Tivicay · 4.3 Contraindications · 2

HOS-096696 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%). Tabulated list of adverse reactions The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute 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), and not known (cannot be estimated from the available data). 12 Table 4 Adverse Reactions Blood and lymphatic Not known Sideroblastic anaemia1 system disorders Immune system Uncommon Hypersensitivity (see section 4.4) disorders Uncommon Immune Reconstitution Syndrome (see section 4.4)2 Psychiatric disorders Common Insomnia Common Abnormal dreams Common Depression Common Anxiety Uncommon Panic attack Uncommon Suicidal ideation*, suicide attempt* *particularly in patients with a pre-existing history of depression or psychiatric illness. Rare Completed suicide* *particularly in patients with a pre-existing history of depression or psychiatric illness. Nervous system Very common Headache disorders Common Dizziness Gastrointestinal Very common Nausea disorders Very common Diarrhoea Common Vomiting Common Flatulence Common Upper abdominal pain Common Abdominal pain Common Abdominal discomfort Hepatobiliary Common Alanine aminotransferase (ALT) and/or Aspartate disorders a

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HOS-096702 · has-adverse-reaction-information · PDF-Seite 42

Summary of the safety profile The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adverse reactions were nausea (13%), diarrhoea (18%) and headache (13%). Tabulated list of adverse reactions The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute 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), and not known (cannot be estimated from the available data). 42 Table 4 Adverse Reactions Blood and lymphatic Not known Sideroblastic anaemia1 system disorders Immune system Uncommon Hypersensitivity (see section 4.4) disorders Uncommon Immune Reconstitution Syndrome (see section 4.4)2 Psychiatric disorders Common Insomnia Common Abnormal dreams Common Depression Common Anxiety Uncommon Panic attack Uncommon Suicidal ideation*, suicide attempt* *particularly in patients with a pre-existing history of depression or psychiatric illness. Rare Completed suicide* *particularly in patients with a pre-existing history of depression or psychiatric illness. Nervous system Very common Headache disorders Common Dizziness Gastrointestinal Very common Nausea disorders Very common Diarrhoea Common Vomiting Common Flatulence Common Upper abdominal pain Common Abdominal pain Common Abdominal discomfort Hepatobiliary Common Alanine aminotransferase (ALT) and/or Aspartate disorders a

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HOS-096698 · has-contraindication-information · PDF-Seite 34

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine; see section 4.5).

HOS-096692 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine; see section 4.5). 4

HOS-096697 · has-indication-information · PDF-Seite 32

Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 4 weeks of age or older and weighing at least 3 kg.

HOS-096691 · has-indication-information · PDF-Seite 2

Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 6 years of age or older and weighing at least 14 kg. 2

HOS-096694 · has-interaction-information · PDF-Seite 6

Effect of other agents on the pharmacokinetics of dolutegravir All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore, medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3). Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 3). The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3). Effect of dolutegravir on the pharmacokinetics of other agents In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2). 6 In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 3). In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3. Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 3. Interaction table Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of dosi

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HOS-096700 · has-interaction-information · PDF-Seite 36

Effect of other agents on the pharmacokinetics of dolutegravir All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore, medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3). Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 3). The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3). Effect of dolutegravir on the pharmacokinetics of other agents In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2). In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 3). 36 In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3. Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 3. Interaction table Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as “AUC”, maximum observed concentration as “Cmax”, concentration at end of do

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HOS-096695 · has-pregnancy-information · PDF-Seite 11

Pregnancy Tivicay can be used during pregnancy if clinically needed. A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. Two large birth outcome surveillance studies (more than 14,000 pregnancy outcomes) in Botswana (Tsepamo) and Eswatini, and other sources, do not indicate an increased risk for neural tube defects after dolutegravir exposure. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%). Data from the Tsepamo study show no significant difference in the prevalence of neural tube defects (0.11%) in infants whose mothers were taking dolutegravir at conception (more than 9,400 exposures) compared to those taking non-dolutegravir containing antiretroviral regimens at conception (0.11%), or compared to women without HIV (0.07%). Data from the Eswatini study show the same prevalence of neural tube defects (0.08%) in infants whose mothers were taking dolutegravir at conception (more than 4,800 exposures), as infants of women without HIV (0.08%). Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies with first trimester dolutegravir treatment do not indicate an increased risk of major birth defects compared to the background rate or women with HIV. In animal reproductive toxicity studies, no adverse development outcomes, including neural tube defects, were identified (see section 5.3). 11 Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration. There is insufficient information on the effects of dolutegravir on neonates. Breast-feeding Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk to maternal plasma ratio of 0.033 has been shown). There is insufficient information on the effects of dolutegravir in neonates/infants. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility (see section 5.3).

HOS-096701 · has-pregnancy-information · PDF-Seite 41

Pregnancy Tivicay can be used during pregnancy if clinically needed. A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. Two large birth outcome surveillance studies (more than 14,000 pregnancy outcomes) in Botswana (Tsepamo) and Eswatini, and other sources, do not indicate an increased risk for neural tube defects after dolutegravir exposure. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births (0.05-0.1%). Data from the Tsepamo study show no significant difference in the prevalence of neural tube defects (0.11%) in infants whose mothers were taking dolutegravir at conception (more than 9,400 exposures) compared to those taking non-dolutegravir containing antiretroviral regimens at conception (0.11%), or compared to women without HIV (0.07%). Data from the Eswatini study show the same prevalence of neural tube defects (0.08%) in infants whose mothers were taking dolutegravir at conception (more than 4,800 exposures), as infants of women without HIV (0.08%). Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies with first trimester dolutegravir treatment do not indicate an increased risk of major birth defects compared to the background rate or women with HIV. In animal reproductive toxicity studies, no adverse development outcomes, including neural tube defects, were identified (see section 5.3). Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration. 41 There is insufficient information on the effects of dolutegravir on neonates. Breast-feeding Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk to maternal plasma ratio of 0.033 has been shown). There is insufficient information on the effects of dolutegravir in neonates/infants. It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmission of HIV. Fertility There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility (see section 5.3).

HOS-096693 · has-warning-information · PDF-Seite 5

Integrase class resistance of particular concern The decision to use dolutegravir in the presence of integrase class resistance should take into account that the activity of dolutegravir is considerably compromised for viral strains harbouring Q148+2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain (see section 5.2). Hypersensitivity reactions Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect medicinal products should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction. Immune Reactivation Syndrome In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are Cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Par

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HOS-096699 · has-warning-information · PDF-Seite 34

Integrase class resistance of particular concern The decision to use dolutegravir in the presence of integrase class resistance should take into account that the activity of dolutegravir is considerably compromised for viral strains harbouring Q148+2 secondary 34 mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain (see section 5.2). Hypersensitivity reactions Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect medicinal products should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction. Immune Reactivation Syndrome In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are Cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recomm

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