dolutegravir 50 MG (as dolutegravir sodium 52.6 MG) Oral Tablet

Generic Name: DOLUTEGRAVIR SODIUM
Brand Name: Tivicay
  • Substance Name(s):
  • DOLUTEGRAVIR SODIUM

DRUG INTERACTIONS

7 •Refer to the full prescribing information for important drug interactions with TIVICAY.

(4, 7) •Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir.

(7.2, 7.3) •TIVICAY 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.

Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food.

(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 and metformin, Table 6) [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 (UDP)-glucuronosyl transferase 1A1 (UGT1A1), 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 6) [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 6 provides clinical recommendations as a result of drug interactions with TIVICAY.

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 6.

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)] 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 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 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose to twice daily (Table 2).

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 inhibitor: Fosamprenavir/ritonavira Tipranavir/ritonavira ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose to twice daily (Table 2).

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 [see Contraindications (4)].

Carbamazepinea ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose to twice daily (Table 2).

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 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 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 Administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron.

Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food.

Metformin ↑Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY.

When stopping TIVICAY, the metformin dose may require an adjustment.

Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended.

Rifampina ↓Dolutegravir Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients.

In pediatric patients, increase the weight-based dose to twice daily (Table 2).

Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.b a See Clinical Pharmacology (12.3) Table 9 or Table 10 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.

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)].

OVERDOSAGE

10 There is no known specific treatment for overdose with TIVICAY.

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.

DESCRIPTION

11 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 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.

dolutegravir chemical structure

CLINICAL STUDIES

14 14.1 Description of Clinical Studies The efficacy and safety of TIVICAY were evaluated in the studies summarized in Table 13.

Table 13.

Trials Conducted with TIVICAY in HIV‑1‑Infected Subjects Population Trial Trial Arms Timepoint (Week) Adults: Treatment-naïve SPRING-2 (ING113086) (NCT01227824) TIVICAY + 2 NRTIs (n = 403) Raltegravir +3 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: 6 years and older without INSTI resistance IMPAACT P1093 (NCT01302847) TIVICAY + BR (n = 46) 48 BR = Background regimen; CAR = Current antiretroviral regimen; OBT = Optimized background therapy 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 14.

Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 14.

Virologic Outcomes of Randomized Treatment in SPRING-2 at Week 96 and SINGLE at Week 144 (Snapshot Algorithm) 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%)d 8.3% (95% CI: 2.0%, 14.6%)e 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 deathb 2% 2% 4% 14% Discontinued study/study drug for other reasonsc 8% 9% 12% 13% Missing data during window but on study 2% <1% 2% 3% Proportion (%) of Subjects with HIV-1 RNA 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% a Adjusted for pre-specified stratification factors.

b 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.

c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

d 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%).

e 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%).

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 15.

Table 15.

Virologic Outcomes of Randomized Treatment in SAILING at 48 Weeks (Snapshot Algorithm) TIVICAY 50 mg Once Daily + BRa (n = 354) Raltegravir 400 mg Twice Daily + BRa (n = 361) HIV-1 RNA <50 copies/mL 71% 64% Adjustedb treatment difference 7.4% (95% CI: 0.7%, 14.2%) Virologic nonresponse 20% 28% No virologic data 9% 9% Reasons Discontinued study/study drug due to adverse event or death 3% 4% Discontinued study/study drug for other reasonsc 5% 4% Missing data during window but on study 2% 1% Proportion (%) with HIV-1 RNA 50,000 copies/mL 62% 47% Background regimen No darunavir use 67% 60% Darunavir use with primary PI substitutions 85% 67% Darunavir use without primary PI substitutions 69% 70% Gender Male 70% 66% Female 74% 60% Race White 75% 71% African-American/African Heritage/Other 67% 57% a BR = Background regimen.

Background regimen was restricted to less than or equal to 2 antiretroviral treatments with at least 1 fully active agent.

b Adjusted for pre-specified stratification factors.

c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

Treatment differences were maintained across the baseline characteristics including CD4+ cell count and age.

The mean changes in CD4+ cell counts from baseline were 162 cells per mm3 in the group receiving TIVICAY and 153 cells per mm3 in the raltegravir group.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects VIKING-3 examined the effect of TIVICAY 50 mg twice daily over 7 days of functional monotherapy, followed by optimized background therapy (OBT) with continued treatment of TIVICAY 50 mg twice daily.

In the multicenter, open-label, single-arm VIKING-3 trial, 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, then received TIVICAY with OBT from Day 8.

A total of 183 subjects enrolled: 133 subjects with INSTI resistance at screening and 50 subjects with only historical evidence of resistance (and not at screening).

At baseline, median age of subjects was 48 years; 23% were female, 29% non-white, and 20% had hepatitis B and/or C virus co-infection.

Median baseline CD4+ cell count was 140 cells per mm3, median duration of prior antiretroviral treatment was 13 years, and 56% were CDC Class C.

Subjects showed multiple-class antiretroviral treatment resistance at baseline: 79% had greater than or equal to 2 NRTI, 75% greater than or equal to 1 NNRTI, and 71% greater than or equal to 2 PI major substitutions; 62% had non-R5 virus.

