Sunlenca · 4.1 Therapeutic indications · 1

HOS-099881 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most common adverse reactions in heavily treatment-experienced adult participants with HIV were ISRs (76%) and nausea (6%). Tabulated list of adverse reactions 9 A tabulated list of adverse reactions is presented in Table 3. 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 3: Tabulated list of adverse reactions Frequencya Adverse reaction Immune system disorders Not known immune reconstitution inflammatory syndrome Gastrointestinal disorders Common nausea General disorders and administration site conditions Very common injection site reactionsb a Frequency based on all participants (Cohorts 1 and 2) in CAPELLA (see section 5.1). b Includes injection site swelling, pain, nodule, erythema, induration, pruritus, extravasation, discomfort, mass, haematoma, oedema, and ulcer from CAPELLA; and necrosis identified from post-marketing surveillance. Description of selected adverse reactions Immune Reconstitution Inflammatory Syndrome In patients with HIV with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4). Local injection site reactions Through Week 156 of treatment, most participants had mild (Grade 1, 54%) or moderate (Grade 2, 17%) ISRs. Six percent (4/72) of participants experienced a severe Grade 3 ISR with a median time to resolution of 15 (range: 1 to 71) days. No participants experienced a Grade 4 ISR. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days. The median time to resolution of nodules and indurations associated with the first injections of Sunlenca was 191 (Q1, Q3: 71, 366) and 113 (Q1, Q3: 29, 224) days, respectively. After a median follow-up of 554 days, nodules associated with the first injections of Sunlenca had not resolved in 10% (7/72) of the participants. All indurations associated with the fir

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HOS-099887 · has-adverse-reaction-information · PDF-Seite 26

Summary of the safety profile The most common adverse reaction in heavily treatment experienced adult participants with HIV was nausea (6%). Tabulated list of adverse reactions A tabulated list of adverse reactions is presented in Table 3. 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 3: Tabulated list of adverse reactions Frequencya Adverse reaction Immune system disorders Not known immune reconstitution inflammatory syndrome Gastrointestinal disorders Common nausea a Frequency based on all participants (Cohorts 1 and 2) in CAPELLA (see section 5.1). Description of selected adverse reactions Immune Reconstitution Inflammatory Syndrome In patients with HIV with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4). 26 Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-099883 · has-contraindication-information · PDF-Seite 21

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with strong inducers of CYP3A, P-gp, and UGT1A1, such as: • antimycobacterials: rifampicin • anticonvulsants: carbamazepine, phenytoin • herbal products: St. John’s wort (Hypericum perforatum) (see section 4.5).

HOS-099877 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with strong inducers of CYP3A, P-gp, and UGT1A1, such as: • antimycobacterials: rifampicin • anticonvulsants: carbamazepine, phenytoin • herbal products: St. John’s wort (Hypericum perforatum) (see section 4.5).

HOS-099876 · has-indication-information · PDF-Seite 2

Sunlenca injection, in combination with other antiretroviral(s), is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen (see sections 4.2 and 5.1).

HOS-099882 · has-indication-information · PDF-Seite 19

Sunlenca tablet, in combination with other antiretroviral(s), is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen, for oral loading prior to administration of long-acting lenacapavir injection (see sections 4.2 and 5.1).

HOS-099885 · has-interaction-information · PDF-Seite 21

Effect of other medicinal products on the pharmacokinetics of lenacapavir Lenacapavir is a substrate of CYP3A, P-gp and UGT1A1. Strong inducers of CYP3A, P-gp, and UGT1A1, such as rifampicin, may significantly decrease plasma concentrations of lenacapavir resulting in loss of therapeutic effect and development of resistance, therefore co-administration is contraindicated (see section 4.3). Moderate inducers of CYP3A and P-gp, such as efavirenz, may also significantly decrease plasma concentrations of lenacapavir, therefore co-administration is not recommended (see section 4.4). 21 Strong inhibitors of CYP3A, P-gp and UGT1A1 together (i.e., all 3 pathways), such as atazanavir/cobicistat, may significantly increase plasma concentrations of lenacapavir, therefore co-administration is not recommended (see section 4.4). Strong CYP3A4 inhibitors alone (e.g. voriconazole) or strong inhibitors of CYP3A4 and P-gp together (e.g. cobicistat) do not result in a clinically meaningful increase in lenacapavir exposures. Effect of lenacapavir on the pharmacokinetics of other medicinal products Lenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. Caution is advised if Sunlenca is co-administered with a sensitive CYP3A and/or P-gp substrate with a narrow therapeutic index. Lenacapavir is not a clinically meaningful inhibitor of BCRP and does not inhibit OATP. Table 2: Interactions between Sunlenca and other medicinal products Medicinal product by therapeutic Effects on concentrations. Recommendation concerning areas Mean percent change in AUC, co-administration with Sunlenca Cmax ANTIMYCOBACTERIALS Rifampicina,b,c (600 mg once daily) Lenacapavir: Co-administration is AUC: ↓84% contraindicated (see section 4.3). Cmax: ↓55% Rifabutin Interaction not studied. Co-administration is not recommended (see section 4.4). Co-administration of rifabutin may decrease lenacapavir plasma concentrations, which may result in

