Sivextro · 4.6 Fertility, pregnancy and lactation · 1

HOS-096898 · has-adverse-reaction-information · PDF-Seite 36

Summary of the safety profile The most frequently reported adverse reactions occurring in patients receiving tedizolid phosphate in the pooled controlled Phase 3 clinical studies (tedizolid phosphate 200 mg once daily for 6 days) were nausea (6.9%), headache (3.5%), diarrhoea (3.2%) and vomiting (2.3%), and were generally mild to moderate in severity. The safety profile was similar when comparing patients receiving intravenous tedizolid phosphate alone to patients who received oral administration alone, except for a higher reported rate of gastrointestinal disorders associated with oral administration. Tabulated list of adverse reactions The following adverse reactions have been identified in two comparative pivotal Phase 3 studies and one post-authorisation study in adults treated with Sivextro (Table 2). Adverse reactions are classified by preferred term and System Organ Class, and by frequency. Frequencies are defined as: 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); not known (cannot be estimated from the available data). Table 2: Adverse reactions System organ class Frequency Adverse reactions Infections and infestations Uncommon: Vulvovaginal mycotic infection, fungal infection, vulvovaginal candidiasis, abscess, Clostridioides difficile colitis, dermatophytosis, oral candidiasis, respiratory tract infection Blood and lymphatic system Uncommon: Lymphadenopathy, anaemia disorders Not known*: Thrombocytopenia* Immune system disorders Uncommon: Drug hypersensitivity Metabolism and nutrition Uncommon: Dehydration, diabetes mellitus inadequate control, disorders hyperkalaemia Psychiatric disorders Uncommon: Insomnia, sleep disorder, anxiety, nightmare Nervous system disorders Common: Headache, dizziness Uncommon: Somnolence, dysgeusia, tremor, paraesthesia, hypoaesthesia Eye disorders Uncommon: Vision blurred, vitreous floaters 36  System

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HOS-096892 · has-adverse-reaction-information · PDF-Seite 20

Summary of the safety profile The most frequently reported adverse reactions occurring in patients receiving tedizolid phosphate in the pooled controlled Phase 3 clinical studies (tedizolid phosphate 200 mg once daily for 6 days) were nausea (6.9%), headache (3.5%), diarrhoea (3.2%) and vomiting (2.3%), and were generally mild to moderate in severity. The safety profile was similar when comparing patients receiving intravenous tedizolid phosphate alone to patients who received oral administration alone, except for a higher reported rate of gastrointestinal disorders associated with oral administration. Safety was additionally evaluated in a randomised, double-blind, multicenter study conducted in China, the Philippines, Taiwan, and the US, which included a total 292 adult patients treated with tedizolid phosphate 200 mg administered intravenous and/or oral once daily for 6 days, and 297 patients treated with linezolid 600 mg administered intravenous and/or oral every 12 hours for 10 days for ABSSSI. The safety profile in this study was similar to the Phase 3 clinical trials; however, infusion site reactions (phlebitis) were reported more frequently (2.7%) in tedizolid phosphate treated subjects than in the linezolid control group (0%), particularly among Asian patients. These findings suggest a higher frequency of infusion related reactions (phlebitis) than was observed in previous clinical studies with tedizolid phosphate. Tabulated list of adverse reactions The following adverse reactions have been identified in two comparative pivotal Phase 3 studies and one post-authorisation study in adults treated with Sivextro (Table 2). Adverse reactions are classified by preferred term and System Organ Class, and by frequency. Frequencies are defined as: 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); not known (cannot be estimated from the available data). Table 2: Adverse reactions System organ class Frequency Adverse reactions Infections and infestations Uncommon: Vulvovaginal mycotic infection, fungal infection, vulvovaginal candidiasis, abscess, Clostridioides difficile colitis, dermatophytosis, oral candidiasis, respiratory tract infection Blood and lymphatic system

