Mycocept 250 250 mg Capsules

MYCOCEPT 250 is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac and hepatic transplants.

Treatment with MYCOCEPT 250 should be initiated and maintained by appropriately qualified transplant specialists.

Posology:

Use in renal transplant:

• Adults: Oral MYCOCEPT 250 should be initiated within 72 hours following transplantation. The recommended dose in renal transplant patients is 1 g orally twice daily (2 g daily dose).
• Paediatric population aged 3 months to 18 years: The recommended dose of MYCOCEPT 250 is 600 mg/m2 administered orally twice daily (up to a maximum of 2 g daily). Patients with a body surface area of 1.25 to 1.5 m2 may be prescribed MYCOCEPT 250 at a dosage of 750 mg twice daily (1.5 g daily dose). Patients with a body surface area greater than 1.5 m2 may be prescribed MYCOCEPT 250 at a dose of 1 g twice daily (2 g daily dose). As some adverse reactions occur with greater frequency in this age group (see section 4.8) compared to adults, temporary dose reduction or interruption may be required; these will need to take into account relevant clinical factors including severity of reaction.

Use in cardiac transplant:

• Adults: Oral MYCOCEPT 250 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: Intravenous mycophenolate mofetil should be administered for the first 4 days following hepatic transplant, with oral MYCOCEPT 250 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.

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

Renal impairment: In renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 mL/min/1.73 m2), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2).

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 MYCOCEPT 250. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of MYCOCEPT 250 is not required. There is no basis for MYCOCEPT 250 dose adjustment following cardiac transplant rejection. No pharmacokinetic data are available during hepatic transplant rejection.

Method of administration: Oral administration: MYCOCEPT 250 can be taken with or without food. MYCOCEPT 250 capsules should not be emptied in order to retain the integrity of the medicine.

Precautions to be taken before handling or administering the medicine: Because mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, MYCOCEPT 250 capsules should not be opened or crushed to avoid inhalation or direct contact with skin or mucous membranes of the powder contained in MYCOCEPT 250 capsules. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.

MYCOCEPT 250 should not be given to patients with hypersensitivity to mycophenolate mofetil, or mycophenolic acid or to any of the excipients (see section 6.1). Hypersensitivity reactions to MYCOCEPT 250 have been observed (see section 4.8).

MYCOCEPT 250 should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6).

MYCOCEPT 250 treatment should not be initiated in women of childbearing potential without providing a pregnancy test result to rule out unintended use in pregnancy (see section 4.6).

MYCOCEPT 250 should not be given to women who are breastfeeding (see section 4.6).

Paediatric (see section 4.2) cardiac and hepatic transplant patients.

Neoplasms: Patients receiving immunosuppressive regimens involving combinations of medicines, including MYCOCEPT 250, 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 medicine. 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 MYCOCEPT 250, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). 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 doctors should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Mycophenolic acid has a cytostatic effect on B- and T- lymphocytes, therefore an increased severity of COVID-19 may occur, and appropriate clinical action should be considered.

There have been reports of hypogammaglobinaemia in association with recurrent infections in patients receiving mycophenolate mofetil in combination with other immunosuppressants. In some of these cases, switching mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on MYCOCEPT 250 who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobinaemia, 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 mycophenolate mofetil in combination with other immunosuppressants. In some of these cases, switching mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobinaemia 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 (see section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea be investigated.

Blood and immune system: Patients receiving MYCOCEPT 250 should be monitored for neutropenia, which may be related to MYCOCEPT 250 itself, concomitant medications, viral infections, or some combination of these causes. Patients taking MYCOCEPT 250 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/u03bcL) it may be appropriate to interrupt or discontinue treatment with MYCOCEPT 250.

Cases of Pure Red Cell Aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil in combination with other immunosuppressants. The mechanism for mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of mycophenolate mofetil therapy. Changes to MYCOCEPT 250 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 MYCOCEPT 250 should be instructed to immediately report any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression. Patients should be advised that during treatment with MYCOCEPT 250, 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: Because MYCOCEPT 250 derivatives have been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract, ulceration and haemorrhage and perforation, MYCOCEPT 250 should be administered with caution in patients with active serious digestive system disease. MYCOCEPT 250 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.

