Tivicay PD (dolutegravir sodium) tablet, for suspension
ViiV Healthcare Company

ViiV Healthcare Company
Tivicay PD
dolutegravir sodium
DOLUTEGRAVIR SODIUM
DOLUTEGRAVIR
CALCIUM SULFATE DIHYDRATE
CROSPOVIDONE, UNSPECIFIED
MANNITOL
MICROCRYSTALLINE CELLULOSE
POVIDONE K30
SODIUM STARCH GLYCOLATE TYPE A CORN
SUCRALOSE
SODIUM STEARYL FUMARATE
HYPROMELLOSE, UNSPECIFIED
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
SV;H75;5
Strawberry Cream
Tivicay
dolutegravir sodium
DOLUTEGRAVIR SODIUM
DOLUTEGRAVIR
MANNITOL
MICROCRYSTALLINE CELLULOSE
POVIDONE, UNSPECIFIED
SODIUM STARCH GLYCOLATE TYPE A CORN
SODIUM STEARYL FUMARATE
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYVINYL ALCOHOL, UNSPECIFIED
TALC
TITANIUM DIOXIDE
SV;572;10
Tivicay
dolutegravir sodium
DOLUTEGRAVIR SODIUM
DOLUTEGRAVIR
MANNITOL
MICROCRYSTALLINE CELLULOSE
POVIDONE, UNSPECIFIED
SODIUM STARCH GLYCOLATE TYPE A CORN
SODIUM STEARYL FUMARATE
FERRIC OXIDE YELLOW
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYVINYL ALCOHOL, UNSPECIFIED
TALC
TITANIUM DIOXIDE
SV;572;25
Tivicay
dolutegravir sodium
DOLUTEGRAVIR SODIUM
DOLUTEGRAVIR
MANNITOL
MICROCRYSTALLINE CELLULOSE
POVIDONE, UNSPECIFIED
SODIUM STARCH GLYCOLATE TYPE A CORN
SODIUM STEARYL FUMARATE
FERRIC OXIDE YELLOW
POLYETHYLENE GLYCOL, UNSPECIFIED
POLYVINYL ALCOHOL, UNSPECIFIED
TALC
TITANIUM DIOXIDE
SV;572;50

1 INDICATIONS AND USAGE

TIVICAY and TIVICAY PD are indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection in adults (treatment-naïve or -experienced) and in pediatric patients (treatment-naïve or -experienced but integrase strand transfer inhibitor [INSTI]-naïve) aged at least 4 weeks and weighing at least 3 kg [see Microbiology (12.4)].

TIVICAY is indicated in combination with rilpivirine as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.

TIVICAY and TIVICAY PD are an HIV-1 integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults (treatment-naïve or -experienced) and in pediatric patients (treatment-naïve or -experienced but INSTI- naïve) aged at least 4 weeks and weighing at least 3 kg. (1)

TIVICAY is indicated in combination with rilpivirine as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent. (1)

2 DOSAGE AND ADMINISTRATION

  • Pregnancy Testing: Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential. (2.1, 5.3, 8.1, 8.3)
  • May be taken without regard to food. (2.2, 2.6)
a  Rilpivirine dose is 25 mg once daily for those switching to dolutegravir plus rilpivirine.
b  Alternative combinations that do not include metabolic inducers should be considered where possible.

Adult Population

Recommended Dose

Treatment-naïve or treatment-experienced INSTI-naïve or virologically suppressed (HIV-1 RNA <50 copies per mL) adults switching to dolutegravir plus rilpivirinea (2.2)

50 mg once daily

Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers (2.2, 7.2, 7.3)

50 mg twice daily

INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistanceb (2.2, 12.4)

50 mg twice daily

Pediatric Patients: Treatment-naïve or treatment-experienced INSTI-naïve patients aged at least 4 weeks and weighing at least 3 kg. See Tables 2, 3, and 4 for complete pediatric dosing recommendations. (2.3, 2.4, 2.5). TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on a milligram-per-milligram basis.

a  If certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY to twice daily. (2.4, 2.5, 7.2, 7.3)

Pediatric Population

Body Weight

Recommended Dosea

TIVICAY PD
Tablets for Oral Suspension

  3 kg to less than 6 kg

5 mg once daily

  6 kg to less than 10 kg

15 mg once daily

  10 kg to less than 14 kg

20 mg once daily

  14 kg to less than 20 kg

25 mg once daily

  20 kg and greater

30 mg once daily

Alternative dosing recommendations for TIVICAY tablets for patients weighing at least 14 kg (Table 4):

  • 14 kg to less than 20 kg: 40 mg once daily.
  • 20 kg and greater: 50 mg once daily.

2.1 Pregnancy Testing before Initiation

Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].

2.2 Recommended Dosage in Adults

TIVICAY tablets may be taken with or without food.

Table 1. Dosing Recommendations for TIVICAY Tablets in Adult Patients
INSTI = integrase strand transfer inhibitor.
a  Rilpivirine dose is 25 mg once daily for those switching to dolutegravir plus rilpivirine.
b  Alternative combinations that do not include metabolic inducers should be considered where possible [see Drug Interactions (7.3)].

Population

Recommended Dosage

Treatment-naïve or treatment-experienced INSTI-naïve or virologically suppressed (HIV-1 RNA <50 copies per mL) adults switching to dolutegravir plus rilpivirinea

50 mg once daily

Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A) or cytochrome P450 (CYP)3A inducers [see Drug Interactions (7.2, 7.3)]

50 mg twice daily

INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistanceb [see Microbiology (12.4)]

50 mg twice daily

2.3 General Dosing and Administration Instructions for Pediatric Patients

Do not interchange TIVICAY tablets and TIVICAY PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]. If switching from the tablets to the tablets for oral suspension, follow the recommended dosage in Table 3. If switching from the tablets for oral suspension to the tablets, follow the recommended dosage in Table 4. See administration instructions in Dosage and Administration (2.6).

2.4 Recommended Dosage in Pediatric Patients Weighing 3 to 14 kg

The recommended weight-based dosage of TIVICAY PD tablets for oral suspension in pediatric patients weighing 3 to 14 kg (4 weeks and older, treatment-naïve, or treatment-experienced but naïve to INSTI treatment) is described in Table 2.

Do not use TIVICAY tablets in patients weighing 3 to 14 kg. See administration instructions in Dosage and Administration (2.6).