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HOS-099879 · has-interaction-information · PDF-Seite 5

Effect of other medicinal products on the pharmacokinetics of lenacapavir Lenacapavir is a substrate of CYP3A, P-gp and UGT1A1. Strong inducers of CYP3A, P-gp, and UGT1A1, such as rifampicin, may significantly decrease plasma concentrations of lenacapavir resulting in loss of therapeutic effect and development of resistance, therefore co-administration is contraindicated (see section 4.3). Moderate inducers of CYP3A and P-gp, such as efavirenz, may also significantly decrease plasma concentrations of lenacapavir, therefore co-administration is not recommended (see section 4.4). Strong inhibitors of CYP3A, P-gp and UGT1A1 together (i.e., all 3 pathways), such as atazanavir/cobicistat, may significantly increase plasma concentrations of lenacapavir, therefore co-administration is not recommended (see section 4.4). Strong CYP3A4 inhibitors alone (e.g. voriconazole) or strong inhibitors of CYP3A4 and P-gp together (e.g. cobicistat) do not result in a clinically meaningful increase in lenacapavir exposures. Effect of lenacapavir on the pharmacokinetics of other medicinal products Lenacapavir is a moderate inhibitor of CYP3A and a P-gp inhibitor. Caution is advised if Sunlenca is co-administered with a sensitive CYP3A and/or P-gp substrate with a narrow therapeutic index. Lenacapavir is not a clinically meaningful inhibitor of BCRP and does not inhibit OATP. Table 2: Interactions between Sunlenca and other medicinal products Medicinal product by Effects on concentrations. Recommendation concerning therapeutic areas Mean percent change in AUC, co-administration with Sunlenca Cmax ANTIMYCOBACTERIALS Rifampicina,b,c (600 mg once daily) Lenacapavir: Co-administration is AUC: ↓84% contraindicated (see section 4.3). Cmax: ↓55% Rifabutin Interaction not studied. Co-administration is not recommended (see section 4.4). 5  Medicinal product by Effects on concentrations. Recommendation concerning therapeutic areas Mean percent change in AUC, co-administration with Sunlenca Cm

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HOS-099880 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no or limited amount of data from the use of lenacapavir in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Sunlenca during pregnancy unless the clinical condition of the women requires treatment with Sunlenca. Breast-feeding In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants. It is unknown whether lenacapavir is excreted in human milk. After administration to rats during pregnancy and lactation, lenacapavir was detected at low levels in the plasma of nursing rat pups, without effects on these nursing pups. Fertility There are no data on the effects of lenacapavir on human male or female fertility. Animal studies indicate no effects on lenacapavir on male or female fertility (see section 5.3).

HOS-099886 · has-pregnancy-information · PDF-Seite 25

Pregnancy There are no or limited amount of data from the use of lenacapavir in pregnant women. 25 Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, foetal development, parturition or postnatal development (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Sunlenca during pregnancy unless the clinical condition of the women requires treatment with Sunlenca. Breast-feeding In order to avoid transmission of HIV to the infant it is recommended that women living with HIV do not breast-feed their infants. It is unknown whether lenacapavir is excreted in human milk. After administration to rats during pregnancy and lactation, lenacapavir was detected at low levels in the plasma of nursing rat pups, without effects on these nursing pups. Fertility There are no data on the effects of lenacapavir on human male or female fertility. Animal studies indicate no effects on lenacapavir on male or female fertility (see section 5.3).

HOS-099884 · has-warning-information · PDF-Seite 21

Immune Reconstitution Inflammatory Syndrome In patients with HIV 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 include 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 reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Opportunistic infections Patients should be advised that Sunlenca or any other antiretroviral therapy 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 patients with HIV associated diseases. Co-administration of other medicinal products Co-administration with medicinal products that are moderate inducers of CYP3A and P-gp (e.g. efavirenz) is not recommended (see section 4.5). Co-administration with medicinal products that are strong inhibitors of CYP3A, P-gp, and UGT1A1 together (i.e. all 3 pathways), such as atazanavir/cobicistat is not recommended (see section 4.5). Excipients This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

HOS-099878 · has-warning-information · PDF-Seite 4

Risk of resistance following treatment discontinuation If Sunlenca is discontinued, to minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen where possible, no later than 28 weeks after the final injection of Sunlenca. If virologic failure is suspected, an alternative regimen should be adopted where possible. Use of other medicinal products after discontinuation of lenacapavir If Sunlenca is discontinued, residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods. These concentrations may affect the exposures of other medicinal products (i.e. sensitive CYP3A substrates) that are initiated within 9 months after the last subcutaneous dose of Sunlenca (see section 4.5). These concentrations are not expected to affect the exposures of other antiretroviral agents that are initiated after discontinuation of Sunlenca. Immune Reconstitution Inflammatory Syndrome In patients with HIV 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 include 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 reactivation; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Injection Site Reactions Injection Site Reactions with Improper Administration Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer. Sunlenca injections must only be administered subcutaneously (see section 4.2). Slow or non-resolving injection site nodules and indurations Administration of Sunlenca may result in local injection site reactions (ISRs), including nodules and indurations. The healthcare professional should inform patients that nodules and indurations at the injection site may take longer to resolve than other IS

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