Caution should be exercised when switching combination therapy from regimens containing immunosuppressants, which interfere with mycophenolic acid (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. Medicines which interfere with MPAu2019s enterohepatic cycle (e.g. cholestyramine, antibiotics) should be used with caution due to their potential to reduce the plasma levels and efficacy of MYCOCEPT 250 (see section 4.5). Therapeutic medicinal 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, additional or removal of interacting medication).

It is recommended that MYCOCEPT 250 should not be administered concomitantly with azathioprine because such concomitant administration has not been studied. MYCOCEPT 250 has been administered in combination with the following medicines in clinical trials: antithymocyte globulin, basiliximab, ciclosporin and corticosteroids. The efficacy and safety of the use of MYCOCEPT 250 with other immunosuppressive medicines have not been established, including the risk/benefit ratio of MYCOCEPT 250 in combination with sirolimus. Caution should be used when co-administering antacids containing magnesium and aluminium hydroxide with MYCOCEPT 250 (see section 4.5).

Women of childbearing potential: Pregnancy whilst taking MYCOCEPT 250 must be avoided. Therefore, women of childbearing potential must use at least one form of reliable contraception before starting MYCOCEPT 250 therapy, during therapy, and for six weeks following discontinuation of therapy (see section 4.3), unless abstinence is the chosen method of contraception. Two complementary forms of contraception simultaneously are preferred.

Men: Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to MYCOCEPT 250. 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. MYCOCEPT 250 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 MYCOCEPT 250. Male patients of reproductive potential should be made aware of and discuss the potential risks of fathering a child with a qualified healthcare professional.

Pregnancy: Safety and efficacy in pregnant women has not been established. MYCOCEPT 250 is contraindicated during pregnancy (see section 4.3). MYCOCEPT 250 therapy should not be initiated until a negative pregnancy test has been obtained. 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 counselled regarding pregnancy prevention and planning. Before starting MYCOCEPT 250 treatment, women of childbearing 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 MYCOCEPT 250. It is recommended that the second test should be performed 8 to 10 days after the first test. For transplants from deceased donors, if it is not possible to perform two tests 8 to 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 to 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 doctor immediately should pregnancy occur. MYCOCEPT 250 is a powerful human teratogen, with an increased risk of spontaneous abortions and congenital malformations in case of exposure during pregnancy:

• Spontaneous abortions have been reported in 45 to 49 % of pregnant women exposed to mycophenolate mofetil, compared to a reported rate of between 12 and 33 % in solid organ transplant patients treated with immunosuppressants other than mycophenolate mofetil.
• Based on literature reports, malformations occurred in 23 to 27 % of live births in women exposed to mycophenolate mofetil during pregnancy (compared to 2 to 3 % of live births in the overall population and approximately 4 to 5 % of live births in solid organ transplant recipients treated with immunosuppressants other than mycophenolate mofetil).
• Congenital malformations, including reports of multiple malformations, have been observed post-marketing in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy.

The following malformations were most frequently reported:

• Facial malformations such as cleft lip, cleft palate, micrognathia and hypertelorism of the orbits.
• Abnormalities of the ear (e.g. abnormally formed or absent external ear), external auditory canal atresia (middle ear).
• Abnormalities of the eye (e.g. coloboma, microphthalmos).
• Malformations of the fingers (e.g. polydactyly, syndactyly, brachydactyly).
• Congenital heart disease such as atrial and ventricular septal defects.
• Malformations of the fingers (e.g. polydactyly, syndactyly).
• Tracheo-oesophageal malformations (e.g. oesophageal atresia).
• Nervous system malformations such as spina bifida.
• Renal abnormalities.

In addition, there have been isolated reports of the following malformations:

• Microphthalmia.
• Congenital choroid plexus cyst.
• Septum pellucidum agenesis.
• Olfactory nerve agenesis.