Table 2. Recommended Dosage of TIVICAY PD in Pediatric Patients 4 Weeks and Older Weighing 3 to 14 kg
a  If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions (7.2, 7.3)].

Body Weight

TIVICAY PD Tablets for Oral Suspension

Daily Dosea

Number of

5-mg Tablets

3 kg to less than 6 kg

5 mg once daily

1

6 kg to less than 10 kg

15 mg once daily

3

10 kg to less than 14 kg

20 mg once daily

4

2.5 Recommended Dosage in Pediatric Patients Weighing 14 kg or Greater

For pediatric patients weighing 14 kg or greater (4 weeks and older, treatment-naïve, or treatment-experienced but naïve to INSTI treatment) administer either:

  • TIVICAY PD tablets for oral suspension (preferred in pediatric patients weighing less than 20 kg) (Table 3), or
  • TIVICAY tablets for oral use (Table 4)
Table 3. Recommended Dosage of TIVICAY PD Tablets for Oral Suspension in Pediatric Patients Weighing 14 kg or Greater
a  If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions (7.2, 7.3)].

Body Weight

TIVICAY PD
Tablets for Oral Suspension

Daily Dosea

Number of

5-mg Tablets

14 kg to less than 20 kg

25 mg once daily

5

20 kg and greater

30 mg once daily

6

Table 4. Recommended Dosage of TIVICAY Tablets in Pediatric Patients Weighing 14 kg or Greater
a  If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions (7.2, 7.3)].

Body Weight

TIVICAY Tablets

Daily Dosea

Number of Tablets

14 kg to less than 20 kg

40 mg once daily

4 x 10-mg

20 kg and greater

50 mg once daily

1 x 50-mg

2.6 Additional Administration Instructions

Administer TIVICAY tablets and TIVICAY PD tablets for oral suspension with or without food.

Administration Instructions for TIVICAY PD

Do not chew, cut, or crush TIVICAY PD [see Instructions for Use]. Instruct patients (or instruct caregivers) to either:

  • Swallow the tablets for oral suspension whole (if more than one tablet is required, swallow one tablet at a time to reduce the risk of choking), or
  • Fully disperse the tablets for oral suspension in 5 mL of drinking water (if using 1 or 3 tablets for oral suspension) or 10 mL (if using 4, 5, or 6 tablets for oral suspension) in the supplied cup; swirl the suspension so that no lumps remain. After full dispersion, administer the oral suspension within 30 minutes of mixing [see Instructions for Use].

3 DOSAGE FORMS AND STRENGTHS

TIVICAY Tablets:

10 mg: Each tablet contains 10 mg of dolutegravir (as dolutegravir sodium). Tablets are white, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “10” on the other side.

25 mg: Each tablet contains 25 mg of dolutegravir (as dolutegravir sodium). Tablets are pale yellow, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “25” on the other side.

50 mg: Each tablet contains 50 mg of dolutegravir (as dolutegravir sodium). Tablets are yellow, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “50” on the other side.

TIVICAY PD Tablets for Oral Suspension:

Each tablet contains 5 mg of dolutegravir (as dolutegravir sodium). Tablets are white, round, strawberry cream flavored, film-coated, biconvex tablets debossed with “SV H7S” on one side and “5” on the other side.

  • TIVICAY tablets: 10 mg, 25 mg, and 50 mg (3)
  • TIVICAY PD tablets for oral suspension: 5 mg (3)

4 CONTRAINDICATIONS

TIVICAY and TIVICAY PD are contraindicated in patients:

  • with previous hypersensitivity reaction to dolutegravir [see Warnings and Precautions (5.1)].
  • receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions (7)].
  • Previous hypersensitivity reaction to dolutegravir. (4)
  • Coadministration with dofetilide. (4)

5 WARNINGS AND PRECAUTIONS

  • Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported. Discontinue TIVICAY or TIVICAY PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. (5.1)
  • Hepatotoxicity has been reported in patients receiving dolutegravir-containing regimens. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations. Monitoring for hepatotoxicity is recommended. (5.2)
  • Embryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception. (2.1, 5.3, 8.1, 8.3)
  • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.5)
  • TIVICAY tablets and TIVICAY PD tablets for oral suspension are not interchangeable. (2.3, 5.6)

5.1 Hypersensitivity Reactions

Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TIVICAY or TIVICAY PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TIVICAY or TIVICAY PD or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. TIVICAY and TIVICAY PD are contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir.

5.2 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TIVICAY or TIVICAY PD [see Adverse Reactions (6.1)]. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

5.3 Embryo-Fetal Toxicity

An ongoing observational study showed an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform adolescents and adults of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester [see Use in Specific Populations (8.1, 8.3)].

Pregnancy testing is recommended before initiation of TIVICAY or TIVICAY PD in adolescents and adults of childbearing potential [see Dosage and Administration (2.1)].

Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception [see Use in Specific Populations (8.1, 8.3)].

TIVICAY or TIVICAY PD may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of TIVICAY or TIVICAY PD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4), Drug Interactions (7.3)]:

  • Loss of therapeutic effect of TIVICAY or TIVICAY PD and possible development of resistance.
  • Possible clinically significant adverse reactions from greater exposures of concomitant drugs.

For concomitant drugs for which the interaction can be mitigated, please see Table 8 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TIVICAY or TIVICAY PD; review concomitant medications during therapy with TIVICAY or TIVICAY PD; and monitor for the adverse reactions associated with the concomitant drugs.

5.5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY or TIVICAY PD. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond 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, and Guillain-Barré syndrome) 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.

5.6 Different Formulations Are Not Interchangeable

TIVICAY and TIVICAY PD are not bioequivalent and are not interchangeable on a milligram-per-milligram basis [see Clinical Pharmacology (12.3)]. If a pediatric patient switches from one formulation to the other, the dose must be adjusted for the new dosage formulation [see Dosage and Administration (2.3)]. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure of dolutegravir.

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)].

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 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)
ALT = Alanine amino transferase; AST = Aspartate amino tranferase; 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)
HDL = High density lipoprotein; LDL = Low density lipoprotein.
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 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 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.

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.

Hepatobiliary Disorders

Acute liver failure, hepatotoxicity.

Investigations

Weight increased.

Musculoskeletal

Arthralgia, myalgia.

Psychiatric

Anxiety.

