Tegrad Adverse Reactions

The following serious adverse drug reactions are discussed in other sections of the labeling: Hypersensitivity reactions [see Precautions].
Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see Precautions]. Fat Redistribution [see Precautions].
Immune Reconstitution Syndrome [see Precautions].
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: Subjects Treatment-Naïve Subjects: The safety assessment of dolutegravir in HIV-1-infected treatment-naïve subjects 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 subjects were randomized and received at least 1 dose of either dolutegravir 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 or emtricitabine/tenofovir. There were 808 subjects 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 subjects were randomized and received at least 1 dose of either dolutegravir 50 mg with fixed-dose abacavir sulfate and lamivudine once daily or fixed-dose efavirenz/emtricitabine/tenofovir 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 subjects receiving dolutegravir 50 mg once daily + Abacavir Sulfate and Lamivudine and 14% in subjects receiving Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate once daily.
Treatment-emergent adverse drug reactions (ADRs) of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 12. Side-by- side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. (See Table 12.)

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In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving dolutegravir and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for dolutegravir and Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate, respectively. These events were not treatment limiting.
In a multicenter, open-label trial (FLAMINGO), 243 subjects received dolutegravir 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either Abacavir Sulfate and Lamivudine or Emtricitabine and Tenovir). There were 484 subjects included in the efficacy and safety analyses. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving dolutegravir and 6% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.
Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV-1-infected, antiretroviral treatment-experienced adults were randomized and received either dolutegravir 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. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving dolutegravir 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen.
The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving dolutegravir 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen.
Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: In a multicenter, open- label, single-arm trial (ING112574, VIKING-3), 183 HIV-1-infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received dolutegravir 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48.
Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50- mg once-daily dose in adult Phase 3 trials.
Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Trials: The following ADRs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving dolutegravir 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 subjects 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 Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 13. The mean change from baseline observed for selected lipid values is presented in Table 14. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. (See Tables 13 and 14.)

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Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE.
Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: 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 Subjects: 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 subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported.
Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trials, subjects 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 subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects 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 subjects receiving dolutegravir 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 subjects with hepatitis B and/or C at the start of therapy with dolutegravir, particularly in the setting where anti-hepatitis therapy was withdrawn [see Precautions].
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 Pharmacology under Actions]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: - 0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects.
Clinical Trials Experience in Pediatric Subjects: IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV-1- infected pediatric subjects aged 4 weeks to less than 18 years, of which 46 treatment-experienced, INSTI- naïve subjects aged 6 to less than 18 years have been enrolled [see Use in Children under Precautions, Pharmacology: Pharmacodynamics: Clinical Studies: Pediatric Subjects under Actions].
The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported by more than one subject were decreased neutrophil count (n = 3) and diarrhea (n = 2).
There were no Grade 3 or 4 drug-related ADRs reported. No ADRs led to discontinuation. The Grade 3 or 4 laboratory abnormalities reported in more than one subject were elevated total bilirubin (n = 3) and decreased neutrophil count (n = 2). The changes in mean serum creatinine were similar to those observed in adults.