Studies in animals have shown reproductive toxicity (see section 5.3).

Breastfeeding: Limited data show that mycophenolic acid is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolic acid in breast-fed infants, MYCOCEPT 250 is contraindicated in nursing mothers (see section 4.3).

MYCOCEPT 250 has moderate influence on the ability to drive and use machines. MYCOCEPT 250 may cause somnolence, confusion, dizziness, tremor or hypotension, and therefore patients are advised to use caution when driving or using machines.

The following undesirable effects cover adverse reactions from clinical trials:

The principal adverse reactions associated with the administration of MYCOCEPT 250 in combination with ciclosporin and corticosteroids include leukopenia, sepsis, vomiting and diarrhoea, and there is evidence of a higher frequency of certain types of infections (see section 4.4).

Malignancies: Patients receiving immunosuppressive regimens involving combinations of medicines, including MYCOCEPT 250, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 0.6 % of patients receiving mycophenolate mofetil (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 (see section 4.4). The most common opportunistic infections in patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials in renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viremia/syndrome and Herpes simplex. The proportion of patients with CMV viremia/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 mycophenolate mofetil 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, leukopenia, anaemia and infection.

Elderly patients: Elderly patients (u2265 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving MYCOCEPT 250 as part of a combination immunosuppressive regimen did not show an increased risk of adverse reaction compared to younger individuals in the MYCOCEPT 250 clinical trial, however elderly patients may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema.

Other Adverse Reactions: The table below contains reported adverse medicine reactions.

Body system Incidence Adverse reaction

Infections and infestations Frequent Sepsis, gastrointestinal candidiasis, viral, bacterial and fungal infections, including urinary tract infection, herpes simplex, herpes zoster, wound infection, osteomyelitis, pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis, abscess, cellulitis, bacterial infections, fungal infections, viral infections.

Less frequent Protozoal Infections.

Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Frequent Skin cancer, including skin papilloma, basal cell carcinoma, Kaposi's sarcoma, squamous cell carcinoma, benign neoplasm of skin, cysts (including lymphocele and hydrocele).

Less frequent Lymphoma, lymphoproliferative disorder.

Blood and lymphatic system disorders Frequent Leukopenia, anaemia, thrombocytopenia, lymphocele, lymphopenia, neutropenia, lymphadenopathy, pancytopenia, leucocytosis, ecchymosis, haemorrhage, petechial, increased prothrombin time, increased thromboplastin time.

Less Frequent Aplasia pure red cell, bones marrow failure, pseudolymphoma.

Endocrine disorders Frequent Diabetes mellitus, parathyroid disorder (elevated PTH level), Cushingu2019s syndrome, hypothyroidism.

Metabolism and nutrition disorders Frequent Anorexia, hyperlipidaemia, diabetes mellitus, hypercholesterolemia, hyperphosphatemia, acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hyperuricemia, gout, weight decreased, hypercholesterolaemia, hyperlipidaemia, weight decreased, elevated blood urea, elevated creatinine, elevated enzyme levels (lactic dehydrogenase, AST and ALT), hypervolaemia, hyponatraemia, hypoproteinaemia, dehydration, alkalosis, hypochloraemia, hypoxia, respiratory acidosis, thirst.

Psychiatric disorders Frequent Agitation, confusional state, depression, anxiety, thinking abnormal, insomnia, emotional lability, hallucinations, delirium, psychosis.

Nervous system disorders Frequent Headache, tremor, convulsion, hypertonia, somnolence, myasthenic syndrome, dizziness, paraesthesia, dysgeusia, hypertonia, neuropathy, vertigo, hyperaesthesia.

Eye disorders Frequent Conjunctivitis, blurred vision, amblyopia, cataract, conjunctivitis, abnormal vision, eye haemorrhage.

Ear and labyrinth disorders Frequent Ear pain, deafness, tinnitus.

