Tivicay
(Dolutegravir Sodium)Dosage & Administration
| UGT = uridine diphosphate glucuronosyltransferase; CYP = cytochrome P450. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 ( TIVICAY tablets may be taken with or without food.
| 50 mg once daily | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers ( TIVICAY tablets may be taken with or without food.
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 [see Drug Interactions , Clinical Pharmacology ] .In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Table 8provides 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 , Clinical Pharmacology ].
| 50 mg twice daily | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistanceb ( TIVICAY tablets may be taken with or without food.
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 IC50values 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 EC50values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/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 EC50value 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 EC50values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50values 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/mLHIV-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 INST-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) . 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 . 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.
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) . 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.
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/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. | 50 mg twice daily | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| aIf certain uridine diphosphate glucuronosyltransferase (UGT)1A or cytochrome P450 (CYP)3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions ] . | ||
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 |
The recommended weight-based dosage of TIVICAY PD tablets for oral suspension in
Do not use TIVICAY tablets in patients weighing 3 to 14 kg. See administration instructions in
| aIf certain uridine diphosphate glucuronosyltransferase (UGT)1A or cytochrome P450 (CYP)3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
For
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions ] . | ||
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 |
Administer TIVICAY tablets and TIVICAY PD tablets for oral suspension with or without food.
Do not chew, cut, or crush TIVICAY PD
a If certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY to twice daily. (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 ] .
For pediatric patients weighing 14 kg or greater (4 weeks and older, treatment-naïve, or treatment-experienced but naïve to INSTI treatment) administer either: | ||||||||||||||||||
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions ] . | ||
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 |
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
In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.
Table 8provides 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
| INSTI = integrase strand transfer inhibitor. | ||
| a See Clinical Pharmacology Table 11or Table 12for magnitude of interaction. bThe lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance [see Microbiology ] ) 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 ] . |
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 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 antacidsaor laxatives | ↓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 |
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 (
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions ] . | ||
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 |
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Tivicay Prescribing Information
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
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 IC50values of 2.7 nM and 12.6 nM.
Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/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 EC50value 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 EC50values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50values against 3 HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.
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.
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.
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 INST-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) . 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 . 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.
| INSTI = integrase strand transfer inhibitor. | |
| aIncludes INSTI-resistance substitutions Y143R/C/H and N155H. bINSTI-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). cThe 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 rates by baseline phenotype were analyzed in an as-treated analysis using all subjects with available baseline phenotypes through Week 48 (n = 163) . 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.
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) |
There were 50 subjects with virologic failure on the dolutegravir twice-daily regimen in VIKING-3 with HIV-1 RNA greater than 400 copies/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.
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/ 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.
• May be taken without regard to food. (, 2.6)2.2 General Dosing and Administration Instructions for Pediatric PatientsDo not substitute TIVICAY tablets and TIVICAY PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles[see Warnings and Precautions (5.5), Clinical Pharmacology ].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 ].
| UGT = uridine diphosphate glucuronosyltransferase; CYP = cytochrome P450. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 ( TIVICAY tablets may be taken with or without food.
| 50 mg once daily | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers ( TIVICAY tablets may be taken with or without food.
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 [see Drug Interactions , Clinical Pharmacology ] .In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Table 8provides 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 , Clinical Pharmacology ].
| 50 mg twice daily | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistanceb ( TIVICAY tablets may be taken with or without food.
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 IC50values 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 EC50values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/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 EC50value 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 EC50values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50values 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/mLHIV-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 INST-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) . 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 . 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.
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) . 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.
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/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. | 50 mg twice daily | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| aIf certain uridine diphosphate glucuronosyltransferase (UGT)1A or cytochrome P450 (CYP)3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions ] . | ||
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 |
The recommended weight-based dosage of TIVICAY PD tablets for oral suspension in
Do not use TIVICAY tablets in patients weighing 3 to 14 kg. See administration instructions in
| aIf certain uridine diphosphate glucuronosyltransferase (UGT)1A or cytochrome P450 (CYP)3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
For
• TIVICAY PD tablets for oral suspension (preferred in pediatric patients weighing less than 20 kg) , or• TIVICAY tablets for oral use
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily [see Drug Interactions ] . | ||
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 |
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions ] . | ||
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 |
Administer TIVICAY tablets and TIVICAY PD tablets for oral suspension with or without food.