Mean reduction from baseline in HIV-1 RNA at Day 8 (primary endpoint) was 1.4 log10 (95% CI: 1.3 log10, 1.5 log10).

Response at Week 48 was affected by baseline INSTI substitutions [see Microbiology (12.4)].

After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible.

Week 48 virologic outcomes for VIKING-3 are shown in Table 16.

Table 16.

Virologic Outcomes of Treatment of VIKING-3 at 48 Weeks (Snapshot Algorithm) TIVICAY 50 mg Twice Daily + OBT (n = 183) HIV-1 RNA <50 copies/mL 63% Virologic nonresponse 32% No virologic data Reasons Discontinued study/study drug due to adverse event or death 3% Proportion (%) with HIV-1 RNA <50 copies/mL by Baseline Category Gender Male 63% Female 64% Race White 63% African-American/African Heritage/Other 64% Subjects harboring virus with Q148 and with additional Q148-associated secondary substitutions also had a reduced response at Week 48 in a stepwise fashion [see Microbiology (12.4)].

The median change in CD4+ cell count from baseline was 80 cells per mm3 at Week 48.

Virologically Suppressed Subjects SWORD-1 and SWORD-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials.

A total of 1,024 adult HIV–1-infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 NRTIs plus either an INSTI, an NNRTI, or a PI) for at least 6 months (HIV-1 RNA less than 50 copies per mL), with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine received treatment in the trials.

Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to TIVICAY 50 mg plus rilpivirine 25 mg administered once daily.

The primary efficacy endpoint for the SWORD trial was the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL at Week 48.

The proportion of subjects with HIV-1 RNA less than 50 copies per mL at Week 48 was 95% for both treatment groups; treatment difference and 95% CI was -0.2% (-3.0%, 2.5%).

The proportion of subjects with HIV-1 RNA greater than or equal to 50 copies per mL (virologic failure) at Week 48 was 0.6% and 1.2% for the dolutegravir plus rilpivirine treatment group and the current antiretroviral regimen treatment groups, respectively; treatment difference and 95% CI was -0.6% (-1.7%, 0.6%).

Refer to the Prescribing Information for JULUCA (dolutegravir and rilpivirine) tablet for complete virologic outcome information.

14.3 Pediatric Subjects IMPAACT P1093 is a Phase 1/2, 48-week, multicenter, open-label trial to evaluate the pharmacokinetic parameters, safety, tolerability, and efficacy of TIVICAY in combination treatment regimens in HIV‑1‑infected infants, children, and adolescents.

Subjects were stratified by age, enrolling adolescents first (Cohort 1: aged 12 to less than 18 years) and then younger children (Cohort 2A: aged 6 to less than 12 years).

All subjects received a weight-based dose of TIVICAY [see Dosage and Administration (2.2)].

These 46 subjects had a mean age of 12 years (range: 6 to 17), were 54% female and 52% black.

At baseline, mean plasma HIV-1 RNA was 4.6 log10 copies per mL, median CD4+ cell count was 639 cells per mm3 (range: 9 to 1,700), and median CD4+% was 23% (range: 1% to 44%).

Overall, 39% had baseline plasma HIV-1 RNA greater than 50,000 copies per mL and 33% had a CDC HIV clinical classification of category C.

Most subjects had previously used at least 1 NNRTI (50%) or 1 PI (70%).

At Week 24, the proportion of subjects with HIV-1 RNA less than 50 copies per mL in Cohort 1 and Cohort 2A was 70% (16/23) and 61% (14/23), respectively.

At Week 48, the proportion of subjects from Cohort 1 with HIV-1 RNA less than 50 copies per mL was 61% (14/23).

Virologic outcomes were also evaluated based on body weight.

Across both cohorts, virologic suppression (HIV-1 RNA less than 50 copies per mL) at Week 24 was achieved in 75% (18/24) of subjects weighing at least 40 kg and 55% (6/11) of subjects in the 30 to less than 40 kg weight-band.

At Week 48, 63% (12/19) of the subjects in Cohort 1 weighing at least 40 kg were virologically suppressed.

The median CD4+ cell count increase from baseline to Week 48 was 84 cells per mm3 in Cohort 1.

For Cohort 2A, the median CD4+ cell count increase from baseline to Week 24 was 209 cells per mm3.

HOW SUPPLIED

16 /STORAGE AND HANDLING Product: 50090-1355 NDC: 50090-1355-0 30 TABLET, FILM COATED in a BOTTLE NDC: 50090-1355-1 5 TABLET, FILM COATED in a BOTTLE

RECENT MAJOR CHANGES

Indications and Usage (1) 11/2017 Dosage and Administration (2.1) Warnings and Precautions, Hepatotoxicity (5.2) 11/2017 11/2017 Warnings and Precautions, Fat Redistribution (previous 5.3) Removed 11/2017 Warnings and Precautions, Risk of Adverse Reactions or Loss of Virologic Response (5.3) 11/2017

DOSAGE FORMS AND STRENGTHS

3 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.

