Dovato · 4.6 Fertility, pregnancy and lactation · 1

HOS-098893 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile The most frequently reported adverse reactions are headache (3%), diarrhoea (2%), nausea (2%) and insomnia (2%). The most severe adverse reaction reported with dolutegravir was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). Tabulated list of adverse reactions The adverse reactions 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 summary of adverse reactions to Dovato based on clinical study and post- marketing experience with Dovato and its individual components Frequency Adverse reaction Blood and lymphatic systems disorders: Uncommon: neutropenia, anaemia, thrombocytopenia Very rare: pure red cell aplasia Not known sideroblastic anaemia1 Immune system disorders: 14 Uncommon: hypersensitivity (see section 4.4), immune reconstitution syndrome (see section 4.4) Metabolism and nutrition disorders: Very rare: lactic acidosis Psychiatric disorders: Common: depression, anxiety, insomnia, abnormal dreams Uncommon: suicidal ideation*, suicide attempt*, panic attack *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 disorders: Very common: headache Common: dizziness, somnolence Very rare: peripheral neuropathy, paraesthesia Gastrointestinal disorders: Very common: nausea, diarrhoea Common: vomiting, flatulence, abdominal pain/ discomfort Rare: pancreatitis Hepatobiliary disorders: Common: alanine aminotransferase (ALT) and/or aspartate

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HOS-098889 · 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-098888 · has-indication-information · PDF-Seite 2

Dovato is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and adolescents above 12 years of age weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine (see section 5.1).

HOS-098891 · has-interaction-information · PDF-Seite 6

No drug interaction studies have been conducted using Dovato. Dovato contains dolutegravir and lamivudine, therefore, any interactions identified for these individually are relevant to Dovato. No clinically significant drug interactions are expected between dolutegravir and lamivudine. Effect of other medicinal products on the pharmacokinetics of dolutegravir 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 Dovato 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. The absorption of dolutegravir is reduced by certain metal cation-containing anti-acid substances and supplements (see Table 1). 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 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 relevant 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 lamivudine is a substrate of BCRP and P-gp in vitro, given its high absolute bioavailability, (see section 5.2), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on lamivudine concentrations. Effect of dolutegravir and lamivudine on the pharmacokinetics of other medicinal products 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

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HOS-098892 · has-pregnancy-information · PDF-Seite 13

Pregnancy Dovato 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. A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/neonatal toxicity with lamivudine. There are no or limited amount of data (less than 300 exposed outcomes) from the use of this dual combination in pregnancy. The safety and efficacy of a dual therapy with dolutegravir + lamivudine has not been studied 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 and more than 1000 pregnancies with first trimester lamivudine treatment, do not indicate an increased risk of major birth defects with either dolutegravir or lamivudine 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 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 concentration of dolutegravir was approximately 1.3-fold greater compared with the maternal peripheral plasma concentration. Placental transfer of lamivudine has been shown to occur in humans. There is

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HOS-098890 · has-warning-information · PDF-Seite 3

Hypersensitivity reactions Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dovato 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 Dovato or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction. Weight and metabolic parameters An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids and weight, there is in some cases evidence for a treatment effect. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate. Liver disease Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products. 3 Dovato includes lamivudine, which is active against hepatitis B. Dolutegravir lacks such activity. Lamivudine monotherapy is generally not considered an adequate treatment for hepatitis B, since the risk for hepatitis B resistance development is high. If Dovato is used in patients co-infected with hepatitis B an additional antiviral is therefore generally needed. Reference should be made to treatment guidelines. If Dovato is discontinued in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of HBV replication is recommended, as withdrawal of lamivudine may result in an acute exacerbation of hepatitis. Patients with pre-existing liver dysfunction, including chronic active hepatitis have an increased frequency of liver function abnormalities during combi

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