Cardiac disorders Frequent Tachycardia, pulmonary oedema, ventricular extrasystoles, dysrhythmia, bradycardia, cardiac failure, pericardial effusion, angina pectoris, atrial fibrillation, cardiac arrest, pulmonary hypertension.

Vascular disorders Frequent Hypotension, hypertension, vasodilatation, venous thrombosis, postural hypotension, syncope, vasospasm, increased venous pressure.

Less Frequent Lymphocele Respiratory, thoracic and mediastinal disorders Frequent Cough, wheezing, pulmonary congestion, pleural effusion, dyspnoea, asthma, atelectasis, pulmonary oedema.

Less Frequent Bronchiectasis, Interstitial lung disease Pulmonary fibrosis Gastrointestinal disorders Frequent Diarrhoea, abdominal pain, nausea, vomiting, abdominal distension, abdominal tenderness, constipation, dyspepsia, flatulence, gastritis, loose stools, ileus, colitis, oesophagitis, peptic ulcer, duodenal ulcer, gastrointestinal haemorrhage, gastro-oesophageal reflux disease, gingival hyperplasia, peritonitis, stomatitis, eructation, decreased appetite, gastritis, gastrointestinal ulcer, pancreatitis, mouth ulceration, enlarged abdomen, hernia, oral moniliasis, cholangitis, gingivitis, gum hyperplasia, melaena, dysphagia, rectal disorder.

Less frequent Pancreatitis, halitosis, subileus, tongue discolouration, dry mouth, eructation.

Immune system disorders Frequent Hypersensitivity.

Less Frequent Hypogammaglobulinaemia Hepato-biliary disorders Frequent Hepatitis, jaundice, hyperbilirubinemia, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, hepatic enzyme increased, ascites.

Skin and subcutaneous tissue disorders Frequent Alopecia, skin hypertrophy, rash, acne.

Less frequent Contusion, skin hypertrophy (including actinic keratosis), rash, acne, alopecia, pruritus, sweating, hirsutism, skin ulcer, facial oedema.

Musculoskeletal and connective tissue disorders Frequent Arthralgia, muscle weakness, pelvic pain, neck pain, leg cramps, myalgia, osteoporosis.

Renal and urinary disorders Frequent Renal tubular necrosis, urethral stricture, renal impairment, blood creatinine increased, blood urea increased, renal impairment, haematuria, abnormal kidney function (decrease in renal function, elevated serum creatinine), oliguria, albuminuria, dysuria, hydronephrosis, pyelonephritis, urinary frequency, nocturia, renal failure, urinary incontinence, urinary retention, scrotal oedema.

General disorders and administration site conditions Frequent Fatigue, pyrexia, influenza-like illness, oedema, pain, asthenia, chills, pallor, hernia and malaise.

Less frequent De novo purine synthesis inhibitors associated acute inflammatory syndrome

Reproductive system and breast disorders Frequent Impotence.

Investigations Frequent Hepatic function tests abnormal, hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood urea increased.

Note: 501 (2 g mycophenolate mofetil daily), 289 (3 g mycophenolate mofetil daily) and 277 (2 g IV/3 g oral mycophenolate mofetil 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 mycophenolate mofetil 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 disorders: Gingival hyperplasia (frequent), colitis including cytomegalovirus (CMV) colitis (frequent), pancreatitis (frequent), intestinal villous atrophy and intestinal perforation.

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 Leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate mofetil. Agranulocytosis (less frequent) and neutropenia have been reported; therefore, regular monitoring of patients taking MYCOCEPT 250 is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow depression in patients treated with mycophenolate mofetil, some of which have been fatal.

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 medicine. It is expected that an overdose of MYCOCEPT 250 could possibly result in over suppression of the immune system and increase susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, dosing with MYCOCEPT 250 should be interrupted or the dose reduced (see section 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 of MYCOCEPT 250. By interfering with enterohepatic circulation of MYCOCEPT 250, bile acid sequestrants, such as cholestyramine, may reduce the systemic MYCOCEPT 250 exposure. Treatment is symptomatic and supportive.