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HOS-096886 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most frequently reported adverse reactions occurring in patients receiving tedizolid phosphate in the pooled controlled Phase 3 clinical studies (tedizolid phosphate 200 mg once daily for 6 days) were nausea (6.9%), headache (3.5%), diarrhoea (3.2%) and vomiting (2.3%), and were generally mild to moderate in severity. The safety profile was similar when comparing patients receiving intravenous tedizolid phosphate alone to patients who received oral administration alone, except for a higher reported rate of gastrointestinal disorders associated with oral administration. Tabulated list of adverse reactions The following adverse reactions have been identified in two comparative pivotal Phase 3 studies in adults treated with Sivextro (Table 1). Adverse reactions are classified by preferred term and System Organ Class, and by frequency. Frequencies are defined as: 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); not known (cannot be estimated from the available data). 6 Table 1: Adverse reactions System organ class Frequency Adverse reactions Infections and infestations Uncommon: Vulvovaginal mycotic infection, fungal infection, vulvovaginal candidiasis, abscess, Clostridioides difficile colitis, dermatophytosis, oral candidiasis, respiratory tract infection Blood and lymphatic system Uncommon: Lymphadenopathy, anaemia disorders Not known*: Thrombocytopenia* Immune system disorders Uncommon: Drug hypersensitivity Metabolism and nutrition Uncommon: Dehydration, diabetes mellitus inadequate control, disorders hyperkalaemia Psychiatric disorders Uncommon: Insomnia, sleep disorder, anxiety, nightmare Nervous system disorders Common: Headache, dizziness Uncommon: Somnolence, dysgeusia, tremor, paraesthesia, hypoaesthesia Eye disorders Uncommon: Vision blurred, vitreous floaters Cardiac disorders Uncommon: Brad

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HOS-096882 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096888 · has-contraindication-information · PDF-Seite 16

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-096894 · has-contraindication-information · PDF-Seite 32

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 32

HOS-096881 · has-indication-information · PDF-Seite 2

Sivextro tablets are indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in: adults adolescents and children weighing at least 35 kg. See sections 4.4 and 5.1. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-096893 · has-indication-information · PDF-Seite 31

Sivextro powder for oral suspension is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in patients from birth (see sections 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-096887 · has-indication-information · PDF-Seite 15

Sivextro powder for concentrate for solution for infusion is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) from birth (see sections 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-096884 · has-interaction-information · PDF-Seite 5

Potential of tedizolid phosphate to affect other medicinal products Breast cancer resistance protein transporter inhibition In a clinical study comparing the single dose (10 mg) pharmacokinetics of rosuvastatin (Breast Cancer Resistant Protein [BCRP] substrate, see section 5.2) alone or in combination with tedizolid phosphate (once-daily 200 mg oral dose), rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when co-administered with tedizolid phosphate. Therefore, orally administered tedizolid phosphate can result in inhibition of BCRP at the intestinal level. If possible, an interruption of the co- administered BCRP substrate medicinal product (such as imatinib, lapatinib, methotrexate, pitavastatin, rosuvastatin, sulfasalazine, and topotecan) should be considered during the 6 days of treatment with oral tedizolid phosphate. Serotonergic interactions The potential for serotonergic interactions has not been studied in either patients or healthy volunteers (see sections 4.4 and 5.2). In Phase 3 studies, subjects taking serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine (5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded. Post-marketing experience: there have been reports of patients experiencing serotonin syndrome while taking tedizolid and serotonergic agents (antidepressants, opioids) which resolved on discontinuation of one or both medications. Monoamine oxidase inhibition Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro (see section 5.2). The interaction with MAO inhibitors could not be evaluated in Phase 2 and 3 trials, as subjects taking such medications were excluded from the trials. Adrenergic interactions Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oral tedizolid phosphate at steady-state to enhance pressor responses to pseudoephedrine and tyramine in healthy individuals. No meaningful changes in blood pressure or heart rate were seen with pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure of ≥ 30 mmHg from pre-dose baseline was 325 mg with tedizolid phosphate compared to 425 mg with placebo. Administration of Sivextro with tyramine-rich foods (i.e., containing tyramine levels of approximately 100 mg) would not be expected to elicit a pressor response. Medicinal pr

