Sunlenca

5 WARNINGS AND PRECAUTIONS Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.1 ) Residual concentrations of lenacapavir may remain in systemic circulation for up to 12 months or longer. Counsel patients regarding the dosing schedule; non-adherence could lead to loss of virologic response and development of resistance. ( 5.2 ) May increase exposure and risk of adverse reactions to drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA. ( 5.2 ) If discontinued, initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs, switch to an alternative regimen if possible. ( 5.2 ) Injection site reactions may occur, and nodules and indurations may be persistent. Improper administration (intradermal injection) has been associated with serious injection site reactions. ( 5.3 ) 5.1 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.2 Long-Acting Properties and Potential Associated Risks with SUNLENCA Residual concentrations of lenacapavir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer after the last subcutaneous dose). It is important to counsel patients that maintenance dosing by injection is required every 6 months, because missed doses or non-adherence to injections could lead to loss of virologic response and development of resistance [see Dosage and Administration (2.1) ] . Lenacapavir, a moderate CYP3A inhibitor, may increase the exposure to, and therefore potential risk of adverse reactions from, drugs primarily metabolized by CYP3A initiated within 9 months after the last subcutaneous dose of SUNLENCA [see Drug Interactions and Clinical Pharmacology (7.2 , 12.3) ] . If SUNLENCA is discontinued, to minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen where possible no later than 28 weeks after the final injection of SUNLENCA. If virologic failure occurs during treatment, switch the patient to an alternative regimen if possible [see Dosage and Administration (2.1) ]. 5.3 Injection Site Reactions Administration of SUNLENCA may result in local injection site reactions (ISRs). If clinically significant ISRs occur, evaluate and institute appropriate therapy and follow-up. Manifestations of ISRs may include swelling, pain, erythema, nodule, induration, pruritus, extravasation or mass. Nodules and indurations at the injection site may take longer to resolve than other ISRs. In clinical studies, after a median follow-up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Measurements and qualitative assessments of ISRs were not routinely reported. Where described, the majority of the injection site nodules and indurations were palpable but not visible, and had a maximum size of approximately 1 to 4 cm [see Adverse Reactions (6.1) ] . The mechanism driving the persistence of injection site nodules and indurations in some patients is not fully understood, but based on available data, they may be related to the presence of the subcutaneous drug depot. In some patients who had a skin biopsy performed of an injection site nodule or induration, dermatopathology revealed foreign body inflammation or granulomatous response. Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer [see Adverse Reactions (6) ] . Ensure SUNLENCA is only administered subcutaneously in the abdomen [see Dosage and Administration (2.5) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Immune Reconstitution Syndrome [see Warnings and Precautions (5.1) ] Injection Site Reactions [see Warnings and Precautions (5.3) ]. Most common adverse reactions (incidence greater than or equal to 3%, all grades) are nausea and injection site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of HIV-1 in Heavily Treatment-Experienced Adults The primary safety assessment of SUNLENCA was based on data from heavily treatment-experienced adult participants with HIV who received SUNLENCA in a Phase 2/3 trial (CAPELLA; N=72) through Week 52 (median duration on study of 71 weeks) [see Clinical Studies (14.1) ] , as well as supportive data in treatment-naïve adult participants with HIV who received SUNLENCA in a Phase 2 trial (CALIBRATE; N=157) through Week 54 (median duration of exposure of 66 weeks). The most common adverse reactions (all Grades) reported in at least 3% of participants in CAPELLA were nausea and injection site reactions. The proportion of participants in CAPELLA who discontinued treatment with SUNLENCA due to adverse events, regardless of severity, was 1% (Grade 1 injection site nodule in 1 participant). Table 6 displays the frequency of adverse reactions (all Grades) greater than or equal to 3% in the SUNLENCA group. Table 6 Adverse Reactions (All Grades) Reported in ≥ 3% Frequencies of adverse reactions are based on all adverse events attributed to trial drug by the investigator, based on all participants (cohorts 1 and 2) in CAPELLA. of Heavily Treatment Experienced Adults with HIV-1 Receiving SUNLENCA in CAPELLA (Week 52 Analysis) Adverse Reactions SUNLENCA + Background Regimen (N=72) Injection Site Reactions 65% Nausea 4% The majority (96%) of all adverse reactions associated with SUNLENCA were mild or moderate in severity. Injection-Associated Adverse Reactions Local Injection Site Reactions (ISRs) : The most frequent adverse reactions were ISRs. Of the 72 participants in CAPELLA, 65% had experienced an ISR attributed to study drug through at least the Week 52 visit. Most participants had mild (Grade 1, 44%) or moderate (Grade 2, 17%) ISRs. Four percent of participants experienced a severe (Grade 3) ISR (erythema, pain, swelling) that resolved within 15 days. The ISRs reported in more than 1% of participants were swelling (36%), pain (31%), erythema (31%), nodule (25%), induration (15%), pruritus (6%), extravasation (3%) and mass (3%). ISRs reported in 1% of participants included discomfort, hematoma, edema, and ulcer. Nodules and indurations at the injection site took longer to resolve than other ISRs. The median time to resolution of all ISRs, excluding nodules and indurations, was 5 days (range: 1 to 183). The median time to resolution of nodules and indurations associated with the first injections of SUNLENCA was 148 (range: 41 to 727) and 70 (range: 3 to 252) days, respectively. After a median follow up of 553 days, 30% of nodules and 13% of indurations (in 10% and 1% of participants, respectively) associated with the first injections of SUNLENCA had not fully resolved. Qualitative descriptions of injection site nodules and indurations were not routinely reported, but, where reported, the majority of injection site nodules and indurations were palpable but not visible. Measurements of injection site nodules and indurations were not routinely performed or standardized, but where measurements were reported, the maximum size for the majority of injection site nodules and indurations was approximately 1 to 4 cm [see Warnings and Precautions (5.3) ] . Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3 to 4) occurring in at least 2% of participants in CAPELLA are presented in Table 7 . A causal association between SUNLENCA and these laboratory abnormalities has not been established. Table 7 Selected Laboratory Abnormalities (Grades 3 to 4) Reported in ≥ 2% of Participants Receiving SUNLENCA in CAPELLA (Week 52 Analysis) Laboratory Parameter Abnormality SUNLENCA + Background Regimen (N=72) Frequencies are based on treatment-emergent laboratory abnormalities in all participants (cohorts 1 and 2) in CAPELLA. Percentages were calculated based on the number of participants with post-baseline toxicity grades for each laboratory parameter (n=72 for all parameters except hyperglycemia fasting n=57). ALT= alanine aminotransferase; AST= aspartate aminotransferase; ULN = upper limit of normal Creatinine ( >1.8 × ULN or ≥1.5 × baseline) 13% Glycosuria (>2+) Grade 3 only (no Grade 4 values reported). 6% Hyperglycemia (fasting) (>250 mg/dL) 5% Proteinuria (>2+) 4% ALT (≥5 × ULN) 3% AST (≥5 × ULN) 3% Direct Bilirubin (>ULN) 3% 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administration site conditions Injection site necrosis [see Warnings and Precautions (5.3) ] .