7 DRUG INTERACTIONS

  • Refer to the full prescribing information for important drug interactions with TIVICAY or TIVICAY PD. (4, 7)
  • Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. (7.2, 7.3)
  • TIVICAY or TIVICAY PD should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. When taken with food, TIVICAY and supplements containing calcium or iron can be taken at the same time. (7.3)

7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents

In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide, dalfampridine, and metformin, Table 8) [see Contraindications (4), Drug Interactions (7.3)].

In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.

In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyltransferase (UGT)1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.

7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir

Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.

Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration.

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir (Table 8) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.

7.3 Established and Other Potentially Significant Drug Interactions

Table 8 provides clinical recommendations as a result of drug interactions with TIVICAY or TIVICAY PD. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [see Dosage and Administration (2), Clinical Pharmacology (12.3)].

Table 8. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)]
INSTI = integrase strand transfer inhibitor.
a  See Clinical Pharmacology (12.3) Table 11 or Table 12 for magnitude of interaction.
b  The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents.

Concomitant Drug Class:
Drug Name

Effect on Concentration of Dolutegravir and/or Concomitant Drug

Clinical Comment

HIV-1 Antiviral Agents

Non-nucleoside reverse transcriptase inhibitor:

  Etravirinea

↓Dolutegravir

Use of TIVICAY or TIVICAY PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.

Non-nucleoside reverse transcriptase inhibitor:

  Efavirenza

↓Dolutegravir

Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

Non-nucleoside reverse transcriptase inhibitor:

  Nevirapine

↓Dolutegravir

Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations.

Protease inhibitors:

  Fosamprenavir/ritonavira

  Tipranavir/ritonavira

↓Dolutegravir

Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

Other Agents

  Dofetilide

↑Dofetilide

Coadministration is contraindicated with TIVICAY or TIVICAY PD [see Contraindications (4)].

  Carbamazepinea

↓Dolutegravir

Adjust dose of TIVICAY to twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

  Oxcarbazepine
  Phenytoin
  Phenobarbital
  St. John’s wort (Hypericum perforatum)

↓Dolutegravir

Avoid coadministration with TIVICAY or TIVICAY PD because there are insufficient data to make dosing recommendations.

Medications containing polyvalent cations (e.g., Mg or Al):

  Cation-containing antacidsa or laxatives
  Sucralfate
  Buffered medications

↓Dolutegravir

Administer TIVICAY or TIVICAY PD 2 hours before or 6 hours after taking medications containing polyvalent cations.

Oral calcium or iron supplements, including multivitamins containing calcium or iron a

↓Dolutegravir

When taken with food, TIVICAY and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TIVICAY or TIVICAY PD should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron.

Potassium channel blocker:

Dalfampridine

↑Dalfampridine

Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TIVICAY or TIVICAY PD should be considered against the risk of seizures in these patients.

Metformin

↑Metformin

Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TIVICAY or TIVICAY PD and metformin.

Rifampina

↓Dolutegravir

Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2, 3, and 4).

Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b

7.4 Drugs without Clinically Significant Interactions with Dolutegravir

Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, daclatasvir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. (2.1, 5.3, 8.1, 8.3)
  • Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2)
  • Females and males of reproductive potential: Pregnancy testing is recommended in adolescents and adults of childbearing potential. Patients should be counseled on the consistent use of effective contraception. (8.1, 8.3)

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TIVICAY or TIVICAY PD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Data from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.

Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TIVICAY and TIVICAY PD. Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. A benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precautions (5.3)].

There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD) of TIVICAY (see Data).

Data

Human Data: In a birth outcome surveillance study in Botswana, there were 7 cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included 3 cases of myelomeningocele, 2 cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with 5 infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.

Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir.

Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.

Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir-containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.

Dolutegravir has been shown to cross the placenta. In a clinical trial in Uganda and South Africa in women during the last trimester of pregnancy receiving dolutegravir 50 mg once daily, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range 0.51-2.11) (n = 15).

Animal Data: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the MRHD and in rats were approximately 27 times the exposure in humans at the MRHD. In the rat pre/postnatal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 27 times human exposure at the MRHD).

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommends that HIV‑1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Dolutegravir is present in human milk. It is not known whether dolutegravir affects human milk production or has effects on the breastfed infant.

Because of the potential for (1) HIV‑1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving dolutegravir.

8.3 Females and Males of Reproductive Potential

In adolescents and adults of childbearing potential currently on TIVICAY or TIVICAY PD who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TIVICAY or TIVICAY PD and discuss with the patient if an alternative treatment should be considered [see Warnings and Precautions (5.3), Use in Specific Populations (8.1)].

Pregnancy Testing

Pregnancy testing is recommended in adolescents and adults of childbearing potential before initiation of TIVICAY or TIVICAY PD [see Dosage and Administration (2.1)].

Contraception

Adolescents and adults of childbearing potential who are taking TIVICAY or TIVICAY PD should be counseled on the consistent use of effective contraception.

8.4 Pediatric Use

The safety, pharmacokinetics, and effectiveness of TIVICAY and TIVICAY PD were evaluated in 75 HIV-1–infected, treatment-naïve or treatment-experienced, INSTI-naïve pediatric and adolescent subjects aged 4 weeks to less than 18 years weighing at least 3 kg in an ongoing, open-label, multicenter, dose-finding clinical trial, IMPAACT P1093 [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.3)]. Additional pharmacokinetics data were evaluated in 2 pharmacokinetic substudies in ODYSSEY, an ongoing open-label, randomized, non-inferiority trial to evaluate the safety, efficacy, and pharmacokinetic parameters of TIVICAY or TIVICAY PD plus two NRTIs compared with standard of care in HIV-1–infected pediatric subjects younger than 18 years [see Clinical Pharmacology (12.3)].

Overall, the safety data in pediatric subjects from the IMPAACT P1093 trial were comparable to those observed in adults [see Adverse Reactions (6.1)]. The pharmacokinetic parameters of TIVICAY or TIVICAY PD in pediatric subjects from IMPAACT P1093 and ODYSSEY were comparable to those of adults receiving 50 mg once daily or twice daily [see Clinical Pharmacology (12.3)]. The effectiveness observed in IMPAACT P1093 is comparable to that of treatment-experienced adult subjects.

Safety and effectiveness of TIVICAY or TIVICAY PD have not been established in pediatric patients aged less than 4 weeks or weighing less than 3 kg or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (e.g., raltegravir, elvitegravir).