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HOS-096896 · has-interaction-information · PDF-Seite 34

Potential of tedizolid phosphate to affect other medicinal products 34 Breast cancer resistance protein transporter inhibition In a clinical study comparing the single dose (10 mg) pharmacokinetics of rosuvastatin (Breast Cancer Resistant Protein [BCRP] substrate, see section 5.2) alone or in combination with tedizolid phosphate (once-daily 200 mg oral dose), rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when co-administered with tedizolid phosphate. Therefore, orally administered tedizolid phosphate can result in inhibition of BCRP at the intestinal level. If possible, an interruption of the co- administered BCRP substrate medicinal product (such as imatinib, lapatinib, methotrexate, pitavastatin, rosuvastatin, sulfasalazine, and topotecan) should be considered during the 6 days of treatment with oral tedizolid phosphate. Serotonergic interactions The potential for serotonergic interactions has not been studied in either patients or healthy volunteers (see sections 4.4 and 5.2). In Phase 3 studies, subjects taking serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine (5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded. Post-marketing experience: there have been reports of patients experiencing serotonin syndrome while taking tedizolid and serotonergic agents (antidepressants, opioids) which resolved on discontinuation of one or both medications. Monoamine oxidase inhibition Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro (see section 5.2). The interaction with MAO inhibitors could not be evaluated in Phase 2 and 3 trials, as subjects taking such medications were excluded from the trials. Adrenergic interactions Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oral tedizolid phosphate at steady-state to enhance pressor responses to pseudoephedrine and tyramine in healthy individuals. No meaningful changes in blood pressure or heart rate were seen with pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure of ≥ 30 mmHg from pre-dose baseline was 325 mg with tedizolid phosphate compared to 425 mg with placebo. Administration of Sivextro with tyramine-rich foods (i.e., containing tyramine levels of approximately 100 mg) would no

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HOS-096890 · has-interaction-information · PDF-Seite 18

Potential of tedizolid phosphate to affect other medicinal products Breast cancer resistance protein transporter inhibition In a clinical study comparing the single dose (10 mg) pharmacokinetics of rosuvastatin (Breast Cancer Resistant Protein [BCRP] substrate, see section 5.2) alone or in combination with tedizolid phosphate (once-daily 200 mg oral dose), rosuvastatin AUC and Cmax increased by approximately 70% and 55%, respectively, when co-administered with tedizolid phosphate. Therefore, orally administered tedizolid phosphate can result in inhibition of BCRP at the intestinal level. If possible, an interruption of the co- administered BCRP substrate medicinal product (such as imatinib, lapatinib, methotrexate, pitavastatin, rosuvastatin, sulfasalazine, and topotecan) should be considered during the 6 days of treatment with oral tedizolid phosphate. Serotonergic interactions The potential for serotonergic interactions has not been studied in either patients or healthy volunteers (see sections 4.4 and 5.2). In Phase 3 studies, subjects taking serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and serotonin 5-hydroxytryptamine (5-HT1) receptor agonists (triptans), meperidine, or buspirone were excluded. 18 Post-marketing experience: there have been reports of patients experiencing serotonin syndrome while taking tedizolid and serotonergic agents (antidepressants, opioids) which resolved on discontinuation of one or both medications. Monoamine oxidase inhibition Tedizolid is a reversible inhibitor of monoamine oxidase (MAO) in vitro (see section 5.2). The interaction with MAO inhibitors could not be evaluated in Phase 2 and 3 trials, as subjects taking such medications were excluded from the trials. Adrenergic interactions Two placebo-controlled crossover studies were conducted to assess the potential of 200 mg oral tedizolid phosphate at steady-state to enhance pressor responses to pseudoephedrine and tyramine in healthy individuals. No meaningful changes in blood pressure or heart rate were seen with pseudoephedrine. The median tyramine dose required to cause an increase in systolic blood pressure of ≥ 30 mmHg from pre-dose baseline was 325 mg with tedizolid phosphate compared to 425 mg with placebo. Administration of Sivextro with tyramine-rich foods (i.e., containing tyramine levels of approximately 100 mg) would n