Do not chew, cut, or crush TIVICAY PD
• 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].
a If certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY to twice daily. (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 ] .
For pediatric patients weighing 14 kg or greater (4 weeks and older, treatment-naïve, or treatment-experienced but naïve to INSTI treatment) administer either:
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 [see Drug Interactions , Clinical Pharmacology ] .In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Table 8provides 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 , Clinical Pharmacology ].
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 (
| aIf certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily [see Drug Interactions ] . | ||
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 |
• 14 kg to less than 20 kg: 40 mg once daily.• 20 kg and greater: 50 mg once daily.
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.
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.
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.
Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini which together include over 14,000 individuals evaluated during pregnancy show similar prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV-negative individuals.
There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the APR do not indicate an increased risk of birth defects
In animal reproduction studies, no evidence of adverse developmental outcomes (including neural tube defects) 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
The Eswatini birth outcome surveillance study includes 9,743 individuals exposed to dolutegravir at conception, 1,838 individuals exposed to non-dolutegravir-containing regimens, and 32,259 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08% (95% CI: 0.04-0.16%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%, 95% CI: 0.06-0.56%) or to HIV-negative individuals (0.08%, 95% CI: 0.06-0.12%). The observed prevalence of neural tube defects in infants delivered to individuals taking non-dolutegravir-containing regimens had a wide confidence interval due to low sample size.
Limitations of these birth outcome surveillance studies include insufficient data to determine if baseline characteristics were balanced between the study groups or to assess other factors such as the use of folic acid during the preconception or first trimester periods.
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 to 2.11) (n = 15).
Dolutegravir was administered orally at up to 1,000 mg/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).
TIVICAY and TIVICAY PD are contraindicated in patients:
• with previous hypersensitivity reaction to dolutegravir[see Warnings and Precautions ()].5.1 Hypersensitivity ReactionsHypersensitivity 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 III 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.
• 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 DRUG INTERACTIONS• Refer to the full prescribing information for important drug interactions with TIVICAY or TIVICAY PD.• Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir.• 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.
7.1 Effect of Dolutegravir on the Pharmacokinetics of Other AgentsIn 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 , Drug Interactions ].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 (IC50greater 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 DolutegravirDolutegravir 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
[see Drug Interactions , Clinical Pharmacology ].In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.
7.3 Established and Other Potentially Significant Drug InteractionsTable 8provides 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 , Clinical Pharmacology ].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 ] INSTI = integrase strand transfer inhibitor. a See Clinical Pharmacology Table 11or Table 12for magnitude of interaction.
bThe lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance[see Microbiology ]) 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 NameEffect on Concentration of Dolutegravir and/or Concomitant DrugClinical CommentHIV-1 Antiviral AgentsNon-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 AgentsDofetilide
↑Dofetilide
Coadministration is contraindicated with TIVICAY or TIVICAY PD
[see Contraindications ].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 antacidsaor 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 irona↓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 DolutegravirBased on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir
[see Clinical Pharmacology ].
• 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 Hypersensitivity ReactionsHypersensitivity 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 III 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.
• 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 HepatotoxicityHepatic 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 ]. 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.• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ()5.4 Immune Reconstitution SyndromeImmune 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 aviuminfection, cytomegalovirus,Pneumocystis jiroveciipneumonia [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.
• TIVICAY tablets and TIVICAY PD tablets for oral suspension are not substitutable. (,2.2 General Dosing and Administration Instructions for Pediatric PatientsDo not substitute TIVICAY tablets and TIVICAY PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles[see Warnings and Precautions (5.5), Clinical Pharmacology ].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 ].)5.5 Different Formulations Are Not SubstitutableTIVICAY and TIVICAY PD are not bioequivalent and are not substitutable on a milligram-per-milligram basis
[see Clinical Pharmacology ]. 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 ]. 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.