8.5 Geriatric Use

Clinical trials of TIVICAY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TIVICAY in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Therefore, TIVICAY and TIVICAY PD are not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Dolutegravir plasma concentrations were decreased in subjects with severe renal impairment compared with those in matched healthy controls. However, no dosage adjustment is necessary for treatment-naïve or treatment-experienced and INSTI-naïve patients with mild, moderate, or severe renal impairment or for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance) with mild or moderate renal impairment. Caution is warranted for INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology (12.4)]) with severe renal impairment, as the decrease in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to TIVICAY, TIVICAY PD, or other coadministered antiretroviral agents [see Clinical Pharmacology (12.3)]. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis.

10 OVERDOSAGE

There is no known specific treatment for overdose with TIVICAY or TIVICAY PD. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

11 DESCRIPTION

TIVICAY contains dolutegravir, as dolutegravir sodium, an HIV INSTI. The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 g per mol. It has the following structural formula:

dolutegravir chemical structure

Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.

Each film-coated tablet of TIVICAY for oral administration contains 10.5, 26.3, or 52.6 mg of dolutegravir sodium, which is equivalent to 10, 25, or 50 mg dolutegravir free acid, respectively, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film‑coating contains the inactive ingredients iron oxide yellow (25-mg and 50-mg tablets only), macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

Each TIVICAY PD tablet for oral suspension contains 5.26 mg of dolutegravir sodium, which is equivalent to 5 mg dolutegravir free acid, and the following inactive ingredients: calcium sulfate dihydrate, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, strawberry cream flavor, sucralose, and sodium stearyl fumarate. The tablet film-coating contains hypromellose, polyethylene glycol, and titanium dioxide.

dolutegravir chemical structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dolutegravir is an HIV-1 antiretroviral agent [see Microbiology (12.4)].

12.2 Pharmacodynamics

Effects on Electrocardiogram

In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). TIVICAY did not prolong the QTc interval over 24 hours postdose.

Effects on Renal Function

The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3‑arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

12.3 Pharmacokinetics

The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV‑1–infected subjects (Table 9) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials.

Table 9. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1–Infected Adults
a  Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2.
b  Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3.

Parameter

50 mg Once Daily

Geometric Meana (%CV)

50 mg Twice Daily

Geometric Meanb (%CV)

AUC(0-24) (mcgh/mL)

53.6 (27)

75.1 (35)

Cmax (mcg/mL)

3.67 (20)

4.15 (29)

Cmin (mcg/mL)

1.11 (46)

2.12 (47)

TIVICAY tablets and TIVICAY PD tablets for oral suspension are not bioequivalent. The relative bioavailability of TIVICAY PD is approximately 1.6-fold higher than TIVICAY; therefore, the 2 dosage forms are not interchangeable on a milligram-per-milligram basis [see Dosage and Administration (2.3)].

Absorption

Following oral administration of dolutegravir, peak plasma concentrations were observed 1 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5.

Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P‑gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established.

Effect of Food: TIVICAY or TIVICAY PD may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir following a 50-mg dose of TIVICAY. Low-, moderate-, and high-fat meals increased dolutegravir AUC(0-∞) by 33%, 41%, and 66%; increased Cmax by 46%, 52%, and 67%; and prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively.

Distribution

Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.

Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng per mL (range: 3.74 ng per mL to 18.3 ng per mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established.

Elimination

Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses.

Metabolism: Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A.

Polymorphisms in DrugMetabolizing Enzymes: In a meta-analysis of healthy subject trials, subjects with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n = 41).

Excretion: After a single oral dose of [14C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose).

Specific Populations

Pediatric Patients: The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in 2 weight-band-based pharmacokinetic substudies from the ODYSSEY trial. Steady-state plasma exposure at doses by weight band are summarized in Table 10  [see Clinical Studies (14.3)].

Mean dolutegravir AUC0-24h and C24h in HIV-1–infected pediatric subjects were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean Cmax is higher in pediatrics, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see Use in Specific Populations (8.4)].

Table 10. Summary of Pharmacokinetic Parameters in Pediatric HIV-1–Infected Subjects (Pooled Analyses for IMPAACT P1093 and ODYSSEYa Trials)
a  Data from 2 weight-band-based pharmacokinetic substudies in the ODYSSEY trial.
b  The bioavailability of TIVICAY PD tablets for oral suspension is ~1.6-fold that of TIVICAY tablets.

Weight Band

Doseb of TIVICAY or TIVICAY PD

n

Pharmacokinetic Parameter
Geometric Mean (%CV)

Cmax
(mcg/mL)

AUC0-24h
(mcg∙h/mL)

C24h
(ng/mL)

3 kg to <6 kg

TIVICAY PD
5 mg once daily

8

3.80 (34)

49.37 (49)

962 (98)

6 kg to <10 kg

TIVICAY PD
15 mg once daily

17

5.27 (50)

57.17 (76)

706 (177)

10 kg to <14 kg

TIVICAY PD
20 mg once daily

13

5.99 (33)

68.75 (48)

977 (100)

14 kg to <20 kg

TIVICAY PD
25 mg once daily

19

5.97 (42)

58.97 (44)

725 (75)

20 kg to <25 kg

TIVICAY PD
30 mg once daily

9

7.16 (26)

71.53 (26)

759 (73)

≥20 kg

TIVICAY
50 mg once daily

49

4.92 (40)

54.98 (43)

778 (62)

Geriatric Patients: Population pharmacokinetic analysis indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir.

Patients with Hepatic Impairment: In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.

Patients with Renal Impairment: In a trial evaluating the pharmacokinetics of a single 50-mg tablet of dolutegravir comparing 8 subjects with severe renal impairment (CrCl less than 30 mL per min) with 8 matched healthy controls, AUC, Cmax, and C24 of dolutegravir were lower by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis.

HBV or HCV Co-infected Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection.

Gender and Race: Population analyses using pooled pharmacokinetic data from adult trials indicated gender and race had no clinically relevant effect on the exposure of dolutegravir.

Drug Interaction Studies

Drug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of dolutegravir on the exposure of coadministered drugs are summarized in Table 11 and the effects of coadministered drugs on the exposure of dolutegravir are summarized in Table 12.

Dosing or regimen recommendations as a result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table 8 [see Dosage and Administration (2.2), Drug Interactions (7.3)].

Table 11. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs
a  The number of subjects represents the maximum number of subjects that were evaluated.

