Myfortic 180 mg / 360 mg TABLETS

MYFORTIC is indicated in combination with ciclosporin for microemulsion and corticosteroids for the prevention of acute transplant rejection in adult patients receiving allogeneic renal transplants.

Posology

• Treatment with MYFORTIC should be initiated and maintained by appropriately qualified transplant specialists.
• MYFORTIC should be initiated in de novo patients within 48 hours following transplantation.
• The recommended dose is 720 mg (four 180 mg or two 360 mg MYFORTIC tablets) administered twice daily (1 440 mg daily dose).
• MYFORTIC can be taken with or without food.
• MYFORTIC tablets should not be crushed in order to retain the integrity of the enteric coating (see section 5.2).
• Avoid inhalation or direct contact with skin or mucous membrane of the powder, in case of accidental breaking of the MYFORTIC tablets.

Special populations

Elderly population:

No dose adjustment is required in this patient population.

Renal impairment:

No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). Patients with severe chronic renal impairment (glomerular filtration rate < 25 mLu00b7min - 1 u00b71,73 m - 2) should be carefully followed up.

Paediatric population:

Safety and efficacy in paediatric patients have not been established.

Treatment during rejection episodes:

Renal transplant rejection does not lead to changes in mycophenolic acid (MPA) pharmacokinetics; dosage reduction or interruption of MYFORTIC is not required.

Method of administration

For oral use.

• MYFORTIC is contraindicated in patients with a hypersensitivity to mycophenolate sodium, mycophenolic acid or mycophenolate mofetil or to any of the excipients.
• Pregnancy and lactation (see section 4.6).
• MYFORTIC should not be used in women of childbearing potential (WOCBP) who are not using highly effective contraception methods.

Patients with rare hereditary deficiency of hypoxanthine - guanine phosphoribosyl - transferase (HGPRT) MYFORTIC is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, 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.

Women of Childbearing potential (WOCBP), pregnancy and breastfeeding

Use of MYFORTIC during pregnancy is associated with an increased risk of pregnancy loss including spontaneous abortion and congenital malformations (see section 4.6). It is recommended that MYFORTIC therapy should not be initiated in woman of childbearing potential (WOCBP) until a negative pregnancy test has been obtained. For information on use in pregnancy and contraceptive requirements, (see section 4.6). MYFORTIC should not be used during breastfeeding (see section 4.6).

Malignancies

Patients receiving immunosuppressive regimens involving combinations of medicines, 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.

Infections

Patients receiving MYFORTIC should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Over suppression of the immune system increases the susceptibility to infection including opportunistic infections, fatal infections and sepsis (see section 4.8). Reactivation of hepatitis B (HBV) or hepatitis C (HCV) have been reported in patients treated with MYFORTIC. Monitoring infected patients for clinical and laboratory signs of active HBV or HCV infection is recommended. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with MYFORTIC (see section 4.8). The reported cases generally had risk factors for PML, including immunosuppressant therapies and impairment of immune functions. In immunosuppressed patients, medical practitioners should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection, should be included in the differential diagnosis in immunosuppressed patients with deteriorating renal function (see section 4.8). Consideration should be given to reducing the total immunosuppression in patients who develop PML or PVAN. In transplant patients, however, reduced immunosuppression may place the graft at risk.

Blood dyscrasias

Patients receiving MYFORTIC should be monitored for blood dyscrasias (e.g. neutropenia or anaemia - 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 dyscrasias occur (e.g. neutropenia with absolute neutrophil count < 1,5 x 10 3 /u03bcl or anaemia) it may be appropriate to interrupt or discontinue MYFORTIC. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MYFORTIC in combination with other immunosuppressive agents (see section 4.8). The mechanism for MYFORTIC MPA derivatives induced PRCA is unknown; the relative contribution of other immunosuppressants and their combinations in an immunosuppressive regimen are also unknown. However, MPA derivatives may cause blood dyscrasias (see above). In some cases, PRCA was found to be reversible with dose reduction or cessation of MYFORTIC therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk. Changes to MYFORTIC therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimize the risk of graft rejection.

