TRIUMEQ

Dolutegravir is an

HIV-1 integrase inhibitor that blocks the strand transfer step of the integration of the viral genome into the host cell (INSTI).

The effect of this drug has no homology in human host cells, which gives it excellent tolerability and minimal toxicity.

Dolutegravir was developed by ViiV Healthcare and FDA-approved on August 12, 2013.

On November 21, 2017, dolutegravir, in combination with rilpivirine, was approved as part of the first complete treatment regimen with only two drugs for the treatment of adults with HIV-1 named Juluca.

Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of patients with HIV-1 infection that comply with the characteristics of being adults or children aged 12 years and older and present at least a weight of 40 kg.

FDA combination therapy approval of dolutegravir and rilpivirine is indicated for adults with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy.

Dolutegravir is available in combination with lamivudine and abacavir for the treatment of adult and pediatric patients with HIV-1 who weigh ≥10 kg.

It is also available in a two-drug, single tablet regimen with lamivudine for patients ≥12 years of age and weighing at 25 kg.

HIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent reduction of antiviral activity with declines of HIV-1 RNA copies per ml. The antiviral response was maintained for 3-4 days after the last dose.

The sustained response obtained in clinical trials indicates that dolutegravir has a tight binding and longer dissociative half-life providing it a high barrier to resistance.

The combination therapy (ripivirine and dolutegravir) presented the same viral suppression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.

When 50 mg of dolutegravir once daily was Oral administered to HIV-1 infected adults, the AUC, Cmax, and Cmin is 53.6 mcg h/mL, 3.67 mcg/mL, and 1.11 mcg/mL, respectively.

The peak plasma concentration was observed 2-3 hours post-dose.

Steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1.2-1.5.

When 50 mg once daily is given to pediatric patients (12 to < 18 years and weighing ≥40 kg) the Cmax, AUC, and C24 is 3.49 mcg/mL, 46 mcg.h/mL, and 0.90 mcg/mL respectively.

The administration of a dose of 50 mg of dolutegravir presents an apparent volume of distribution of 17.4 L. The median dolutegravir concentration in CSF was 18 ng/mL after 2 weeks of treatment.

Dolutegravir is highly metabolized through three main pathways and it forms no long-lived metabolites.

The first pathway is defined by the glucuronidation by UGT1A1, the second pathway by carbon oxidation by CYP3A4 and the third pathway is what appears to be a sequential oxidative defluorination and glutathione conjugation.

The main metabolite found in blood plasma is the ether glucuronide form (M2) and its chemical properties disrupt its ability to bind metal ions, therefore, it is inactive.

Hover over products below to view reaction partners Dolutegravir ether glucuronide dolutegravir (M2) hydroxilated form of dolutegravir (M3) 2,4.

• difluorobenzaldehyde (M5 dolutegravir) + hydrolized form of dolutegravir (M1) defluorinated and gutathione conjugated form of dolutegravir (M4.1) defluorinated and gutathione conjugated form of dolutegravir (M4.2).

When a single oral dose of dolutegravir is given, nearly all complete dose is recovered in a proportion of 53% excreted unchanged in the feces and 31% excreted in urine.

The renal eliminated recovered dose consists of ether glucuronide of dolutegravir (18.9%), a metabolite formed by oxidation at the benzylic carbon (3.0%), a hydrolytic N-dealkylation product (3.6%) and unchanged drug (< 1%).

The apparent clearance rate of dultegravir is 1.0 L/h.

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Data from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir is administered at the time of conception.

As defects related to the closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.

Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with the use of TIVICAY and TIVICAY PD.

Assess the risks and benefits of TIVICAY and TIVICAY PD and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester.

A benefit-risk assessment should consider factors such as the feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in-utero dolutegravir exposure during critical periods of fetal development.

There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage.

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

In the

U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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

There is no known specific treatment for an overdose with TIVICAY or TIVICAY PD.

If an 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.

• who have the HLA-B*5701 allele.

• with prior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine.

• receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir.

• with moderate or severe hepatic impairment.

• Presence of HLA-B*5701 allele.

• Prior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine.

• Coadministration with dofetilide.

• Moderate or severe hepatic impairment.

• Before initiating TRIUMEQ or TRIUMEQ PD, screen for the HLA‑B*5701 allele because TRIUMEQ and TRIUMEQ PD contain abacavir. .

• Prior to or when initiating TRIUMEQ or TRIUMEQ PD, test patients for HBV infection.

• TRIUMEQ and TRIUMEQ PD may be taken with or without food.

• Adults: One tablet of TRIUMEQ daily.

ABC = abacavir, DTG = dolutegravir, 3TC = lamivudine.

