of mycophenolate.
See prescribing information for full details.

Lymphomas and other malignancies (particularly of the skin), Viral, bacterial and fungal infections,Upper respiratory tract infections, pneumonia,Leukopenia, Anaemia, thrombocytopenia, Hypocalcemia, hypokalemia, hyperuricemia, Hyperkalemia, hypomagnesemia, Anxiety, Dizziness, headache, Hypertension, Hypotension, Cough, dyspnoea, Diarrhoea, Abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, nausea, vomiting, Liver function tests abnormal, Acne, pruritus, Arthralgia, Myalgia, Blood creatinine increased, Asthenia, Fatigue, oedema peripheral, pyrexia.
See prescribing information for full details.

The following interactions have been reported between MPA and other medicinal products:
Aciclovir and ganciclovir: 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.
Gastroprotective agents:
Magnesium and aluminium containing antacids: 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 Mycophenolic Acid. 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.
Proton pump inhibitors: In healthy volunteers, no changes in the pharmacokinetics of MPA were observed following concomitant administration of Mycophenolic Acid 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.
Oral contraceptives: Interaction studies between MMF and oral contraceptives indicate no interaction. Given the metabolic profile of MPA, no interactions would be expected for Mycophenolic Acid and oral contraceptives.
Cholestyramine and drugs that bind bile acids: 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 Mycophenolic Acid.
Ciclosporin: When studied in stable renal transplant patients, ciclosporin pharmacokinetics were unaffected by steady state dosing of Mycophenolic Acid. When co-administered with mycophenolate mofetil, ciclosporin is known to decrease the exposure of MPA.
Tacrolimus: In a calcineurin cross-over study in stable renal transplant patients, steady-state Myfortic pharmacokinetics were measured during both Neoral and tacrolimus treatment.
Live attenuated vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished.
See prescribing information for full details.

Pregnancy: 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.
Lactation: 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 contraindicated in women who are breast-feeding.
See prescribing information for full details.

There have been reports of intentional or accidental overdoses with Myfortic, whereas not all patients experienced related adverse events.
In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the class (mainly blood dyscrasias, sepsis…). Although dialysis may be used to remove the inactive metabolite MPAG, it would not be expected to remove clinically significant amounts of the active moiety MPA. This is in large part due to the very high plasma protein binding of MPA, 97%. By interfering with enterohepatic circulation of MPA, bile acid sequestrants, such as cholestyramine, may reduce the systemic MPA exposure.

Food: Mycophenolic Acid can be taken with or without food. Patients may select either option but must adhere to their selected option.
Storage: Do not store above 30°C. Store in the original package in order to protect from moisture.