Vaccinations

Patients should be advised that during treatment with MYFORTIC, 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.

Gastrointestinal disorders

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.

Combination with other medicines

MYFORTIC has been administered in combination with the following medicines in clinical trials: antithymocyte globulin, basiliximab, ciclosporin for microemulsion and corticosteroids. The efficacy and safety of the use of MYFORTIC with other immunosuppressive agents have not been studied.

Lactose warning:

MYFORTIC tablets contain lactose, which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with the rare hereditary conditions of galactose intolerance e.g., galactosaemia, Lapp lactase deficiency, glucose - galactose malabsorption or fructose intolerance should not take MYFORTIC.

Observed interactions resulting in a concomitant use not recommended

• Azathioprine: It is recommended that MYFORTIC not be administered concomitantly with azathioprine because such concomitant administration has not been studied.
• Live vaccines: Live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see section 4.4).

Observed interactions to be considered

Aciclovir: Higher plasma concentrations of both MPAG (mycophenolic acid glucuronide) and aciclovir may occur in the presence of renal impairment. Therefore, the potential exists for these two medicines to compete for tubular secretion, resulting in a further increase in the concentration of both MPAG and aciclovir. In this situation patients should be carefully followed up.

Gastroprotective medicines

Antacids with magnesium and aluminium hydroxides: The absorption of mycophenolate sodium was decreased when administered with antacids. Concomitant administration of MYFORTIC and antacids containing magnesium and aluminium hydroxide results in a 37 % decrease in MPA systemic exposure and a 25 % decrease in MPA maximal concentration. Caution should be used when co-administering antacids (containing magnesium and aluminium hydroxide) with MYFORTIC.

Proton Pump inhibitors: No changes in the pharmacokinetics of MPA were observed following concomitant administration of MYFORTIC and pantoprazole.

Anticipated interactions to be considered

Cholestyramine and medicines that interfere with enterohepatic circulation: Due to its capacity to block the enteric circulation of medicines, cholestyramine may decrease the systemic exposure of MPA. Caution should be used when co-administering cholestyramine or medicines that interfere with enterohepatic circulation because of the potential to reduce the efficacy of MYFORTIC.

Ganciclovir: MPA and MPAG pharmacokinetics are unaffected by the addition of ganciclovir. The clearance of ganciclovir is unchanged in the setting of therapeutic MPA exposure. However, in patients with renal impairment in which MYFORTIC and ganciclovir are co-administered the dose recommendations for ganciclovir should be observed and patients monitored carefully.

Tacrolimus: In a calcineurin cross - over study in stable renal transplant patients, steady state MYFORTIC pharmacokinetics were measured during both ciclosporin for microemulsion and tacrolimus treatments. Mean MPA AUC was 19 % higher and C max about 20 % lower. Conversely mean MPAG AUC and C max were about 30 % lower on tacrolimus treatment compared to Neoral u00ae treatment.

Oral contraceptives: Oral contraceptives undergo oxidative metabolism while MYFORTIC is metabolised by glucuronidation. A clinically significant effect of oral contraceptives on MYFORTIC pharmacokinetics is not anticipated. However, given that the long - term effect of MYFORTIC dosing on the pharmacokinetics of oral contraceptives is not known, it is possible that the efficacy of oral contraceptives may be adversely affected.

Ciclosporin A: When studied in stable renal transplant patients, ciclosporin A pharmacokinetics were unaffected by steady state dosing of MYFORTIC.

Women of childbearing potential/ Contraception in males and females

Effective contraception must be used before beginning MYFORTIC therapy, during therapy, and for six weeks following discontinuation of therapy (see section 4.5).

