Mycophenolate mofetil Teva · 4.1 Therapeutic indications · 2

HOS-154314 · has-adverse-reaction-information · PDF-Seite 33

Summary of the safety profile Diarrhoea (up to 52.6%), leukopenia (up to 45.8%), bacterial infections (up to 39.9%) and vomiting (up to 39.1%) were among the most common and/or serious adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4). Tabulated list of adverse reactions The adverse reactions from clinical trials and post marketing experience are listed in Table 1, by MedDRA system organ class (SOC) along with their frequencies. The corresponding frequency category for each adverse reaction is based on the following convention: 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) and not known (cannot be estimated from the available data). Due to the large differences observed in the frequency of certain adverse reactions across the different transplant indications, the frequency is presented separately for renal, hepatic and cardiac transplant patients. Table 1 Adverse reactions in studies investigating mycophenolate mofetil treatment in adults and adolescents, or through post-marketing surveillance Adverse reaction Renal transplant Hepatic transplant Cardiac transplant (MedDRA) System Organ Class Frequency Frequency Frequency Infections and infestations 33 Adverse reaction Renal transplant Hepatic transplant Cardiac transplant (MedDRA) System Organ Class Frequency Frequency Frequency Bacterial infections Very common Very common Very common Fungal infections Common Very common Very common Protozoal infections Uncommon Uncommon Uncommon Viral infections Very common Very common Very common Neoplasms benign, malignant and unspecified (including cysts and polyps) Benign neoplasm of skin Common Common Common Lymphoma Uncommon Uncommon Uncommon Lymphoproliferative disorder Uncommon Uncommon Uncommon Neoplasm Common Commo

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HOS-154308 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile Diarrhoea (up to 52.6%), leukopenia (up to 45.8%), bacterial infections (up to 39.9%) and vomiting (up to 39.1%) were among the most common and/or serious adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids. There is also evidence of a higher frequency of certain types of infections (see section 4.4). Tabulated list of adverse reactions The adverse reactions from clinical trials and post marketing experience are listed in Table 1, by MedDRA system organ class (SOC) along with their frequencies. The corresponding frequency category for each adverse reaction is based on the following convention: 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) and not known (cannot be estimated from the available data). Due to the large differences observed in the frequency of certain adverse reactions across the different transplant indications, the frequency is presented separately for renal, hepatic and cardiac transplant patients. Table 1 Adverse reactions in studies investigating mycophenolate mofetil treatment in adults and adolescents, or through post-marketing surveillance 11 Adverse reaction Renal transplant Hepatic transplant Cardiac transplant (MedDRA) System Organ Class Frequency Frequency Frequency Infections and infestations Bacterial infections Very common Very common Very common Fungal infections Common Very common Very common Protozoal infections Uncommon Uncommon Uncommon Viral infections Very common Very common Very common Neoplasms benign, malignant and unspecified (including cysts and polyps) Benign neoplasm of skin Common Common Common Lymphoma Uncommon Uncommon Uncommon Lymphoproliferative disorder Uncommon Uncommon Uncommon Neoplasm Common Common Common Skin cancer Common Uncommon Common Blood and lymphatic system disorders Anaemia Very common Very common Very common Aplasia pure red cell

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HOS-154304 · has-contraindication-information · PDF-Seite 4

Mycophenolate mofetil Teva should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions to this medicinal product have been observed (see section 4.8). Treatment should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6). 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). Treatment should not be used during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6). Treatment should not be given to women who are breastfeeding (see section 4.6).

HOS-154310 · has-contraindication-information · PDF-Seite 26

Mycophenolate mofetil Teva should not be given to patients with hypersensitivity to mycophenolate mofetil, mycophenolic acid or to any of the excipients listed in section 6.1. Hypersensitivity reactions to this medicinal product have been observed (see section 4.8). Treatment should not be given to women of childbearing potential who are not using highly effective contraception (see section 4.6). 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). Treatment should not be used during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection (see section 4.6). Treatment should not be given to women who are breastfeeding (see section 4.6).

HOS-154303 · has-indication-information · PDF-Seite 2

Mycophenolate mofetil Teva is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult and paediatric (1 to 18 years of age) patients receiving allogeneic renal, cardiac or hepatic transplants.

HOS-154309 · has-indication-information · PDF-Seite 24

Mycophenolate mofetil Teva is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adult and paediatric (1 to 18 years of age) patients receiving allogeneic renal, cardiac or hepatic transplants.

