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adverse reactions
6 ADVERSE REACTIONS The following serious adverse drug reactions are discussed in other sections of the labeling: • Hypersensitivity reactions [see Warnings and Precautions ( 5.1 )] . • Hepatotoxicity [see Warnings and Precautions ( 5.2 )] . • Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.4 )] . The most common adverse reactions of moderate to severe intensity and incidence at least 2% (in those receiving TIVICAY in any one adult trial) are insomnia, fatigue, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adult Participants Treatment-Naïve Participants: The safety assessment of TIVICAY in treatment naïve participants with HIV‑1 is based on the analyses of data from 2 international, multicenter, double-blind trials, SPRING‑2 (ING113086) and SINGLE (ING114467) and data from the international, multicenter, open-label FLAMINGO (ING114915) trial. In SPRING‑2, 822 participants were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 participants included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms. In SINGLE, 833 participants were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rates of adverse events leading to discontinuation were 4% in participants receiving TIVICAY 50 mg once daily + EPZICOM and 14% in participants receiving ATRIPLA once daily. Treatment‑emergent adverse reactions of moderate to severe intensity observed in at least 2% of participants in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 5 . Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 5. Treatment-Emergent Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naïve Participants in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis) NRTI = Nucleoside Reverse Transcriptase Inhibitor. a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. System Organ Class/ Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Psychiatric Insomnia <1% <1% 3% 3% Depression <1% <1% 1% 2% Abnormal dreams <1% <1% <1% 2% Nervous System Dizziness <1% <1% <1% 5% Headache <1% <1% 2% 2% Gastrointestinal Nausea 1% 1% <1% 3% Diarrhea <1% <1% <1% 2% Skin and Subcutaneous Tissue Rash a 0 <1% <1% 6% General Disorders Fatigue <1% <1% 2% 2% Ear and Labyrinth Vertigo 0 <1% 0 2% In addition, Grade 1 insomnia was reported by 1% and less than 1% of participants receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting. In a multicenter, open-label trial (FLAMINGO), 243 participants received TIVICAY 50 mg once daily versus 242 participants who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 participants included in the efficacy and safety analyses. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in participants receiving TIVICAY and 6% in participants receiving darunavir/ritonavir. The adverse reactions observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Participants: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 participants with HIV‑1, were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. Participants were antiretroviral treatment-experienced adults. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in participants receiving TIVICAY 50 mg once daily + background regimen and 4% in participants receiving raltegravir 400 mg twice daily + background regimen. The only treatment‑emergent adverse reaction of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in participants receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in participants receiving raltegravir 400 mg twice daily + background regimen. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Participants: In a multicenter, open-label, single‑arm trial (ING112574, VIKING-3), 183 participants with HIV‑1 received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. Participants were antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance. The rate of adverse events leading to discontinuation was 4% of participants at Week 48. Treatment‑emergent adverse reactions in VIKING-3 were generally similar compared with observations with the 50‑mg once-daily dose in adult Phase III trials. Virologically Suppressed Participants: The adverse reactions observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from 2 identical, international, multicenter, open‑label trials (SWORD‑1 and SWORD‑2) of 513 virologically suppressed participants with HIV‑1, switching from their current antiretroviral regimen to TIVICAY plus rilpivirine, were consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. There were no adverse reactions (Grades 2 to 4) with an incidence of at least 2% in either treatment arm at Week 48. The safety profile during the additional follow-up period through Week 148 were consistent with Week 48. The rate of adverse events leading to discontinuation through Week 48 was 4% in participants receiving TIVICAY plus rilpivirine once daily and less than 1% in participants who remained on their current antiretroviral regimen. In the pooled analyses, the proportion of participants receiving TIVICAY plus rilpivirine who discontinued treatment due to an adverse event through Week 148 was 8%. Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Trials: The following adverse reactions occurred in less than 2% of treatment-naïve or treatment-experienced participants receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting. Hepatobiliary Disorders: Hepatitis. Musculoskeletal Disorders: Myositis. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in participants with a pre-existing history of depression or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naïve Participants: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of participants are presented in Table 6 . The mean change from baseline observed for selected lipid values is presented in Table 7 . Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 6. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naïve Participants in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis) ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; NRTI = Nucleoside Reverse Transcriptase Inhibitor; ULN = Upper limit of normal. Laboratory Parameter Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) ALT Grade 2 (>2.5-5.0 x ULN) 4% 4% 3% 5% Grade 3 to 4 (>5.0 x ULN) 2% 2% 1% <1% AST Grade 2 (>2.5-5.0 x ULN) 5% 3% 3% 4% Grade 3 to 4 (>5.0 x ULN) 3% 2% 1% 3% Total Bilirubin Grade 2 (1.6-2.5 x ULN) 3% 2% <1% <1% Grade 3 to 4 (>2.5 x ULN) <1% <1% <1% <1% Creatine kinase Grade 2 (6.0-9.9 x ULN) 2% 5% 5% 3% Grade 3 to 4 (≥10.0 x ULN) 7% 4% 7% 8% Hyperglycemia Grade 2 (126-250 mg/dL) 6% 6% 9% 6% Grade 3 (>250 mg/dL) <1% 2% 2% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 7% 7% 11% 11% Grade 3 to 4 (>3.0 x ULN) 2% 5% 5% 4% Total neutrophils Grade 2 (0.75-0.99 x 10 9 ) 4% 3% 4% 5% Grade 3 to 4 (<0.75 x 10 9 ) 2% 2% 3% 3% Table 7. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Participants in SPRING-2 (Week 96 Analysis a ) and SINGLE Trials (Week 144 Analysis a ) HDL = High density lipoprotein; LDL = Low density lipoprotein; NRTI = Nucleoside Reverse Transcriptase Inhibitor. a Participants on lipid-lowering agents at baseline were excluded from these analyses (19 participants in each arm in SPRING-2, and in SINGLE: TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Ninety-four participants initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless of whether they discontinued the agent (SPRING-2: TIVICAY n = 9, raltegravir n = 13; SINGLE: TIVICAY + EPZICOM n = 36, ATRIPLA n = 36). Laboratory Parameter Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Cholesterol (mg/dL) 8.1 10.1 24.0 26.7 HDL cholesterol (mg/dL) 2.0 2.3 5.4 7.2 LDL cholesterol (mg/dL) 5.1 6.1 16.0 14.6 Triglycerides (mg/dL) 6.7 6.6 13.6 31.9 Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Participants: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Participants: The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of participants had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported. Virologically Suppressed Adults: Laboratory abnormalities observed in SWORD-1 and SWORD-2 were generally similar compared with observations seen in the other Phase III trials. Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase III trials, participants with hepatitis B and/or C virus co‑infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in participants with hepatitis B and/or C virus co‑infection was similar to that observed in participants without hepatitis B or C co‑infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co‑infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co‑infected compared with HIV mono-infected participants receiving TIVICAY were observed in 18% vs. 3% with the 50‑mg once‑daily dose and 13% vs. 8% with the 50‑mg twice‑daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some participants with hepatitis B and/or C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn [see Warnings and Precautions ( 5.2 )] . Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology ( 12.2 )] . Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 96 weeks. In treatment-naïve participants, a mean change from baseline of 0.15 mg/dL (range: -0.32 mg/dL to 0.65 mg/dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced participants. Clinical Trials Experience in Pediatric Participants Children and Adolescent Participants with HIV‑1: The safety and pharmacokinetics of TIVICAY and TIVICAY PD in pediatric participants with HIV‑1 aged at least 4 weeks and weighing at least 3 kg was evaluated in the IMPAACT P1093 trial and 2 weight-band-based pharmacokinetic substudies of the ODYSSEY trial [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 )] . Overall, the safety data in these pediatric studies were similar to those seen in adults, and there was no clinically significant difference in dolutegravir exposure [see Clinical Pharmacology ( 12.3 )] . IMPAACT P1093 is a multicenter, open-label, non-comparative trial of pediatric participants with HIV‑1 aged 4 weeks to less than 18 years [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.3 )] . The safety analysis based on participants (n = 75) who received the recommended dose (determined by weight and age) through Week 24 showed that 11% of participants experienced drug-related clinical adverse reactions. The only Grade 1 to 2 drug-related clinical adverse reactions reported by more than one participant was immune reconstitution inflammatory syndrome (IRIS) (n = 2). There were no Grade 3 or 4 drug‑related adverse reactions reported. No adverse reactions led to discontinuation. The Grade 3 or 4 laboratory abnormalities reported in more than one participant were decreased neutrophil count (n = 11), decreased blood bicarbonate (n = 4), decreased hemoglobin (n = 3), increased lipase (n = 2), and increased blood potassium (n = 2). These laboratory events were not considered to be drug-related. Median laboratory values were similar at baseline and Week 24. Changes in median serum creatinine were similar to those observed in adults. Neonates Exposed to HIV‑1: Forty‑eight term neonates exposed to HIV‑1 (from birth and weighing at least 2 kg) received dolutegravir for up to 6 weeks, and followed for a total of 16 weeks in IMPAACT 2023. The safety profile in neonates was similar to that observed in older populations and there were no new safety findings identified [see Use in Specific Populations ( 8.4 )] . 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. Blood and Lymphatic Systems Sideroblastic anemia. Hepatobiliary Disorders Acute liver failure, hepatotoxicity. Investigations Weight increased. Musculoskeletal Arthralgia, myalgia. Psychiatric Anxiety.