Tivicay PD (Page 3 of 9)

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 (5.5)].

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 Subjects

Treatment-Naïve Subjects: The safety assessment of TIVICAY 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 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 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 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 subjects receiving TIVICAY 50 mg once daily + EPZICOM and 14% in subjects receiving ATRIPLA once daily.

Treatment‑emergent adverse reactions 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 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 Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis)
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

Rasha

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 subjects 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 subjects received TIVICAY 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 EPZICOM or TRUVADA). 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 TIVICAY and 6% in subjects 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 Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV‑1–infected, antiretroviral treatment-experienced adults 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. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + background regimen and 4% in subjects 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 subjects receiving TIVICAY 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 TIVICAY 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 adverse reactions in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials.

Virologically Suppressed Subjects: 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 HIV-1–infected, virologically suppressed subjects 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 subjects receiving TIVICAY plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. In the pooled analyses, the proportion of subjects 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 subjects 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 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 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 Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis)
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 109)

4%

3%

4%

5%

Grade 3 to 4 (<0.75 x 109)

2%

2%

3%

3%

Table 7. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Subjects in SPRING-2 (Week 96 Analysisa) and SINGLE Trials (Week 144 Analysisa)
a Subjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Ninety-four subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if 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 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.

Virologically Suppressed Adults: Laboratory abnormalities observed in SWORD-1 and SWORD-2 were generally similar compared with observations seen in the other Phase 3 trials.

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 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 subjects 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 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

The safety and pharmacokinetics of TIVICAY and TIVICAY PD in HIV-1–infected pediatric subjects 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 an ongoing, multicenter, open-label, non-comparative trial of HIV‑1–infected pediatric subjects 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 subjects (n = 75) who received the recommended dose (determined by weight and age) through Week 24 showed that 11% of subjects experienced drug-related clinical adverse reactions. The only Grade 1 to 2 drug-related clinical adverse reactions reported by more than one subject 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 subject 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.

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