Coadministered Drug(s)

and Dose(s)

Dose of TIVICAY

n

Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir
No Effect = 1.00

Cmax

AUC

Cτ or C24

Daclatasvir
  60 mg once daily

50 mg
once daily

12

1.03
(0.84 to 1.25)

0.98
(0.83 to 1.15)

1.06
(0.88 to 1.29)

Elbasvir

  50 mg once daily

50 mg

single dose

12

0.97

(0.89, 1.05)

0.98

(0.93, 1.04)

0.98

(0.93, 1.03)

Ethinyl estradiol
  0.035 mg

50 mg
twice daily

15

0.99
(0.91 to 1.08)

1.03
(0.96 to 1.11)

1.02
(0.93 to 1.11)

Grazoprevir

  200 mg once daily

50 mg

single dose

12

0.64

(0.44, 0.93)

0.81

(0.67, 0.97)

0.86

(0.79, 0.93)

Metformin
  500 mg twice daily

50 mg
once daily

15a

1.66
(1.53 to 1.81)

1.79
(1.65 to 1.93)

_

Metformin
  500 mg twice daily

50 mg
twice daily

15a

2.11
(1.91 to 2.33)

2.45
(2.25 to 2.66)

_

Methadone
  16 to 150 mg

50 mg
twice daily

11

1.00
(0.94 to 1.06)

0.98
(0.91 to 1.06)

0.99
(0.91 to 1.07)

Midazolam
  3 mg

25 mg
once daily

10

_

0.95
(0.79 to 1.15)

_

Norelgestromin
  0.25 mg

50 mg
twice daily

15

0.89
(0.82 to 0.97)

0.98
(0.91 to 1.04)

0.93
(0.85 to 1.03)

Rilpivirine
  25 mg once daily

50 mg
once daily

16

1.10
(0.99 to 1.22)

1.06
(0.98 to 1.16)

1.21
(1.07 to 1.38)

Sofosbuvir

  400 mg once daily

  Metabolite (GS-331007)

50 mg

once daily

24

0.88

(0.80, 0.98)

0.92

(0.85, 0.99)

NA

1.01

(0.93, 1.10)

0.99

(0.97, 1.01)

0.99

(0.97, 1.01)

Tenofovir disoproxil fumarate
  300 mg once daily

50 mg
once daily

15

1.09
(0.97 to 1.23)

1.12
(1.01 to 1.24)

1.19
(1.04 to 1.35)

Velpatasvir

  100 mg once daily

50 mg

once daily

24

0.94

(0.86, 1.02)

0.91

(0.84, 0.98)

0.88

(0.82, 0.94)

Table 12. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir
a  The number of subjects represents the maximum number of subjects that were evaluated.
b  Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily.
c  Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.

Coadministered Drug(s)

and Dose(s)

Dose of TIVICAY

n

Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs
No Effect = 1.00

Cmax

AUC

Cτ or C24

Atazanavir
  400 mg once daily

30 mg
once daily

12

1.50
(1.40 to 1.59)

1.91
(1.80 to 2.03)

2.80
(2.52 to 3.11)

Atazanavir/ritonavir
  300/100 mg once daily

30 mg
once daily

12

1.34
(1.25 to 1.42)

1.62
(1.50 to 1.74)

2.21
(1.97 to 2.47)

Darunavir/ritonavir
  600/100 mg twice daily

30 mg
once daily

15

0.89
(0.83 to 0.97)

0.78
(0.72 to 0.85)

0.62
(0.56 to 0.69)

Efavirenz
  600 mg once daily

50 mg
once daily

12

0.61
(0.51 to 0.73)

0.43
(0.35 to 0.54)

0.25
(0.18 to 0.34)

Elbasvir/grazoprevir

  50/200 mg once daily

50 mg

single dose

12

1.22

(1.05, 1.40)

1.16

(1.00, 1.34)

1.14

(0.95, 1.36)

Etravirine
  200 mg twice daily

50 mg
once daily

16

0.48
(0.43 to 0.54)

0.29
(0.26 to 0.34)

0.12
(0.09 to 0.16)

Etravirine + darunavir/ritonavir
  200 mg + 600/100 mg twice daily

50 mg
once daily

9

0.88
(0.78 to 1.00)

0.75
(0.69 to 0.81)

0.63
(0.52 to 0.76)

Etravirine + lopinavir/ritonavir
  200 mg + 400/100 mg twice daily

50 mg
once daily

8

1.07
(1.02 to 1.13)

1.11
(1.02 to 1.20)

1.28
(1.13 to 1.45)

Fosamprenavir/ritonavir
  700 mg/100 mg twice daily

50 mg
once daily

12

0.76
(0.63 to 0.92)

0.65
(0.54 to 0.78)

0.51
(0.41 to 0.63)

Lopinavir/ritonavir
  400/100 mg twice daily

30 mg
once daily

15

1.00
(0.94 to 1.07)

0.97
(0.91 to 1.04)

0.94
(0.85 to 1.05)

Rilpivirine
  25 mg once daily

50 mg
once daily

16

1.13
(1.06 to 1.21)

1.12
(1.05 to 1.19)

1.22
(1.15 to 1.30)

Tenofovir
  300 mg once daily

50 mg
once daily

15

0.97
(0.87 to 1.08)

1.01
(0.91 to 1.11)

0.92

(0.82 to 1.04)

Tipranavir/ritonavir
  500/200 mg twice daily

50 mg
once daily

14

0.54
(0.50 to 0.57)

0.41
(0.38 to 0.44)

0.24
(0.21 to 0.27)

Antacid (MAALOX)
  simultaneous administration

50 mg
single dose

16

0.28
(0.23 to 0.33)

0.26
(0.22 to 0.32)

0.26
(0.21 to 0.31)

Antacid (MAALOX)
  2 h after dolutegravir

50 mg
single dose

16

0.82
(0.69 to 0.98)

0.74
(0.62 to 0.90)

0.70
(0.58 to 0.85)

Calcium carbonate 1,200 mg
  simultaneous administration (fasted)

50 mg
single dose

12

0.63
(0.50 to 0.81)

0.61
(0.47 to 0.80)

0.61
(0.47 to 0.80)

Calcium carbonate 1,200 mg
  simultaneous administration (fed)

50 mg
single dose

11

1.07
(0.83 to 1.38)

1.09
(0.84 to 1.43)

1.08
(0.81 to 1.42)

Calcium carbonate 1,200 mg
  2 h after dolutegravir

50 mg
single dose

11

1.00
(0.78 to 1.29)

0.94
(0.72 to 1.23)

0.90
(0.68 to 1.19)

Carbamazepine
  300 mg twice daily

50 mg
once daily

16a

0.67
(0.61 to 0.73)

