Xerava · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-217401 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile In clinical trials, the most common adverse reactions in patients with cIAI treated with eravacycline (n=576) were nausea (3.0%), vomiting, infusion site phlebitis (each 1.9%), phlebitis (1.4%), infusion site thrombosis (0.9%), diarrhoea (0.7%), vessel puncture site erythema (0.5%), hyperhidrosis, 5 thrombophlebitis, infusion site hypoaesthesia, and headache (each 0.3%), which were generally mild or moderate in severity. Tabulated list of adverse reactions The adverse reactions identified with eravacycline are presented in Table 1. Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived according to the following conventions: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Tabulated list of adverse reactions to eravacycline in clinical trials System Organ Class Common Uncommon Blood and lymphatic system Hypofibrinogenaemia disorders Increased international normalised ratio (INR) Prolonged activated partial thromboplastin time (aPTT) Prolonged prothrombin time (PT) Immune system disorders Hypersensitivity Dizziness Nervous system disorders Headache Thrombophlebitisa Vascular disorders Phlebitisb Nausea Pancreatitis Gastrointestinal disorders Vomiting Diarrhoea Aspartate aminotransferase (AST) increased Hepatobiliary disorders Alanine aminotransferase (ALT)

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HOS-217407 · has-adverse-reaction-information · PDF-Seite 18

Summary of the safety profile In clinical trials, the most common adverse reactions in patients with cIAI treated with eravacycline (n=576) were nausea (3.0%), vomiting, infusion site phlebitis (each 1.9%), phlebitis (1.4%), infusion site thrombosis (0.9%), diarrhoea (0.7%), vessel puncture site erythema (0.5%), hyperhidrosis, 18 thrombophlebitis, infusion site hypoaesthesia, and headache (each 0.3%), which were generally mild or moderate in severity. Tabulated list of adverse reactions The adverse reactions identified with eravacycline are presented in Table 1. Adverse reactions are classified according to MedDRA system organ classification and frequency. Frequency categories are derived according to the following conventions: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Tabulated list of adverse reactions to eravacycline in clinical trials System Organ Class Common Uncommon Blood and lymphatic system Hypofibrinogenaemia disorders Increased international normalised ratio (INR) Prolonged activated partial thromboplastin time (aPTT) Prolonged prothrombin time (PT) Immune system disorders Hypersensitivity Dizziness Nervous system disorders Headache Thrombophlebitisa Vascular disorders Phlebitisb Nausea Pancreatitis Gastrointestinal disorders Vomiting Diarrhoea Aspartate aminotransferase (AST) increased Hepatobiliary disorders Alanine aminotransferase (ALT)

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HOS-217397 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1. Hypersensitivity to tetracycline class antibiotics.

HOS-217403 · has-contraindication-information · PDF-Seite 16

Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1. Hypersensitivity to tetracycline class antibiotics.

HOS-217402 · has-indication-information · PDF-Seite 15

Xerava is indicated in adolescents from the age of 12 years weighing at least 50 kg, and in adults, for the treatment of complicated intra-abdominal infections (cIAI) (see sections 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-217396 · has-indication-information · PDF-Seite 2

Xerava is indicated in adolescents from the age of 12 years weighing at least 50 kg, and in adults, for the treatment of complicated intra-abdominal infections (cIAI) (see sections 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-217405 · has-interaction-information · PDF-Seite 17

Potential for other medicinal products to affect the pharmacokinetics of eravacycline Concomitant administration of the strong CYP 3A4/3A5 inducer rifampicin altered the pharmacokinetics of eravacycline, decreasing exposure by approximately 32% and increasing clearance by approximately 54%. The eravacycline dose should be increased by approximately 50% (1.5 mg/kg intravenous q12h) when co-administered with rifampicin or other strong CYP3A inducers such as phenobarbital, carbamazepine, phenytoin and St. John’s Wort (see sections 4.2 and 4.4). Concomitant administration of the strong CYP3A inhibitor itraconazole altered the pharmacokinetics of eravacycline, increasing Cmax by approximately 5% and AUC0-24 by approximately 23%, and decreasing clearance. The increased exposure is not likely to be clinically significant; thus, no dose adjustment is required when eravacycline is co-administered with CYP3A inhibitors. However, patients receiving strong CYP3A inhibitors (for example ritonavir, itraconazole, clarithromycin) with a combination of factors that may increase the exposure, such as severe hepatic impairment and/or obesity should be monitored for adverse reactions (see sections 4.4 and 4.8). In vitro, eravacycline was shown to be a substrate for the transporters P-gp, OATP1B1 and OATP1B3. A drug-drug interaction in vivo cannot be excluded and co-administration of eravacycline and other 17 medicinal products that inhibit these transporters (examples of OATP1B1/3 inhibitors; atazanavir, cyclosporine, lopinavir, and saquinavir) may increase the eravacycline plasma concentration. Potential for eravacycline to affect the pharmacokinetics of other medicinal products In vitro, eravacycline and its metabolites are not inhibitors or inducers of CYP enzymes or transport proteins (see section 5.2). Interactions with medicinal products that are substrates for these enzymes or transporters are therefore unlikely.