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HOS-096885 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no data from the use of tedizolid phosphate in pregnant women. Studies in mice and rats showed developmental effects (see section 5.3). As a precautionary measure, it is preferable to avoid the use of tedizolid phosphate during pregnancy. Breast-feeding It is unknown whether tedizolid phosphate or its metabolites are excreted in human milk. Tedizolid is excreted in the breast milk of rats (see section 5.3). A risk to the breast-feeding infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tedizolid phosphate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility The effects of tedizolid phosphate on fertility in humans have not been studied. Animal studies with tedizolid phosphate do not indicate harmful effects with respect to fertility (see section 5.3).

HOS-096897 · has-pregnancy-information · PDF-Seite 35

Pregnancy There are no data from the use of tedizolid phosphate in pregnant women. Studies in mice and rats showed developmental effects (see section 5.3). As a precautionary measure, it is preferable to avoid the use of tedizolid phosphate during pregnancy. 35 Breast-feeding It is unknown whether tedizolid phosphate or its metabolites are excreted in human milk. Tedizolid is excreted in the breast milk of rats (see section 5.3). A risk to the breast-feeding infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tedizolid phosphate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility The effects of tedizolid phosphate on fertility in humans have not been studied. Animal studies with tedizolid phosphate do not indicate harmful effects with respect to fertility (see section 5.3).

HOS-096891 · has-pregnancy-information · PDF-Seite 19

Pregnancy There are no data from the use of tedizolid phosphate in pregnant women. Studies in mice and rats showed developmental effects (see section 5.3). As a precautionary measure, it is preferable to avoid the use of tedizolid phosphate during pregnancy. Breast-feeding It is unknown whether tedizolid phosphate or its metabolites are excreted in human milk. Tedizolid is excreted in the breast milk of rats (see section 5.3). A risk to the breast-feeding infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tedizolid phosphate therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility The effects of tedizolid phosphate on fertility in humans have not been studied. Animal studies with tedizolid phosphate do not indicate harmful effects with respect to fertility (see section 5.3).

HOS-096889 · has-warning-information · PDF-Seite 16

Patients with neutropenia The safety and efficacy of tedizolid phosphate in patients with neutropenia (neutrophil counts < 1 000 cells/mm3) have not been investigated. In an animal model of infection, the antibacterial activity of tedizolid was reduced in the absence of granulocytes. The clinical relevance of this finding is unknown. Alternative therapies should be considered when treating patients with neutropenia and ABSSSI (see section 5.1). Mitochondrial dysfunction Tedizolid inhibits mitochondrial protein synthesis. Adverse reactions such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur as a result of this inhibition. These events have been observed with another member of the oxazolidinone class when administered over a duration exceeding that recommended for tedizolid phosphate. 16 Myelosuppression Thrombocytopenia, decreased haemoglobin and decreased neutrophils have been observed during treatment with tedizolid phosphate (see section 4.8). Anaemia, leucopenia and pancytopenia have been reported in patients treated with another member of the oxazolidinone class and the risk of these effects appeared to be related to the duration of treatment. Most cases of thrombocytopenia occurred with treatment lasting longer than the recommended duration. There may be an association with thrombocytopenia in patients with renal insufficiency. Patients who develop myelosuppression should be monitored and the benefit-risk should be re- evaluated. If treatment is continued, close monitoring of blood counts and appropriate management strategies should be implemented. Peripheral neuropathy and optic nerve disorders Peripheral neuropathy, as well as optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with another member of the oxazolidinone class with treatment durations exceeding that recommended for tedizolid phosphate. Neuropathy (optic and peripheral) has not been reported in patients treated with tedizolid phosphate at the recommended treatment duration of 6 days. All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. Lactic acidosis Lactic acidosis has been reported with the use of another member of the oxazolidinone cla