0.51
(0.48 to 0.55)

0.27
(0.24 to 0.31)

Daclatasvir
  60 mg once daily

50 mg
once daily

12

1.29
(1.07 to 1.57)

1.33
(1.11 to 1.59)

1.45
(1.25 to 1.68)

Ferrous fumarate 324 mg
  simultaneous administration (fasted)

50 mg
single dose

11

0.43
(0.35 to 0.52)

0.46
(0.38 to 0.56)

0.44
(0.36 to 0.54)

Ferrous fumarate 324 mg
  simultaneous administration (fed)

50 mg
single dose

11

1.03
(0.84 to 1.26)

0.98
(0.81 to 1.20)

1.00
(0.81 to 1.23)

Ferrous fumarate 324 mg
  2 h after dolutegravir

50 mg
single dose

10

0.99
(0.81 to 1.21)

0.95
(0.77 to 1.15)

0.92
(0.74 to 1.13)

Multivitamin (One-A-Day)
  simultaneous administration

50 mg
single dose

16

0.65
(0.54 to 0.77)

0.67
(0.55 to 0.81)

0.68
(0.56 to 0.82)

Omeprazole
  40 mg once daily

50 mg
single dose

12

0.92
(0.75 to 1.11)

0.97
(0.78 to 1.20)

0.95
(0.75 to 1.21)

Prednisone
  60 mg once daily with taper

50 mg
once daily

12

1.06
(0.99 to 1.14)

1.11
(1.03 to 1.20)

1.17
(1.06 to 1.28)

Rifampinb
  600 mg once daily

50 mg
twice daily

11

0.57
(0.49 to 0.65)

0.46
(0.38 to 0.55)

0.28
(0.23 to 0.34)

Rifampinc
  600 mg once daily

50 mg
twice daily

11

1.18
(1.03 to 1.37)

1.33
(1.15 to 1.53)

1.22
(1.01 to 1.48)

Rifabutin
  300 mg once daily

50 mg
once daily

9

1.16
(0.98 to 1.37)

0.95
(0.82 to 1.10)

0.70
(0.57 to 0.87)

12.4 Microbiology

Mechanism of Action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Antiviral Activity in Cell Culture

Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50 values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M clades A, B, C, D, E, F, and G, and 3 in group O) with EC50 values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50 values against 3 HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.

Antiviral Activity in Combination with Other Antiviral Agents

The antiviral activity of dolutegravir was not antagonistic when combined with the INSTI, raltegravir; non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz or nevirapine; the NRTIs, abacavir or stavudine; the protease inhibitors (PIs), amprenavir or lopinavir; the CCR5 co-receptor antagonist, maraviroc; or the fusion inhibitor, enfuvirtide. Dolutegravir antiviral activity was not antagonistic when combined with the HBV reverse transcriptase inhibitor, adefovir, or inhibited by the antiviral, ribavirin.

Resistance

Cell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Passage of mutant viruses containing the Q148R or Q148H substitutions selected for additional substitutions in integrase that conferred decreased susceptibility to dolutegravir (fold-change increase of 13 to 46). The additional integrase substitutions included T97A, E138K, G140S, and M154I. Passage of mutant viruses containing both G140S and Q148H selected for L74M, E92Q, and N155H.

Treatment-Naïve Subjects: No subject who received dolutegravir 50-mg once-daily in the treatment-naïve trials SPRING-2 (96 weeks) and SINGLE (144 weeks) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 12 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies per mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to the background regimen was observed in the dolutegravir arm in either the SPRING-2 or SINGLE trials. No treatment-emergent primary resistance substitutions were observed in either treatment group in the FLAMINGO trial through Week 96.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: In the dolutegravir arm of the SAILING trial for treatment-experienced and INSTI-naïve subjects (n = 354), treatment-emergent integrase substitutions were observed in 6 of 28 (21%) subjects who had virologic failure and resistance data. In 5 of the 6 subjects’ isolates emergent INSTI substitutions included L74L/M/I, Q95Q/L, V151V/I (n = 1 each), and R263K (n = 2). The change in dolutegravir phenotypic susceptibility for these 5 subject isolates was less than 2-fold. One subject isolate had pre-existing raltegravir resistance substitutions E138A, G140S, and Q148H at baseline and had additional emergent INSTI-resistance substitutions T97A and E138A/T with a corresponding 148-fold reduction in dolutegravir susceptibility at failure. In the comparator raltegravir arm, 21 of 49 (43%) subjects with post-baseline resistance data had evidence of emergent INSTI-resistance substitutions (L74M, E92Q, T97A, E138Q, G140S/A, Y143R/C, Q148H/R, V151I, N155H, E157Q, and G163K/R) and raltegravir phenotypic resistance.

Virologically Suppressed Subjects: SWORD-1 and SWORD-2 are identical trials in virologically suppressed subjects receiving 2 NRTIs plus either an INSTI, an NNRTI, or a PI, that switched to dolutegravir plus rilpivirine (n = 513) or remained on their current antiviral regimen (n = 511). In the pooled SWORD-1 and SWORD-2 trials, 12 subjects (7 in SWORD-1 and 5 in SWORD-2) had confirmed virologic failure (HIV-1 RNA greater than 200 copies/mL) while receiving dolutegravir plus rilpivirine at any time through Week 148. Ten of the confirmed virologic failures had post-baseline resistance data, with 6 isolates showing evidence of rilpivirine resistance, and 2 with evidence of dolutegravir resistance substitutions. Six isolates showed genotypic and/or phenotypic resistance to rilpivirine with emergent NNRTI-resistance substitutions E138E/A (rilpivirine 1.6-fold change), M230M/L (rilpivirine 2-fold change), L100L/I, K101Q, and E138A (rilpivirine 4.1-fold change), K101K/E (rilpivirine 1.2-fold change), K101K/E, M230M/L (rilpivirine 2-fold change), and L100L/V/M, M230M/L (rilpivirine 31-fold change). In addition, 1 virologic failure subject had NNRTI‑resistance substitutions K103N and V179I at Week 88 with rilpivirine phenotypic fold change of 5.2 but had no baseline sample.

One virologic failure isolate had emergent INSTI‑resistance substitution V151V/I present post-baseline with baseline INSTI‑resistance substitutions N155N/H and G163G/R (by exploratory HIV proviral DNA archive sequencing); no integrase phenotypic data were available for this isolate at virologic failure. One other subject had the dolutegravir resistance substitution G193E at baseline and virologic failure, but no detectable phenotypic resistance (fold change = 1.02) at Week 24.