Pregnancy

Use of MYFORTIC during pregnancy is associated with an increased risk of congenital malformations. Although there are no adequate and well controlled studies in pregnant women. MYFORTIC is teratogenic in animals. MYFORTIC therapy should not be initiated until a negative pregnancy test has been obtained. Patients should be instructed to consult their medical practitioner immediately should pregnancy occur. Congenital malformations that have been reported with MYFORTIC include outer ear and other facial abnormalities including cleft lip and palate, congenital diaphragmatic hernia, anomalies of the distal limbs, heart, esophagus and kidney. Use of MYFORTIC during pregnancy was also reported to be associated with increased risk of spontaneous abortion.

Breastfeeding

It is not known whether MPA (mycophenolic acid) as contained in MYFORTIC is excreted in human milk. MYFORTIC should not be used during breastfeeding (see section 4.4). Because many drugs are excreted in human milk, and of the potential for serious adverse reactions in breastfed newborns/ infants a decision should be made whether to abstain from breastfeeding while on treatment and during 6 weeks after stopping the treatment or to abstain from using the medicinal product, taking into account the importance of the drug to the mother.

Fertility

Mycophenolate sodium had no effect on fertility of male rats at oral doses up to 40 mg/kg/day. The systemic exposure at this dose represents approximately 9 times the clinical exposure at the tested clinical dose of 1.44 g of MYFORTIC per day. No effects on female fertility were seen up to a dose of 20 mg/kg, a dose at which maternal toxicity and embryo toxicity were already observed.

Male patients

Sexually active men are recommended to use condoms during treatment, and for a total of 13 weeks after their last dose of MYFORTIC. In addition, female partners of the male patients are recommended to use highly effective contraception during treatment of the patient, and for a total of 13 weeks after the patientu2019s last dose of MYFORTIC. Semen donation: Based on animal data, men should not donate semen during therapy and for 90 days following discontinuation of MYFORTIC.

MYFORTIC has minor influence on psychomotor performance but may cause dizziness. Patients should be cautioned not to drive or use machines until they know how MYFORTIC affects them.

a. Summary of the safety profile

The following side effects cover adverse medicine reactions from two controlled clinical trials. The very common (u2265 10 %) adverse medicine reactions associated with the administration of MYFORTIC in combination with ciclosporin for microemulsion and corticosteroids, include leucopenia and diarrhoea. Malignancies: Patients receiving immunosuppressive regimens involving combinations of medicines, including MPA (mycophenolic acid), are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Overall rates of malignancies observed in MYFORTIC clinical trials are as follows: 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 % de novo and 1,8 % maintenance patients receiving MYFORTIC for up to 1 year; other types of malignancy occurred in 0,5 % de novo and 0,6 % maintenance patients.

Opportunistic infections: 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 CMV, candidiasis and herpes simplex. The overall rate of CMV infections (serology, viraemia or disease) observed in MYFORTIC clinical trials was reported in 21,6 % of de novo and in 1,9 % of maintenance renal transplant patients.

Elderly patients: Elderly patients may generally be at increased risk of adverse medicine reactions due to immunosuppression. Elderly patients receiving MYFORTIC as part of a combination immunosuppressive regimen did not show an increased risk of adverse reactions, compared to younger individuals in the MYFORTIC clinical trials.

Other Adverse Medicine Reactions: The table 1 below contains adverse medicine reactions possibly or probably related to MYFORTIC reported in the two phase III randomised, double-blind, controlled, multi-centre trials: 1 in de novo kidney transplant patients and 1 in maintenance kidney transplant patients, in which MYFORTIC was administered at a dose of 1 440 mg/day for 12 months together with ciclosporin microemulsion and corticosteroids.

Tabulated summary of adverse drug reactions from clinical trials

Adverse reactions are listed according to the following categories: Very common u2265 10 % (u2265 1/10) Common u2265 1 % and < 10 % (u2265 1/100 and < 1/10) Uncommon u2265 0,1 % and <1 % (u2265 1/1 000 and < 1/100) Rare u2265 0,01 % and < 0,1 % (u2265 1/10 000 and < 1/1 000) Very rare < 0,01 % (< 1/10 000)