Tablets: 10 mg, 25 mg, and 50 mg (3)

MECHANISM OF ACTION

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

INDICATIONS AND USAGE

1 TIVICAY is indicated in combination with: •other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 30 kg [see Microbiology (12.4)].

• 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 is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with: •other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 30 kg.

(1) •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.

PREGNANCY

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TIVICAY during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary There are insufficient human data on the use of TIVICAY during pregnancy to inform a drug-associated risk of birth defects and miscarriage.

Given the limited number of pregnancies exposed to dolutegravir-based regimens reported to the APR, no definitive conclusions can be drawn on the safety of TIVICAY in pregnancy, and continued monitoring is ongoing through the APR.

The background rate for major birth defects in a U.S.

reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%.

The rate of miscarriage is not reported in the APR.

The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S.

general population is 15% to 20%.

The background risk for major birth defects and miscarriage for the indicated population is unknown.

The APR uses the MACDP as the U.S.

reference population for birth defects in the general population.

The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir (see Data).

During organogenesis in the rat and rabbit, systemic exposures (AUC) to dolutegravir were less than (rabbits) and approximately 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD).

In the rat pre/post-natal developmental study, maternal systemic exposure (AUC) to dolutegravir was approximately 27 times the exposure in humans at the MRHD.

Data 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 also to rats on gestation day 6 to lactation/post-partum Day 20.

No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (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/post-natal 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).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported.

Discontinue TIVICAY 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 hepatoxicity is recommended.

(5.2) •Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy.

(5.4) 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 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 other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.

TIVICAY is 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 [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 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of TIVICAY 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 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 6 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; review concomitant medications during therapy with TIVICAY; and monitor for the adverse reactions associated with the concomitant drugs.

5.4 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TIVICAY.

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.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Drug Interactions TIVICAY may interact with other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St.

John’s wort [see Contraindications (4), Drug Interactions (7)].

Hypersensitivity Reactions Advise patients to immediately contact their healthcare provider if they develop rash.

Instruct patients to immediately stop taking TIVICAY and other suspect agents, and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as severe hypersensitivity: fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters or peeling of the skin; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; breathing difficulty; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes, dark or tea-colored urine, pale-colored stools or bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on the right side below the ribs) [see Warnings and Precautions (5.1)].

Hepatotoxicity Inform patients that hepatotoxicity has been reported with dolutegravir [see Warnings and Precautions (5.2)].

Advise patients that laboratory monitoring for hepatoxicity during therapy with TIVICAY is recommended, especially for patients with liver disease, such as hepatitis B or C.

Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any signs or symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TIVICAY is started [see Warnings and Precautions (5.3)].

Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TIVICAY during pregnancy [see Use in Specific Populations (8.1)].

Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].

Missed Dosage Instruct patients that if they miss a dose of TIVICAY, to take it as soon as they remember.

Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].

Storage Instruct patients to store the TIVICAY 10-mg tablets in the original package, keep the bottle tightly closed, and protect from moisture.

Do not remove desiccant [see How Supplied/Storage and Handling (16)].

TIVICAY, EPZICOM, JULUCA, and TRIUMEQ are trademarks owned by or licensed to the ViiV Healthcare group of companies.

The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies.

The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

Manufactured for: ViiV Healthcare Research Triangle Park, NC 27709 by: GlaxoSmithKline Research Triangle Park, NC 27709 ©2017 ViiV Healthcare group of companies or its licensor.

TVC:9PI PHARMACIST‑DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

DOSAGE AND ADMINISTRATION

2 May be taken without regard to food.

(2) 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 (2.1) 50 mg once daily Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers (2.1, 7.3) 50 mg twice daily INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistanceb (12.4) 50 mg twice daily 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.

Pediatric Patients: (Treatment-naïve or treatment-experienced INSTI-naïve patients weighing at least 30 kg).

(2.2) •If at least 40 kg: The recommended dose is TIVICAY 50 mg once daily.

•Patients 30 kg to less than 40 kg: The recommended dose is TIVICAY 35 mg once daily.

•If certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY to twice daily.

(2.2, 7.3) 2.1 Adults TIVICAY tablets may be taken with or without food.

Table 1.

Dosing Recommendations for TIVICAY in Adult Patients 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 50 mg once daily Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers [see Drug Interactions (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 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)].

2.2 Pediatric Patients TIVICAY tablets may be taken with or without food.

Treatment-Naïve or Treatment-Experienced INSTI-Naïve The recommended dose of TIVICAY in pediatric patients weighing at least 30 kg is provided in Table 2.

Table 2.

Dosing Recommendations for TIVICAY in Pediatric Patients Weighing at Least 30 kg Body Weight (kg) Daily Dosea (Number of Tablets per Dose when Different Strength(s) are Required) 30 to less than 40 35 mg once daily (One 25-mg tablet and one 10-mg tablet) 40 or greater 50 mg once daily a If certain UGT1A or CYP3A inducers are coadministered, then increase the weight-based dose of TIVICAY to twice daily [see Drug Interactions (7.3) for relevant inducers].

Safety and efficacy of TIVICAY have not been established in pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (raltegravir, elvitegravir).