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Tivicay

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Tivicay

Tivicay Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Tivicay (dolutegravir) is an integrase strand transfer inhibitor (INSTI) used in combination with other antiretroviral agents to treat human immunodeficiency virus type 1 (HIV-1) infection in adults and children aged 12 years and older. Common side effects include trouble sleeping, headache, allergic reactions such as rash, changes in liver tests, changes in body fat, and changes in your immune system.

The recommended dose of Tivicay is 50 mg administered orally once or twice daily. Tivicay may interact with other HIV/AIDS medicines; antacids or laxatives that contain aluminum, magnesium or calcium; sucralfate; iron or calcium supplements, or buffered medicines; anti-seizure medicines, St. John's wort, metformin, or rifampin. Tell your doctor all medications and supplements you use. It is unknown if Tivicay will harm a fetus. Tell your doctor if you become pregnant while taking this drug. There is a registry for women who take antiviral medicines during pregnancy. It is unknown if this drug passes into breast milk. Because breast milk can transmit HIV, do not breastfeed.

Our Tivicay (dolutegravir) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Tivicay FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

The following adverse drug reactions (adverse events assessed as causally related by the investigator or ADRs) are discussed in other sections of the labeling:

  • Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].
  • Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see WARNINGS AND PRECAUTIONS].
  • Fat Redistribution [see WARNINGS AND PRECAUTIONS].
  • Immune Reconstitution Syndrome [see WARNINGS AND PRECAUTIONS].

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-Emergent Adverse Drug Reactions (ADRs)

Treatment-Na´ve Subjects: The safety assessment of TIVICAY in HIV-1-infected treatment-na´ve subjects is based on the analyses of 48-week data from 2 ongoing, international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467).

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. 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. The rates of adverse events leading to discontinuation were 2% in subjects receiving TIVICAY 50 mg once daily + EPZICOM and 10% in subjects receiving ATRIPLA once daily.

Treatment-emergent ADRs of moderate to severe intensity observed in ≥ 2% of subjects in either treatment arm are provided in Table 2. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 2: Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and ≥ 2% Frequency in Treatment-Na´ve Subjects in SPRING-2 and SINGLE Trials (Week 48 Analysis)

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% 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%
Ear and Labyrinth
Vertigo 0 < 1% 0 2%
aIncludes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.

In addition, Grade 1 insomnia was reported by 1% and < 1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 3% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve 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 24 weeks, the rates of adverse events leading to discontinuation were 2% 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 ADR of moderate to severe intensity with ≥ 2% frequency in either treatment group was diarrhea, 1% (5/354) in subjects receiving TIVICAY 50 mg once daily + background regimen and 2% (6/361) 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 3% of subjects at Week 24.

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-Na´ve and Treatment-Experienced Trials

The following ADRs occurred in < 2% of treatment-na´ve 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.

General Disorders: Fatigue.

Hepatobiliary Disorders: Hepatitis.

Musculoskeletal Disorders: Myositis.

Renal and Urinary Disorders: Renal impairment.

Skin and Subcutaneous Tissue Disorders: Pruritus.

Laboratory Abnormalities

Treatment-Na´ve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in ≥ 2% of subjects are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 3: Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Na´ve Subjects in SPRING-2 and SINGLE Trials (Week 48 Analysis)

Laboratory Parameter Preferred Term SPRING-2 SINGLE
TIVICAY 50 mg Once Daily +2 NRTIs
(N = 403)
Raltegravir 400 mg Twice Daily + 2NRTIs
(N = 405)
TIVICAY 50 mg +EPZICOM Once Daily
(N = 414)
ATRIPLA Once Daily
(N = 419)
ALT
  Grade 2 ( > 2.5-5.0 x ULN) 2% 3% 2% 5%
  Grade 3 to 4 ( > 5.0 x ULN) 2% 1% < 1% < 1%
AST
  Grade 2 ( > 2.5-5.0 x ULN) 3% 3% 2% 3%
  Grade 3 to 4 ( > 5.0 x ULN) 2% 2% 0 2%
Total Bilirubin
  Grade 2 (1.6-2.5 x ULN) 2% 2% < 1% 0
  Grade 3 to 4 ( > 2.5 x ULN) < 1% < 1% < 1% 0
Creatine kinase
  Grade 2 (6.0-9.9 x ULN) 1% 3% 3% 1%
  Grade 3 to 4 ( ≥ 10.0 x ULN) 4% 3% 3% 4%
Hyperglycemia
  Grade 2 (126-250 mg/dL) 5% 5% 7% 4%
  Grade 3 ( > 251 mg/dL) < 1% 1% 1% < 1%
Lipase
  Grade 2 ( > 15-3.0 x ULN) 5% 6% 8% 7%
  Grade 3 to 4 ( > 3.0 x ULN) 1% 3% 3% 2%
Total neutrophils
  Grade 2 (0.75-0.99 x 109) 3% 3% 2% 4%
  Grade 3 to 4 ( < 0.75 x 109) 2% 1% 2% 3%
ULN = Upper limit of normal.

Table 4: Mean Change From Baseline in Fasted Lipid Values in Treatment-Na´ve Subjects in SPRING-2 and SINGLE Trials (Week 48 Analysis)

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) 6.7 8.3 17.1 24.0
HDL cholesterol (mg/dL) 2.8 2.6 5.2 7.9
LDL cholesterol (mg/dL) 2.7 2.8 8.5 13.1
Triglycerides (mg/dL) 7.7 9.8 17.7 18.6
aSubjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY n = 27 and ATRIPLA n = 26). Forty-nine 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 = 5, raltegravir n = 8; SINGLE: TIVICAY n = 19 and ATRIPLA: n = 17).

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Na´ve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-na´ve (SPRING-2 and SINGLE) trials.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: The most common treatment-emergent laboratory abnormalities ( > 5% for Grades 2 to 4 combined) were elevated ALT (8%), AST (6%), cholesterol (8%), hyperglycemia (12%), and lipase (8%). Two percent (3/183) of subjects had a Grade 3 to 4, treatment-emergent hematology laboratory abnormality, with neutropenia (1% [2/183]) 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 TIVICAY were observed in 16% vs. 2% with the 50-mg once-daily dose and 8% vs. 7% 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].

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]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 24 to 48 weeks. In treatment-na´ve subjects, a mean change from baseline of 0.11 mg/dL (range: -0.60 mg/dL to 0.62 mg/dL) was observed after 48 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 multi-center, open-label, non-comparative trial of approximately 160 HIV-1-infected pediatric subjects aged 6 weeks to less than 18 years, of which 23 treatment-experienced, INSTI-na´ve subjects aged 12 to less than 18 years were enrolled [see Use in Specific Populations, Clinical Studies].

The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported in at least 1 subject were rash (n = 1), abdominal pain (n = 1), and diarrhea (n = 1). No Grade 3 or 4 ADRs were reported. The Grade 3 laboratory abnormalities were elevated total bilirubin and lipase reported in 1 subject each. No Grade 4 laboratory abnormalities were reported. The changes in mean serum creatinine were similar to those observed in adults.

Read the entire FDA prescribing information for Tivicay (Doutegravir 50mg Tablets) »

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