No resistance-associated substitutions were observed for the 2 subjects meeting confirmed virologic failure in the comparative current antiretroviral regimen arms at Week 48.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: VIKING-3 examined the efficacy of dolutegravir 50 mg twice daily plus optimized background therapy in subjects with prior or current virologic failure on an INSTI- (elvitegravir or raltegravir) containing regimen. Use of TIVICAY in INSTI-experienced patients should be guided by the number and type of baseline INSTI substitutions. The efficacy of TIVICAY 50 mg twice daily is reduced in patients with an INSTI-resistance Q148 substitution plus 2 or more additional INSTI-resistance substitutions, including T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R.

Response by Baseline Genotype

Of the 183 subjects with baseline data, 30% harbored virus with a substitution at Q148, and 33% had no primary INSTI-resistance substitutions (T66A/I/K, E92Q/V, Y143R/C/H, Q148H/R/K, and N155H) at baseline, but had historical genotypic evidence of INSTI-resistance substitutions, phenotypic evidence of elvitegravir or raltegravir resistance, or genotypic evidence of INSTI-resistance substitutions at screening.

Response rates by baseline genotype were analyzed in an “as-treated” analysis at Week 48 (n = 175) (Table 13). The response rate at Week 48 to dolutegravir-containing regimens was 47% (24 of 51) when Q148 substitutions were present at baseline; Q148 was always present with additional INSTI-resistance substitutions (Table 13). In addition, a diminished virologic response of 40% (6 of 15) was observed when the substitution E157Q or K was present at baseline with other INSTI-resistance substitutions but without a Q148H or R substitution.

Table 13. Response by Baseline Integrase Genotype in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3
INSTI = integrase strand transfer inhibitor.
a  Includes INSTI-resistance substitutions Y143R/C/H and N155H.
b  INSTI-resistance substitutions included T66A, L74I/M, E138A/K/T, G140S/A/C, Y143R/C/H, E157Q, G163S/E/K/Q, or G193E/R. Two additional subjects had baseline genotypes of Q148Q/R plus L74L/I/M (virologic failure) and Q148R plus E138K (responder).
c  The most common pathway with Q148H/R + greater than or equal to 2 INSTI-resistance substitutions had Q148+G140+E138 substitutions (n = 16).

Baseline Genotype

Week 48
(<50 copies/mL)
n = 175

Overall Response

66% (116/175)

No Q148 substitutiona

74% (92/124)

Q148H/R + G140S/A/C without additional INSTI-resistance substitutionb

61% (17/28)

Q148H/R + ≥2 INSTI-resistance substitutionsb,c

29% (6/21)

Response by Baseline Phenotype

Response rates by baseline phenotype were analyzed in an as-treated analysis using all subjects with available baseline phenotypes through Week 48 (n = 163) (Table 14). These baseline phenotypic groups are based on subjects enrolled in VIKING-3 and are not meant to represent definitive clinical susceptibility cut points for dolutegravir. The data are provided to guide clinicians on the likelihood of virologic success based on pretreatment susceptibility to dolutegravir in INSTI-resistant patients.

Table 14. Response by Baseline Dolutegravir Phenotype (Fold-Change from Reference) in Subjects with Prior Experience to an Integrase Strand Transfer Inhibitor in VIKING-3

Baseline Dolutegravir Phenotype
(Fold-Change from Reference)

Response at Week 48
(<50 copies/mL)
Subset n = 163

Overall Response

64% (104/163)

<3-fold change

72% (83/116)

3- <10-fold change

53% (18/34)

≥10-fold change

23% (3/13)

Integrase Strand Transfer Inhibitor Treatment-Emergent Resistance

There were 50 subjects with virologic failure on the dolutegravir twice-daily regimen in VIKING-3 with HIV-1 RNA greater than 400 copies per mL at the failure timepoint, Week 48 or beyond, or the last timepoint on trial. Thirty-nine subjects with virologic failure had resistance data that were used in the Week 48 analysis. In the Week 48 resistance analysis 85% (33 of 39) of the subjects with virologic failure had treatment-emergent INSTI-resistance substitutions in their isolates. The most common treatment-emergent INSTI-resistance substitution was T97A. Other frequently emergent INSTI-resistance substitutions included L74M, I or V, E138K or A, G140S, Q148H, R or K, M154I, or N155H. Substitutions E92Q, Y143R or C/H, S147G, V151A, and E157E/Q each emerged in 1 to 3 subjects’ isolates. At failure, the median dolutegravir fold-change from reference was 61-fold (range: 0.75 to 209) for isolates with emergent INSTI-resistance substitutions (n = 33).

Resistance to one or more background drugs in the dolutegravir twice-daily regimen also emerged in 49% (19 of 39) of subjects in the Week 48 resistance analysis.

In VIKING-4 (ING116529), 30 subjects with current virological failure on an INSTI-containing regimen and genotypic evidence of INSTI-resistance substitutions at screening were randomized to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for 7 days and then all subjects received open-label dolutegravir plus optimized background regimen from Day 8. Virologic responses at Week 48 by baseline genotypic and phenotypic INSTI-resistance categories and the INSTI resistance-associated substitutions that emerged on dolutegravir treatment in VIKING-4 were consistent with those seen in VIKING-3.

Cross-Resistance

Site-Directed Integrase Strand Transfer Inhibitor-Resistant Mutant HIV-1 and HIV-2 Strains: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions) and 6 INSTI-resistant site-directed mutant HIV-2 viruses. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.

Reverse Transcriptase Inhibitor- and Protease Inhibitor-Resistant Strains: Dolutegravir demonstrated equivalent antiviral activity against 2 NNRTI-resistant, 3 NRTI-resistant, and 2 PI-resistant HIV-1 mutant clones compared with the wild-type strain.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 14 times higher than those in humans at the maximum recommended dose. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 10 times and 15 times higher in males and females, respectively, than those in humans at the maximum recommended dose.

Mutagenesis

Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Impairment of Fertility

In a study conducted in rats, there were no effects on mating or fertility with dolutegravir up to 1,000 mg per kg per day. This dose is associated with an exposure that is approximately 24 times higher than the exposure in humans at the maximum recommended dose.

14 CLINICAL STUDIES

14.1 Description of Clinical Studies

The efficacy and safety of TIVICAY or TIVICAY PD were evaluated in the studies summarized in Table 15.