HOS-217399 · has-interaction-information · PDF-Seite 4

Potential for other medicinal products to affect the pharmacokinetics of eravacycline Concomitant administration of the strong CYP 3A4/3A5 inducer rifampicin altered the pharmacokinetics of eravacycline, decreasing exposure by approximately 32% and increasing clearance by approximately 54%. The eravacycline dose should be increased by approximately 50% (1.5 mg/kg intravenous q12h) when co-administered with rifampicin or other strong CYP3A inducers such as phenobarbital, carbamazepine, phenytoin and St. John’s Wort (see sections 4.2 and 4.4). Concomitant administration of the strong CYP3A inhibitor itraconazole altered the pharmacokinetics of eravacycline, increasing Cmax by approximately 5% and AUC0-24 by approximately 23%, and decreasing clearance. The increased exposure is not likely to be clinically significant; thus, no dose adjustment is required when eravacycline is co-administered with CYP3A inhibitors. However, patients receiving strong CYP3A inhibitors (for example ritonavir, itraconazole, clarithromycin) with a combination of factors that may increase the exposure, such as severe hepatic impairment and/or obesity should be monitored for adverse reactions (see sections 4.4 and 4.8). In vitro, eravacycline was shown to be a substrate for the transporters P-gp, OATP1B1 and OATP1B3. A drug-drug interaction in vivo cannot be excluded and co-administration of eravacycline and other 4 medicinal products that inhibit these transporters (examples of OATP1B1/3 inhibitors; atazanavir, cyclosporine, lopinavir, and saquinavir) may increase the eravacycline plasma concentration. Potential for eravacycline to affect the pharmacokinetics of other medicinal products In vitro, eravacycline and its metabolites are not inhibitors or inducers of CYP enzymes or transport proteins (see section 5.2). Interactions with medicinal products that are substrates for these enzymes or transporters are therefore unlikely.

HOS-217406 · has-pregnancy-information · PDF-Seite 18

Pregnancy There are limited data on the use of eravacycline in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. As for other tetracycline class antibiotics, eravacycline may induce permanent dental defects (discolouration and enamel defects) and a delay in ossification processes in foetuses exposed in utero during the 2nd and 3rd trimester, due to accumulation in tissues with a high calcium turnover and formation of calcium chelate complexes (see sections 4.4 and 5.3). Xerava should not be used during pregnancy unless the clinical condition of the woman requires treatment with eravacycline. Women of childbearing potential Women of childbearing potential should avoid becoming pregnant while receiving eravacycline. Breast-feeding It is unknown whether eravacycline and its metabolites are excreted in human breast milk. Animal studies have shown excretion of eravacycline and its metabolites in breast milk (see section 5.3). Long term use of other tetracyclines during breast-feeding may result in significant absorption by the breast-fed infant and is not recommended because of the risk of dental discolouration and delay in ossification processes of the breast-fed infant. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Xerava should be made, taking into account the benefit of breast-feeding for the child, and the benefit of therapy for the woman. Fertility There are no human data on the effect of eravacycline on fertility. Eravacycline did affect mating and fertility in male rats at clinically relevant exposures (see section 5.3).

HOS-217400 · has-pregnancy-information · PDF-Seite 5

Pregnancy There are limited data on the use of eravacycline in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. As for other tetracycline class antibiotics, eravacycline may induce permanent dental defects (discolouration and enamel defects) and a delay in ossification processes in foetuses exposed in utero during the 2nd and 3rd trimester, due to accumulation in tissues with a high calcium turnover and formation of calcium chelate complexes (see sections 4.4 and 5.3). Xerava should not be used during pregnancy unless the clinical condition of the woman requires treatment with eravacycline. Women of childbearing potential Women of childbearing potential should avoid becoming pregnant while receiving eravacycline. Breast-feeding It is unknown whether eravacycline and its metabolites are excreted in human breast milk. Animal studies have shown excretion of eravacycline and its metabolites in breast milk (see section 5.3). Long term use of other tetracyclines during breast-feeding may result in significant absorption by the breast-fed infant and is not recommended because of the risk of dental discolouration and delay in ossification processes of the breast-fed infant. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Xerava should be made, taking into account the benefit of breast-feeding for the child, and the benefit of therapy for the woman. Fertility There are no human data on the effect of eravacycline on fertility. Eravacycline did affect mating and fertility in male rats at clinically relevant exposures (see section 5.3).

