dolutegravir sodium;rilpivirine hydrochloride

HOS-098247 · has-adverse-reaction-information · PDF-Seite 18

Summary of the safety profile The most frequently reported adverse reactions with Juluca (from clinical studies – see section 5.1) were diarrhoea (2%) and headache (2%). The most severe adverse reaction, related to the treatment with dolutegravir (from pooled Phase IIb and Phase III clinical studies), seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). Tabulated list of adverse reactions The sources of information for the safety database include 2 identical, randomised, open-label studies SWORD-1 and SWORD-2 (see section 5.1), pooled studies from individual components and post-marketing experience. The adverse reactions considered at least possibly related to treatment with the components of Juluca from clinical studies and post-marketing experience are listed in Table 2 by body system, organ class and 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 to Juluca based on clinical study and post- marketing experience with Juluca and its individual components System organ class Frequency Adverse drug reactions (SOC) category1 Blood and lymphatic common decreased white blood cell count systems disorders: decreased haemoglobin decreased platelet count not known sideroblastic anaemia2 Immune system uncommon hypersensitivity (see section 4.4) disorders not known immune reconstitution syndrome Metabolism and very common increased total cholesterol (fasted) nutrition disorders increased LDL cholesterol (fasted) common decreased appetite increased triglycerides (fasted) Psychiatric disorders very common insomnia common abnormal dreams depression sleep disorders

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HOS-098243 · 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 the following medicinal products: - fampridine (also known as dalfampridine); - carbamazepine, oxcarbazepine, phenobarbital, phenytoin; - rifampicin, rifapentine; - proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole; - systemic dexamethasone, except as a single dose treatment; - St John's wort (Hypericum perforatum).

HOS-098242 · has-indication-information · PDF-Seite 2

Juluca is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults who are virologically-suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least six months with no history of virological failure and no known or suspected resistance to any non-nucleoside reverse transcriptase inhibitor or integrase inhibitor (see section 5.1).

HOS-098245 · has-interaction-information · PDF-Seite 5

Juluca is intended for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medicinal products for the treatment of HIV. Therefore, information regarding drug-drug interactions with other antiretroviral medicinal products is not provided. Juluca contains dolutegravir and rilpivirine, therefore, any interactions identified with these active substances are relevant to Juluca. Interaction studies have only been performed in adults. Effect of other medicinal products on the pharmacokinetics of dolutegravir and rilpivirine Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT)1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, cytochrome P450 (CYP)3A4, P- glycoprotein (P-gp), and breast cancer resistance protein (BCRP); therefore, medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1). Co-administration of dolutegravir/rilpivirine and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 1). The absorption of dolutegravir is reduced by certain anti-acid medicinal products (see Table 1). Rilpivirine is primarily metabolised by CYP3A. Medicinal products that induce or inhibit CYP3A may thus affect the clearance of rilpivirine (see section 5.2). Co-administration of dolutegravir/rilpivirine with medicinal products that induce CYP3A may result in decreased plasma concentrations of rilpivirine, which 5 could reduce the therapeutic effect of dolutegravir/rilpivirine (see Table 1). Co-administration of dolutegravir/rilpivirine with medicinal products that inhibit CYP3A may result in increased plasma concentrations of rilpivirine (see Table 1). In patients with severe renal impairment or end stage renal disease, the combination of dolutegravir/rilpivirine with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk (see section 4.2). Co-administration of dolutegravir/rilpivirine with medicinal products that increase gastric pH may result in decreased plasma concentrations of rilpivirine which could potentially reduce the therapeutic effect of dolutegravir/rilpivirine. Effect of dolutegravir and rilpivirine on the pharmacokinetics of other medicinal products Based on in vivo and/or in vitro data, dolutegravir

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HOS-098246 · has-pregnancy-information · PDF-Seite 16

Pregnancy Lower exposures of dolutegravir and rilpivirine were observed during pregnancy (see sections 5.1, 5.2). In phase 3 studies, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure. The use of Juluca during pregnancy is not recommended. A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor feto/ neonatal toxicity associated with dolutegravir. A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative nor feto/neonatal toxicity of rilpivirine. There are no or limited amount (less than 300 exposed outcomes) from the use of this dual combination in pregnancy. The safety and efficacy of a dual therapy with dolutegravir + rilpivirine has not been studied in pregnancy. 16 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 between 300-1000 pregnancies with first trimester rilpivirine treatment, do not indicate an increased risk of major birth defects with either dolutegravir or rilpivirine 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 + rilpivirine in pregnant women. In animal reproductive toxicology studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified. For rilpivirine, a

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HOS-098244 · has-warning-information · PDF-Seite 3

Hypersensitivity reactions Hypersensitivity reactions have been reported with dolutegravir, and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. dolutegravir/rilpivirine 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/rilpivirine after the onset of hypersensitivity may result in a life-threatening allergic reaction. 3 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. Cardiovascular At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG) (see sections 4.5 and 5.1). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Dolutegravir/rilpivirine should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes. Opportunistic infections Patients should be advised that dolutegravir/rilpivirine does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases. Osteonecrosis Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint

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