Triumeq · 4.8 Undesirable effects · 1

HOS-096710 · has-adverse-reaction-information · PDF-Seite 17

Summary of the safety profile The most frequently reported adverse reactions related to dolutegravir and abacavir/lamivudine were nausea (12%), insomnia (7%), dizziness (6%) and headache (6%). Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued. The most severe adverse reaction related to the treatment with dolutegravir and abacavir/lamivudine, seen in individual patients, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4 and Description of selected adverse reactions in this section). Tabulated list of adverse reactions The adverse reactions with the components of Triumeq from clinical study and post-marketing experience are listed in Table 2 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). Table 2: Tabulated list of adverse reactions associated with the combination of dolutegravir + abacavir/lamivudine in an analysis of pooled data from: Phase IIb to Phase IIIb clinical studies or post- marketing experience; and adverse reactions to treatment with dolutegravir, abacavir and lamivudine from clinical studies and post-marketing experience when used with other antiretrovirals Frequency Adverse reaction Blood and lymphatic systems disorders: Uncommon: Neutropenia1, anaemia1, thrombocytopenia1 Very rare: pure red cell aplasia1 Not known sideroblastic anaemia2 Immune system disorders: Common: hypersensitivity (see section 4.4) Uncommon: immune reconstitution syndrome (see section 4.4) 17 Metabolism and nutrition disorders: Common: anorexia1 Uncommon: hypertriglyceridaemia,

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HOS-096716 · has-adverse-reaction-information · PDF-Seite 53

Summary of the safety profile The most frequently reported adverse reactions related to dolutegravir and abacavir/lamivudine were nausea (12%), insomnia (7%), dizziness (6%) and headache (6%). 53 Many of the adverse reactions listed in the table below occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity (see section 4.4). Very rarely cases of erythema multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported where abacavir hypersensitivity could not be ruled out. In such cases medicinal products containing abacavir should be permanently discontinued. The most severe adverse reaction related to the treatment with dolutegravir and abacavir/lamivudine, seen in individual patients, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4 and Description of selected adverse reactions in this section). Tabulated list of adverse reactions The adverse reactions with the components of Triumeq from clinical study and post-marketing experience are listed in Table 4 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). Table 4: Tabulated list of adverse reactions associated with the combination of dolutegravir + abacavir/lamivudine in an analysis of pooled data from: Phase IIb to Phase IIIb clinical studies or post- marketing experience; and adverse reactions to treatment with dolutegravir, abacavir and lamivudine from clinical studies and post-marketing experience when used with other antiretrovirals Frequency Adverse reaction Blood and lymphatic systems disorders: Uncommon: Neutropenia1, anaemia1, thrombocytopenia1 Very rare: pure red cell aplasia1 Not known sideroblastic anaemia2 Immune system disorders: Common: hypersensitivity (see section 4.4) Uncommon: immune reconstitution syndrome (see section 4.4) Metabolism and nutrition disorders: Common: anorexia1 Uncommon: hypertriglyceridaemia, hy

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HOS-096706 · has-contraindication-information · PDF-Seite 3

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

HOS-096712 · has-contraindication-information · PDF-Seite 41

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

HOS-096705 · has-indication-information · PDF-Seite 2

Triumeq is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infected adults, adolescents and children weighing at least 25 kg (see sections 4.4 and 5.1). Before initiating treatment with abacavir-containing products, screening for carriage of the HLA- B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin (see section 4.4). Abacavir should not be used in patients known to carry the HLA-B*5701 allele.

HOS-096711 · has-indication-information · PDF-Seite 38

Triumeq is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infected children of at least 3 months of age and weighing at least 6 kg to less than 25 kg (see sections 4.4 and 5.1). Before initiating treatment with abacavir-containing products, screening for carriage of the HLA- B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin (see section 4.4). Abacavir should not be used in patients known to carry the HLA-B*5701 allele.

HOS-096714 · has-interaction-information · PDF-Seite 44

Triumeq contains dolutegravir, abacavir and lamivudine, therefore any interactions identified for these individually are relevant to Triumeq. No clinically significant drug interactions are expected between dolutegravir, abacavir and lamivudine. 44 Effect of other medicinal products on the pharmacokinetics of dolutegravir, abacavir and lamivudine Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P- glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Co-administration of Triumeq and other medicinal products that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may therefore increase dolutegravir plasma concentration. Medicinal products that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3). The absorption of dolutegravir is reduced by certain anti-acid medicinal products (see Table 3). Abacavir is metabolised by UGT (UGT2B7) and alcohol dehydrogenase; co-administration of inducers (e.g. rifampicin, carbamazepine and phenytoin) or inhibitors (e.g. valproic acid) of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however the resulting increase was not clinically significant (see Table 3). Dolutegravir is an OCT2 and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co- administration of dolutegravir based on a cross study analysis, indicating that dolutegravir has no effect on lamivudine exposure in vivo. Lamivudine is also a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance. Although abacavir and lamivudine are substrates of BCRP and P-gp in vitro, given the high absolute bioavailability of abacavir and lamivudine, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on abacavi

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HOS-096708 · has-interaction-information · PDF-Seite 7