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HOS-096883 · has-warning-information · PDF-Seite 3

Patients with neutropenia The safety and efficacy of tedizolid phosphate in patients with neutropenia (neutrophil counts < 1 000 cells/mm3) have not been investigated. In an animal model of infection, the antibacterial activity of tedizolid was reduced in the absence of granulocytes. The clinical relevance of this finding is unknown. Alternative therapies should be considered when treating patients with neutropenia and ABSSSI (see section 5.1). Mitochondrial dysfunction Tedizolid inhibits mitochondrial protein synthesis. Adverse reactions such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur as a result of this inhibition. These events have been observed with another member of the oxazolidinone class when administered over a duration exceeding that recommended for tedizolid phosphate. Myelosuppression Thrombocytopenia, decreased haemoglobin and decreased neutrophils have been observed during treatment with tedizolid phosphate (see section 4.8). Anaemia, leucopenia and pancytopenia have been reported in patients treated with another member of the oxazolidinone class and the risk of these effects appeared to be related to the duration of treatment. Most cases of thrombocytopenia occurred with treatment lasting longer than the recommended duration. There may be an association with thrombocytopenia in patients with renal insufficiency. Patients who develop myelosuppression should be monitored and the benefit-risk should be re- evaluated. If treatment is continued, close monitoring of blood counts and appropriate management strategies should be implemented. Peripheral neuropathy and optic nerve disorders Peripheral neuropathy, as well as optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with another member of the oxazolidinone class with treatment durations exceeding that recommended for tedizolid phosphate. Neuropathy (optic and peripheral) has not been reported in patients treated with tedizolid phosphate at the recommended treatment duration of 6 days. All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. 3 Lactic acidosis Lactic acidosis has been reported with the use of another member of the oxazolidinone clas

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HOS-096895 · has-warning-information · PDF-Seite 33

Patients with neutropenia The safety and efficacy of tedizolid phosphate in patients with neutropenia (neutrophil counts < 1 000 cells/mm3) have not been investigated. In an animal model of infection, the antibacterial activity of tedizolid was reduced in the absence of granulocytes. The clinical relevance of this finding is unknown. Alternative therapies should be considered when treating patients with neutropenia and ABSSSI (see section 5.1). Mitochondrial dysfunction Tedizolid inhibits mitochondrial protein synthesis. Adverse reactions such as lactic acidosis, anaemia and neuropathy (optic and peripheral) may occur as a result of this inhibition. These events have been observed with another member of the oxazolidinone class when administered over a duration exceeding that recommended for tedizolid phosphate. Myelosuppression Thrombocytopenia, decreased haemoglobin and decreased neutrophils have been observed during treatment with tedizolid phosphate (see section 4.8). Anaemia, leucopenia and pancytopenia have been reported in patients treated with another member of the oxazolidinone class and the risk of these effects appeared to be related to the duration of treatment. Most cases of thrombocytopenia occurred with treatment lasting longer than the recommended duration. There may be an association with thrombocytopenia in patients with renal insufficiency. Patients who develop myelosuppression should be monitored and the benefit-risk should be re- evaluated. If treatment is continued, close monitoring of blood counts and appropriate management strategies should be implemented. Peripheral neuropathy and optic nerve disorders Peripheral neuropathy, as well as optic neuropathy sometimes progressing to loss of vision, have been reported in patients treated with another member of the oxazolidinone class with treatment durations exceeding that recommended for tedizolid phosphate. Neuropathy (optic and peripheral) has not been reported in patients treated with tedizolid phosphate at the recommended treatment duration of 6 days. All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in colour vision, blurred vision, or visual field defect. In such cases, prompt evaluation is recommended with referral to an ophthalmologist as necessary. Lactic acidosis Lactic acidosis has been reported with the use of another member of the oxazolidinone class. Lactic acidosis has not been reported in patients tr

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