<table width="75%" ID="table6"><caption>Table 6 Adverse Reactions (All Grades) Reported in &#x2265; 3% <footnote>Frequencies of adverse reactions are based on all adverse events attributed to trial drug by the investigator, based on all participants (cohorts 1 and 2) in CAPELLA.</footnote> of Heavily Treatment Experienced Adults with HIV-1 Receiving SUNLENCA in CAPELLA (Week 52 Analysis)</caption><col width="70%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom">Adverse Reactions</th><th styleCode="Rrule">SUNLENCA + Background Regimen (N=72)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection Site Reactions</td><td styleCode="Rrule">65%</td></tr><tr><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">4%</td></tr></tbody></table>

<table width="60%" ID="table7"><caption>Table 7 Selected Laboratory Abnormalities (Grades 3 to 4) Reported in &#x2265; 2% of Participants Receiving SUNLENCA in CAPELLA (Week 52 Analysis)</caption><col width="70%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom">Laboratory Parameter Abnormality</th><th styleCode="Rrule">SUNLENCA + Background Regimen (N=72) <footnote>Frequencies are based on treatment-emergent laboratory abnormalities in all participants (cohorts 1 and 2) in CAPELLA. Percentages were calculated based on the number of participants with post-baseline toxicity grades for each laboratory parameter (n=72 for all parameters except hyperglycemia fasting n=57).</footnote></th></tr></thead><tfoot><tr><td align="left" valign="top" colspan="2">ALT= alanine aminotransferase; AST= aspartate aminotransferase; ULN = upper limit of normal</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Creatinine ( &gt;1.8 &#xD7; ULN or &#x2265;1.5 &#xD7; baseline)</td><td styleCode="Rrule">13%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Glycosuria (&gt;2+) <footnote ID="foot2">Grade 3 only (no Grade 4 values reported).</footnote></td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperglycemia (fasting) (&gt;250 mg/dL)</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Proteinuria (&gt;2+) <footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">ALT (&#x2265;5 &#xD7; ULN) <footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">AST (&#x2265;5 &#xD7; ULN)</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Direct Bilirubin (&gt;ULN) <footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">3%</td></tr></tbody></table>