Pediatric Population Body Weight Number of

Tablets (once daily) Recommended Daily Dose TRIUMEQ PD Tablets (6 kg to <25 kg) 6 kg to <10 kg 3 180 mg ABC, 15 mg DTG, and 90 mg 3TC 10 kg to <14 kg 4 240 mg ABC, 20 mg DTG, and 120 mg 3TC 14 kg to <20 kg 5 300 mg ABC, 25 mg DTG, and 150 mg 3TC 20 kg to <25 kg 6 360 mg ABC, 30 mg DTG, and 180 mg 3TC TRIUMEQ Tablets (≥25 kg) ≥25 kg 1 600 mg ABC, 50 mg DTG, and 300 mg 3TC.

• Do not substitute TRIUMEQ and TRIUMEQ PD on a milligram-per-milligram basis.

• If dosing with certain UGT1A or CYP3A inducers, then the recommended dolutegravir dosage regimen should be adjusted.

Table for complete dosing recommendations.

• Because TRIUMEQ and TRIUMEQ PD are fixed-dose tablets and cannot be dose adjusted, TRIUMEQ and TRIUMEQ PD are not recommended in patients with creatinine clearance <30 mL/min and pediatric patients with a similar degree of renal impairment based on age-appropriate assessment of renal function, or patients with hepatic impairment. 2.1 Screening for HLA−B5701 Allele prior to Initiating TRIUMEQ Screen for the HLA‑B5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD. 2.2 Testing prior to or When Initiating Treatment with TRIUMEQ Prior to or when initiating TRIUMEQ or TRIUMEQ PD, test patients for HBV infection. 2.3 Overview of TRIUMEQ Dosage Forms TRIUMEQ is available in two dosage forms.

Do not substitute TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles for the dolutegravir component.

• TRIUMEQ tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine.

TRIUMEQ is recommended in adults and pediatric patients weighing at least 25 kg.

• TRIUMEQ PD tablets for oral suspension: 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.

PD is recommended in pediatric patients weighing 6 kg to less than 25 kg.

• Because TRIUMEQ PD is a fixed-dose tablet and the dosage of individual components cannot be adjusted, it may lead to a suboptimal dosing for patients weighing ≥25 kg. TRIUMEQ PD is not recommended in patients weighing 25 kg or more. 2.4 Recommended Dosage in Adults TRIUMEQ is a fixed-dose containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine.

The recommended dosage regimen of

TRIUMEQ in adults is one tablet once daily orally with or without food.

Do not use TRIUMEQ

PD in adults. 2.5 Recommended Dosage and Administration Instructions for Pediatric Patients Weighing at Least 6 kg The dosage and dosage form recommended for pediatric patients varies by weight as shown in Table 1 below.

Table 1.

Recommended Dosage of TRIUMEQ Tablets and TRIUMEQ PD Tablets for Oral Suspension in Pediatric Patients a TRIUMEQ is a fixed-dose containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. b TRIUMEQ PD is a fixed-dose containing 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.

Body Weight TRIUMEQ Tablets a TRIUMEQ PD b Number of Tablets Total Daily Dose 6 kg to <10 kg Not recommended 3 tablets once daily 180 mg abacavir, 15 mg dolutegravir, and 90 mg lamivudine once daily 10 kg to <14 kg Not recommended 4 tablets once daily 240 mg abacavir, 20 mg dolutegravir, and 120 mg lamivudine once daily 14 kg to <20 kg Not recommended 5 tablets once daily 300 mg abacavir, 25 mg dolutegravir, and 150 mg lamivudine once daily 20 kg to <25 kg Not recommended 6 tablets once daily 360 mg abacavir, 30 mg dolutegravir, and 180 mg lamivudine once daily ≥25 kg 1 tablet once daily Not recommended 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine Administer TRIUMEQ PD tablets for oral suspension with or without food.

Instruct patients (or instruct caregivers) to fully disperse the tablets for oral suspension in 20 mL of drinking water (if using 4, 5, or 6 tablets for oral suspension) or 15 mL (if using 3 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.

Do not swallow the tablets for oral suspension whole, and do not chew, cut, or crush the tablets.

For children unable to use the supplied cup, an appropriate-sized syringe may be used to administer the oral suspension.

TRIUMEQ tablet with or without food.

Do not chew, cut, or crush the tablet. 2.6 Dosage Recommendation with Certain Concomitant Medications The dolutegravir dose in TRIUMEQ (50 mg) and TRIUMEQ PD (5 mg) is insufficient when coadministered with medications listed in Table 2 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.

Table 2.

Dosing Recommendations for TRIUMEQ and TRIUMEQ PD with Coadministered Medications Coadministered Drug Dosing Recommendation Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin In adults and in pediatric patients weighing at least 25 kg, the recommended dolutegravir dosage regimen is 50 mg twice daily.

Thus, an additional TIVICAY 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken.

In pediatric patients weighing 6 kg to <25 kg, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD.

• 6 to <10 kg: administer an additional 15-mg dose of dolutegravir (3 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.

• 10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.

• 14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.