Table 15. Trials Conducted with TIVICAY or TIVICAY PD in HIV-1–Infected Subjects
NRTI = nucleoside reverse transcriptase inhibitor; BR = Background regimen; INSTI = integrase strand transfer inhibitor; OBT = Optimized background therapy; CAR = Current antiretroviral regimen.

Population

Trial

Trial Arms

Timepoint (Week)

Adults:

  •  Treatment-naïve

SPRING-2 (ING113086)
(NCT01227824)

TIVICAY + 2 NRTIs (n = 403)

Raltegravir + 2 NRTIs (n = 405)

96

SINGLE (ING114467)
(NCT01263015)

TIVICAY + EPZICOM (n = 414)

ATRIPLA (n = 419)

144

FLAMINGO (ING114915)
(NCT01449929)

TIVICAY + NRTI BR (n = 243)

Darunavir/ritonavir + NRTI BR (n = 242)

96

  •  Treatment-experienced, INSTI-naïve

SAILING (ING111762)
(NCT01231516)

TIVICAY + BR (n = 354)

Raltegravir + BR (n = 361)

48

  •  INSTI-experienced

VIKING-3 (ING112574)

(NCT01328041)

TIVICAY + OBT (n = 183)

48

  •  Virologically suppressed

SWORD-1 (NCT02429791)

SWORD-2 (NCT02422797)

Pooled presentation

TIVICAY + Rilpivirine (n = 513)

CAR (n = 511)

48

Pediatrics:

  •  4 weeks and older and weighing at least 3 kg without INSTI resistance



IMPAACT P1093 (NCT01302847)



TIVICAY or TIVICAY PD + BR (n = 75)



24

14.2 Adult Subjects

Treatment-Naïve Subjects

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 NRTI treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 36 years, 13% female, 15% non-white, 11% had hepatitis B and/or C virus co-infection, 2% were CDC Class C (AIDS), 28% had HIV-1 RNA greater than 100,000 copies per mL, 48% had CD4+ cell count less than 350 cells per mm3, and 39% received EPZICOM; these characteristics were similar between treatment groups.

In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir sulfate and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups.

Outcomes for SPRING-2 (Week 96 analysis) and SINGLE (Week 144 open-label phase analysis which followed the Week 96 double-blind phase) are provided in Table 16. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 16. Virologic Outcomes of Randomized Treatment in SPRING-2 at Week 96 and SINGLE at Week 144 (Snapshot Algorithm)
NRTI = Nucleoside reverse transcriptase inhibitor.
a  Adjusted for pre-specified stratification factors.
b  The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 86% in the raltegravir group, with a treatment difference of 2.6% and 95% CI of (-1.9%, 7.2%).
c  The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%).
d  Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window.
e  Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

SPRING-2
Week 96

SINGLE
Week 144

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)

HIV-1 RNA <50 copies/mL

82%

78%

71%

63%

    Treatment differencea

4.9% (95% CI: -0.6%, 10.3%)b

8.3% (95% CI: 2.0%, 14.6%)c

Virologic nonresponse

5%

10%

10%

7%

    Data in window not <50 copies/mL

1%

3%

4%

<1%

    Discontinued for lack of efficacy

2%

3%

3%

3%

    Discontinued for other reasons while not suppressed

<1%

3%

3%

4%

    Change in ART regimen

<1%

<1%

0

0

No virologic data

12%

12%

18%

30%

Reasons

    Discontinued study/study drug due to adverse event or deathd

2%

2%

4%

14%

    Discontinued study/study drug for other reasonse

8%

9%

12%

13%

    Missing data during window but on study

2%

<1%

2%

3%

Proportion (%) of Subjects with HIV-1 RNA <50 copies/mL by Baseline Category

Plasma viral load (copies/mL)

    ≤100,000

84%

83%

73%

64%

    >100,000

79%

63%

69%

61%

Gender

    Male

84%

79%

72%

66%

    Female

70%

68%

69%

48%

Race

    White

83%

78%

72%

71%

    African-American/African Heritage/Other

77%

75%

71%

47%

SPRING-2: Virologic outcomes were also comparable across baseline characteristics including CD4+ cell count, age, and use of EPZICOM or TRUVADA as NRTI background regimen. The median change in CD4+ cell counts from baseline was 276 cells per mm3 in the group receiving TIVICAY and 264 cells per mm3 for the raltegravir group at 96 weeks.

There was no treatment-emergent resistance to dolutegravir or to the NRTI background.

SINGLE: Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race.

The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm3 in the group receiving TIVICAY + EPZICOM and 332 cells per mm3 for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm3 (15.6 cells per mm3, 78.2 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count).

There was no treatment-emergent resistance to dolutegravir, abacavir, or lamivudine.

FLAMINGO: In FLAMINGO, 485 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily (n = 243) or darunavir + ritonavir 800 mg/100 mg once daily (n = 242), both in combination with investigator-selected NRTI background regimen (either fixed-dose abacavir and lamivudine [EPZICOM] or fixed-dose emtricitabine/tenofovir disoproxil fumarate [TRUVADA]). There were 484 subjects included in the efficacy and safety analyses. At baseline, the median age of subjects was 34 years, 15% female, 28% non-white, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), 25% had HIV‑1 RNA greater than 100,000 copies per mL, and 35% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. Overall response rates by Snapshot algorithm through Week 96 were 80% for TIVICAY and 68% for darunavir/ritonavir. The proportion of subjects who were non-responders (HIV-1 RNA greater than or equal to 50 copies per mL) at Week 96 was 8% and 12% in the arms receiving TIVICAY and darunavir + ritonavir, respectively; no virologic data were available for 12% and 21% for subjects treated with TIVICAY and darunavir + ritonavir, respectively. The adjusted overall response rate difference in proportion and 95% CI was 12.4% (4.7%, 20.2%). No treatment-emergent primary resistance substitutions were observed in either treatment group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects

In the international, multicenter, double-blind trial (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 1 fully active agent. There were 715 subjects included in the efficacy and safety analyses. At baseline, the median age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C virus co-infection, 46% were CDC Class C (AIDS), 20% had HIV-1 RNA greater than 100,000 copies per mL, and 72% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. All subjects had at least 2-class antiretroviral treatment resistance, and 49% of subjects had at least 3-class antiretroviral treatment resistance at baseline. Week 48 outcomes for SAILING are shown in Table 17.

Table 17. Virologic Outcomes of Randomized Treatment in SAILING at 48 Weeks (Snapshot Algorithm)