Table 1 Adverse drug reactions possibly or probably related to MYFORTIC reported in the two - phase III pivotal trials Infections and infestations Very common Viral, bacterial and fungal infections Common Upper respiratory tract infections, pneumonia Uncommon Wound infection, sepsis*, osteomyelitis* Blood and lymphatic system disorders Very common Leucopenia Common Anaemia, thrombocytopenia Uncommon Lymphocele*, lymphopenia*, neutropenia*, lymphadenopathy* Nervous system disorders Common Headache, dizziness Uncommon Tremor, insomnia* Respiratory, thoracic and mediastinal disorders Common Cough, dyspnoea, dyspnoea exertional Uncommon Interstitial lung disease including fatal pulmonary fibrosis, pulmonary congestion*, wheezing* Gastrointestinal disorders Very common Diarrhoea Common Abdominal distension, abdominal pain, constipation, dyspepsia, flatulence, gastritis, loose stools, nausea, vomiting Uncommon Abdominal tenderness, pancreatitis, eructation, halitosis*, ileus*, oesophagitis*, peptic ulcer*, subileus*, gastrointestinal haemorrhage, dry mouth*, lip ulceration*, parotid duct obstruction*, gastro - oesophageal reflux disease*, gingival hyperplasia*, peritonitis* General disorders and administration site conditions Common Fatigue, oedema peripheral pyrexia Uncommon Influenza like illness, oedema lower limb*, pain, rigors*, weakness* Metabolism and nutrition disorders Very common Hypocalcaemia, hypokalaemia, hyperuricaemia Common Hyperkalaemia, hypomagnesaemia Uncommon Anorexia, hyperlipidaemia, diabetes mellitus*, hypercholesterolaemia*, hypophosphataemia Skin and subcutaneous tissue disorders Uncommon Alopecia, contusion*, acne, pruritis Hepato - biliary disorders Common Hepatic function tests abnormal Vascular disorders Very common Hypertension, hypotension Common Aggravated hypertension

*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. Adverse drug reactions from post marketing experience Skin and subcutaneous tissue disorders: Cardiac disorders Uncommon Tachycardia, pulmonary oedema* Eye disorders Uncommon Conjunctivitis*, vision blurred* Musculoskeletal, connective tissue and bone disorders Common Arthralgia, asthenia, myalgia Uncommon Back pain*, muscle cramps Neoplasms benign and malignant Uncommon Skin papilloma*, Basal cell carcinoma*, Kaposi's sarcoma*, lymphoproliferative disorder, squamous cell carcinoma* Psychiatric disorders Common Anxiety Uncommon Delusional perception* Renal and urinary disorders Common Increased blood creatinine Uncommon Haematuria*, renal tubular necrosis*, urethral stricture

Rash has been identified as an adverse drug reaction from post-approval clinical trials, post marketing surveillance and spontaneous reports. General disorders and administration site conditions: De novo purine synthesis inhibitors - associated acute inflammatory syndrome. The following adverse reactions have not been observed in the context of the two phase III randomised clinical trials with MYFORTIC, but are attributed to mycophenolic acid compounds as a class effect. The side effects listed below under each system organ class have been reported but frequencies are unknown. Gastrointestinal disorders: Colitis, CMV gastritis, intestinal perforation, duodenal ulcers. Infections and infestations: Serious, sometimes life-threatening infections, including meningitis, infectious endocarditis, tuberculosis, and atypical mycobacterial infection. Polyomavirus associated nephropathy (PVAN), especially due to BK virus infection. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported (see section 4.4).

Blood and lymphatic system disorders: Agranulocytosis, pancytopenia, neutropenia. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with MYFORTIC in combination with other immunosuppressive agents (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201cReport Drug Reaction Processu201d, found online under SAHPRAu2019s safety publications: https://www.sahpra.org.za/.

In overdose, side effects can be precipitated and/or be of increased severity. Symptomatic and supportive management should be used during overdose with MYFORTIC. If blood dyscrasias occur (e.g. neutropenia with absolute neutrophil count < 1.5 x 10 3 / micro L or anaemia) it may be appropriate to interrupt or discontinue MYFORTIC (see sections 4.4). 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.