• 20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD. 2.7 Not Recommended Due to Lack of Dosage Adjustment Because TRIUMEQ and TRIUMEQ PD are fixed-dose tablets and cannot be dose adjusted, TRIUMEQ and TRIUMEQ PD are not recommended in:

• patients with creatinine clearance <30 mL/min and pediatric patients with a similar degree of renal impairment based on age-appropriate renal function assessment.

There are no data available on the use of lamivudine, a component of TRIUMEQ and TRIUMEQ PD, in pediatric patients with renal impairment.

• patients with mild hepatic impairment.

PD are contraindicated in patients with moderate or severe hepatic impairment.

tablets TRIUMEQ tablets are purple, oval, film-coated, biconvex tablets debossed with “572 Tri” on one side and contain 600 mg of abacavir (as abacavir sulfate), 50 mg of dolutegravir (as dolutegravir sodium), and 300 mg lamivudine.

Bottle of 30 tablets with desiccant and child-resistant closure.

NDC 49702-231-13.

Store and dispense in the original package, protect from moisture, and keep the bottle tightly closed.

Do not remove desiccant.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F). .

TRIUMEQ PD tablets for oral suspension TRIUMEQ PD tablets for oral suspension, are yellow, capsule-shaped, strawberry cream flavored, film-coated, biconvex tablets debossed with “SV WTU” on one side and contain 60 mg of abacavir (as abacavir sulfate), 5 mg of dolutegravir (as dolutegravir sodium), and 30 mg lamivudine.

Bottle of 90 tablets (NDC 49702-272-59) with desiccant and child-resistant closure.

Each bottle is packaged as a kit (NDC 49702-258-37) with one 40-mL dosing cup.

Store and dispense in the original bottle, protect from moisture, and keep the bottle tightly closed.

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TRIUMEQ 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 TRIUMEQ during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage.

However, available human data from the APR with the individual components of TRIUMEQ do not indicate an increased risk of birth defects.

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

In the

U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, no evidence of adverse developmental outcomes (including neural tube defects) was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 50 times (rats) the exposure in humans at the recommended human dose (RHD) .

Oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the RHD.

No adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures approximately 9 times the human exposure (AUC) at the RHD.

Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at a human exposure (AUC) similar to the RHD; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the RHD.

Dolutegravir: Observational studies: The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy.

A subsequent analysis was conducted based on a larger cohort from the birth outcome surveillance study in Botswana and included over 9,460 individuals exposed to dolutegravir at conception, 23,664 individuals exposed to non-dolutegravir-containing regimens, and 170,723 HIV-negative pregnant individuals.

The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11% (95% CI: 0.05-0.19%).

The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.11%, 95% CI: 0.07-0.16%), or to HIV-negative individuals (0.06%, 95% CI: 0.05-0.08%).

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.

Based on prospective reports to the APR, of over 1,300 exposures to dolutegravir during pregnancy resulting in live births (including 874 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.2% to 4.7%) following first-trimester exposure to dolutegravir-containing regimens and 5.0% (95% CI: 3.2% to 7.3%) following second-/third-trimester exposure to dolutegravir-containing regimens.

U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.

Dolutegravir has been shown to cross the placenta.

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

Based on prospective reports to the APR of over 2,800 exposures to abacavir during pregnancy resulting in live births (including 1,455 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.

The prevalence of defects in live births was 3.2% (95% CI: 2.4% to 4.3%) following first trimester exposure to abacavir-containing regimens and 3.0% (95% CI: 2.2% to 4.1%) following second/third trimester exposure to abacavir-containing regimens.

Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.

Based on prospective reports to the APR of over 13,000 exposures to lamivudine during pregnancy resulting in live births (including 5,613 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.

The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa.

The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals.

These trials were not designed or powered to provide efficacy information.

Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans.

Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (1.2 - to 12.8-fold) greater compared with paired maternal serum concentration (n = 8).

Dolutegravir: Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg/kg/day) on Gestation Days to 17 and to 18, respectively, and to rats on Gestation Day to lactation/post-partum Day 20.

No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested.

During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD.

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 50 times human exposure at the RHD).

Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg/kg/day) and rabbits (at 125, 350, or 700 mg/kg/day) during organogenesis (on Gestation Days 6 through and 6 through 20, respectively).

Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown‑rump length) were observed in rats at doses up to 1,000 mg/kg/day, resulting in exposures approximately 35 times the human exposure (AUC) at the RHD.

No developmental effects were observed in rats at 100 mg/kg/day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose.

In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg/kg/day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg/kg/day. No developmental effects were observed in rats at 60 mg/kg/day, resulting in exposures (AUC) approximately 4 times the human exposure at the RHD.

Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta.

In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the RHD.

Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]).

No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) approximately 35 times higher than human exposure at the recommended daily dose.

Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (C max ) 35 times higher than human exposure at the recommended daily dose.

Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta.

In the fertility/pre.

• and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg/kg/day (from prior to mating through postnatal Day 20).

In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.