Triumeq contains dolutegravir, abacavir and lamivudine, therefore any interactions identified for these individually are relevant to Triumeq. No clinically significant drug interactions are expected between dolutegravir, abacavir and lamivudine. Effect of other medicinal products on the pharmacokinetics of dolutegravir, abacavir and lamivudine Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P- glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Co-administration of Triumeq and other medicinal products that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may therefore increase dolutegravir plasma concentration. Medicinal products that induce those enzymes or 7 transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1). The absorption of dolutegravir is reduced by certain anti-acid medicinal products (see Table 1). Abacavir is metabolised by UGT (UGT2B7) and alcohol dehydrogenase; co-administration of inducers (e.g. rifampicin, carbamazepine and phenytoin) or inhibitors (e.g. valproic acid) of UGT enzymes or with compounds eliminated through alcohol dehydrogenase could alter abacavir exposure. Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however the resulting increase was not clinically significant (see Table 1). Dolutegravir is an OCT2 and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co- administration of dolutegravir based on a cross study analysis, indicating that dolutegravir has no effect on lamivudine exposure in vivo. Lamivudine is also substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance. Although abacavir and lamivudine are substrates of BCRP and P-gp in vitro, given the high absolute bioavailability of abacavir and lamivudine, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on abacavir

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HOS-096715 · has-pregnancy-information · PDF-Seite 52

Pregnancy Triumeq 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 associated with dolutegravir. In pregnant women treated with abacavir, a large amount of data (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. In pregnant women treated with lamivudine, a large amount of data (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. There are no or limited amount of data (less than 300 pregnancy outcomes) on the use of this triple combination in pregnancy. 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, more than 1000 pregnancies with first trimester abacavir treatment and more than 1000 pregnancies with first trimester lamivudine treatment do not indicate an increased risk of major birth defects with dolutegravir, lamivudine or abacavir compared to the background rate or women with HIV. There are no or limited amount of APR data (less than 300 first trimester exposures) from the use of dolutegravir + lamivudine + abacavir in pregnant women.. In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified (see section 5.3). 52 Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetal umbilical cord concentra

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HOS-096709 · has-pregnancy-information · PDF-Seite 15

Pregnancy Triumeq 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 associated with dolutegravir. In pregnant women treated with abacavir, a large amount of data (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. In pregnant women treated with lamivudine, a large amount of data (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity. There are no or limited amount of data (less than 300 pregnancy outcomes) on the use of this triple combination in pregnancy. 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) 15 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, more than 1000 pregnancies with first trimester abacavir treatment and more than 1000 pregnancies with first trimester lamivudine treatment do not indicate an increased risk of major birth defects with dolutegravir, lamivudine or abacavir compared to the background rate or women with HIV. There are no or limited amount of APR data (less than 300 first trimester exposures) from the use of dolutegravir + lamivudine + abacavir in pregnant women. In animal reproductive toxicology studies with dolutegravir, 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 concentrati

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HOS-096713 · has-warning-information · PDF-Seite 41

Hypersensitivity reactions (see section 4.8) Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR) (see section 4.8), and share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement. Clinically it is not possible to determine whether a HSR with Triumeq would be caused by abacavir or dolutegravir. Hypersensitivity reactions have been observed more commonly with abacavir, some of which have been life-threatening, and in rare cases, fatal, when not managed appropriately. The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele. However, abacavir HSRs have been reported at a low frequency in patients who do not carry this allele. Therefore, the following should always be adhered to: - HLA-B*5701 status must always be documented prior to initiating therapy. - Triumeq should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir- containing regimen. - Triumeq must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an HSR is suspected. Delay in stopping treatment with Triumeq after the onset of hypersensitivity may result in an immediate and life-threatening reaction. Clinical status including liver aminotransferases and bilirubin should be monitored. - After stopping treatment with Triumeq for reasons of a suspected HSR, Triumeq or any other medicinal product containing abacavir or dolutegravir must never be re-initiated. - Restarting abacavir containing products following a suspected abacavir HSR can result in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death. 41  - In order to avoid restarting abacavir and dolutegravir, patients who have experienced a suspected HSR should be instructed to dispose of their remaining Triumeq tablets. Clinical description of HSRs Hypersensitivity reactions have been reported in <1% of patients treated with dolutegravir in clinical studies, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Abacavir HSR has been well characterised through clinical studies and during post marketing fol

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HOS-096707 · has-warning-information · PDF-Seite 3

Hypersensitivity reactions (see section 4.8) 3 Both abacavir and dolutegravir are associated with a risk for hypersensitivity reactions (HSR) (see section 4.8), and share some common features such as fever and/or rash with other symptoms indicating multi-organ involvement. Clinically it is not possible to determine whether a HSR with Triumeq would be caused by abacavir or dolutegravir. Hypersensitivity reactions have been observed more commonly with abacavir, some of which have been life-threatening, and in rare cases fatal, when not managed appropriately. The risk for abacavir HSR to occur is high for patients who test positive for the HLA-B*5701 allele. However, abacavir HSRs have been reported at a low frequency in patients who do not carry this allele. Therefore, the following should always be adhered to: - HLA-B*5701 status must always be documented prior to initiating therapy. - Triumeq should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir- containing regimen. - Triumeq must be stopped without delay, even in the absence of the HLA-B*5701 allele, if an HSR is suspected. Delay in stopping treatment with Triumeq after the onset of hypersensitivity may result in an immediate and life-threatening reaction. Clinical status including liver aminotransferases and bilirubin should be monitored. - After stopping treatment with Triumeq for reasons of a suspected HSR, Triumeq or any other medicinal product containing abacavir or dolutegravir must never be re-initiated. - Restarting abacavir containing products following a suspected abacavir HSR can result in a prompt return of symptoms within hours. This recurrence is usually more severe than on initial presentation, and may include life-threatening hypotension and death. - In order to avoid restarting abacavir and dolutegravir, patients who have experienced a suspected HSR should be instructed to dispose of their remaining Triumeq tablets. Clinical description of HSRs Hypersensitivity reactions have been reported in <1% of patients treated with dolutegravir in clinical studies, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Abacavir HSR has been well characterised through clinical studies and during post marketing follow-up. Symptoms usually appea

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