HOS-154306 · has-interaction-information · PDF-Seite 7

Aciclovir Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur. Antacids and proton pump inhibitors (PPIs) Decreased MPA exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with mycophenolate mofetil. When comparing rates of transplant rejection or rates of graft loss between mycophenolate mofetil patients taking PPIs vs. mycophenolate mofetil patients not taking PPIs, no significant differences were seen. These data support extrapolation of this finding to all antacids because the reduction in exposure when mycophenolate mofetil was co- administered with magnesium and aluminium hydroxides is considerably less than when mycophenolate mofetil was co-administered with PPIs. Medicinal products that interfere with enterohepatic recirculation (e.g. cholestyramine, ciclosporin A, antibiotics) Caution should be used with medicinal products that interfere with enterohepatic recirculation because of their potential to reduce the efficacy of mycophenolate mofetil. Cholestyramine Following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g three times a day (TID) of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of mycophenolate mofetil. Ciclosporin A Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, if concomitant CsA treatment is stopped, an increase in MPA AUC of around 30% should be expected. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30-50% in renal transplant patients treated with mycophenolate mofetil and CsA compared with patients receiving sirolimus or belatacept and similar d

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HOS-154312 · has-interaction-information · PDF-Seite 29

Aciclovir Higher aciclovir plasma concentrations were observed when mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8%) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion and further increases in concentrations of both substances may occur. Antacids and proton pump inhibitors (PPIs) Decreased MPA exposure has been observed when antacids, such as magnesium and aluminium hydroxides, and PPIs, including lansoprazole and pantoprazole, were administered with mycophenolate mofetil. When comparing rates of transplant rejection or rates of graft loss between mycophenolate mofetil patients taking PPIs vs. mycophenolate mofetil patients not taking PPIs, no significant differences were seen. These data support extrapolation of this finding to all antacids because the reduction in exposure when mycophenolate mofetil was co-administered with magnesium and aluminium hydroxides is considerably less than when mycophenolate mofetil was co-administered with PPIs. Medicinal products that interfere with enterohepatic recirculation (e.g. cholestyramine, ciclosporin A, antibiotics) Caution should be used with medicinal products that interfere with enterohepatic recirculation because of their potential to reduce the efficacy of mycophenolate mofetil. Cholestyramine Following single dose administration of 1.5 g of mycophenolate mofetil to normal healthy subjects pre-treated with 4 g three times a day (TID) of cholestyramine for 4 days, there was a 40% reduction in the AUC of MPA (see section 4.4 and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of mycophenolate mofetil. Ciclosporin A Ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, if concomitant CsA treatment is stopped, an increase in MPA AUC of around 30% should be expected. CsA interferes with MPA enterohepatic recycling, resulting in reduced MPA exposures by 30 50% in renal transplant patients treated with mycophenolate mofetil and CsA compared with patients receiving sirolimus or belatacept and similar do

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HOS-154313 · has-pregnancy-information · PDF-Seite 31

Women of childbearing potential Pregnancy whilst taking mycophenolate mofetil must be avoided. Therefore, women of childbearing potential must use at least one form of reliable contraception (see section 4.3) before starting the 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. Pregnancy Mycophenolate mofetil is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy (see section 4.3). 31 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 treatment, women of childbearing potential must have two negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL in order to exclude unintended exposure of an 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 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; • 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 t

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HOS-154307 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential Pregnancy whilst taking mycophenolate mofetil must be avoided. Therefore, women of childbearing potential must use at least one form of reliable contraception (see section 4.3) before starting the 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. Pregnancy 9 Mycophenolate mofetil is contraindicated during pregnancy unless there is no suitable alternative treatment to prevent transplant rejection. Treatment should not be initiated without providing a negative pregnancy test result to rule out unintended use in pregnancy (see section 4.3). 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 treatment, women of childbearing potential must have two negative serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL in order to exclude unintended exposure of an 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 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; • 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

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HOS-154305 · has-warning-information · PDF-Seite 4

Neoplasms Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Mycophenolate mofetil Teva, 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 ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Infections Patients treated with immunosuppressants, including mycophenolate mofetil, 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 physicians 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 Tlymphocytes, therefore an increased severity of COVID19 may occur, and appropriate clinical action should be considered. There have been reports of hypogammaglobulinaemia 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 mycophenolate mofetil 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 mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophe

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HOS-154311 · has-warning-information · PDF-Seite 26

Neoplasms Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Mycophenolate mofetil Teva, 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 ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Infections Patients treated with immunosuppressants, including mycophenolate mofetil, 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 physicians 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 Tlymphocytes, therefore an increased severity of COVID19 may occur, and appropriate clinical action should be considered. There have been reports of hypogammaglobulinaemia 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 mycophenolate mofetil 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 mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching mycophe

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