HOS-217398 · has-warning-information · PDF-Seite 3

Anaphylactic reactions Serious and occasionally fatal hypersensitivity reactions are possible and have been reported with other tetracycline class antibiotics (see section 4.3). In case of hypersensitivity reactions, treatment with eravacycline must be discontinued immediately and appropriate emergency measures must be initiated. Clostridioides difficile-associated diarrhoea Antibiotic-associated colitis and pseudomembranous colitis have been reported with the use of nearly all antibiotics and may range in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to treatment with eravacycline (see section 4.8). In such circumstances, the discontinuation of eravacycline and the use of supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Infusion-site reactions Eravacycline is administered via intravenous infusion, using an infusion time of approximately 1 hour to minimise the risk of infusion-site reactions. Infusion-site erythema, pain/tenderness, phlebitis and thrombophlebitis were observed with intravenous eravacycline in clinical trials (see section 4.8). In case of serious reactions, eravacycline should be discontinued until a new intravenous access site is established. Additional measures to reduce the occurrence and severity of infusion site reactions include decreasing the eravacycline infusion rate and/or concentration. Non-susceptible micro-organisms Prolonged use may result in the overgrowth of non-susceptible micro-organisms, including fungi. If superinfection occurs during therapy, it may require interruption of treatment. Other appropriate measures should be taken and alternative antimicrobial treatment should be considered in accordance with existing therapeutic guidelines. Pancreatitis Pancreatitis has been reported with eravacycline and has been severe in some cases (see section 4.8). If pancreatitis is suspected, eravacycline should be discontinued. 3 Paediatric population Xerava should not be used during tooth development (during the 2nd and 3rd trimester of pregnancy, and in children under 8 years of age) as it may cause permanent discolouration of the teeth (yellow- grey-brown) (see section 4.6). Concomitant use of strong CYP3A4 inducers Medicines t

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HOS-217404 · has-warning-information · PDF-Seite 16

Anaphylactic reactions Serious and occasionally fatal hypersensitivity reactions are possible and have been reported with other tetracycline class antibiotics (see section 4.3). In case of hypersensitivity reactions, treatment with eravacycline must be discontinued immediately and appropriate emergency measures must be initiated. Clostridioides difficile-associated diarrhoea Antibiotic-associated colitis and pseudomembranous colitis have been reported with the use of nearly all antibiotics and may range in severity from mild to life-threatening. It is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to treatment with eravacycline (see section 4.8). In such circumstances, the discontinuation of eravacycline and the use of supportive measures together with the administration of specific treatment for Clostridioides difficile should be considered. Medicinal products that inhibit peristalsis should not be given. Infusion-site reactions Eravacycline is administered via intravenous infusion, using an infusion time of approximately 1 hour to minimise the risk of infusion-site reactions. Infusion-site erythema, pain/tenderness, phlebitis and thrombophlebitis were observed with intravenous eravacycline in clinical trials (see section 4.8). In case of serious reactions, eravacycline should be discontinued until a new intravenous access site is established. Additional measures to reduce the occurrence and severity of infusion site reactions include decreasing the eravacycline infusion rate and/or concentration. Non-susceptible micro-organisms Prolonged use may result in the overgrowth of non-susceptible micro-organisms, including fungi. If superinfection occurs during therapy, it may require interruption of treatment. Other appropriate measures should be taken and alternative antimicrobial treatment should be considered in accordance with existing therapeutic guidelines. Pancreatitis Pancreatitis has been reported with eravacycline and has been severe in some cases (see section 4.8). If pancreatitis is suspected, eravacycline should be discontinued. 16 Paediatric population Xerava should not be used during tooth development (during the 2nd and 3rd trimester of pregnancy, and in children under 8 years of age) as it may cause permanent discolouration of the teeth (yellow- grey-brown) (see section 4.6). Concomitant use of strong CYP3A4 inducers Medicines t

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