[1%:<1% 5% Headache 2% 2% Gastrointestinal Nausea> <1% 3% Diarrhea> <1% 2% General Disorders Fatigue 2% 2% Skin and Subcutaneous Tissue Rash a> <1% 6% Ear and Labyrinth Vertigo 0 2% a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. Treatment-Experienced Subjects: SAILING is an international, double-blind trial in INSTI-naïve, antiretroviral treatment-experienced adult subjects. Subjects were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events leading to discontinuation was consistent with that seen in the overall treatment-naïve patient population. See full prescribing information for TIVICAY. The ADRs observed in the subset of subjects who received TIVICAY + EPZICOM were generally consistent with those seen in the overall treatment-naïve patient population. Less Common Adverse Reactions Observed in Clinical Trials The following adverse reactions occurred in less than 2% of treatment-naïve or treatment-experienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting. General Disorders: Fever, lethargy. Hepatobiliary Disorders: Hepatitis. Metabolism and Nutrition Disorders: Anorexia, hypertriglyceridemia. Musculoskeletal Disorders: Arthralgia, myositis. Nervous: Somnolence. Psychiatric: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Table 3. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naïve Subjects in SINGLE (Week 144 Analysis) Laboratory Abnormality TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) ALT Grade 2 (> 2.5-5.0 x ULN) 3% 5% Grade 3 to 4 (>5.0 x ULN) 1% <1% AST Grade 2 (> 2.5-5.0 x ULN) 3% 4% Grade 3 to 4 (>5.0 x ULN) 1% 3% Creatine kinase Grade 2 (6.0-9.9 x ULN) 5% 3% Grade 3 to 4 ( 10.0 x ULN) 7% 8% Hyperglycemia Grade 2 (126-250 mg/dL) 9% 6% Grade 3 (>250 mg/dL) 2% <1% Lipase Grade 2 (> 1.5-3.0 x ULN) 11% 11% Grade 3 to 4 (>3.0 ULN) 5% 4% Total neutrophils Grade 2 (0.75-0.99 x 10 9 ) 4% 5% Grade 3 to 4 ( <0.75 x 10 9 ) 3% 3% ULN = Upper limit of normal. Table 4. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Subjects in SINGLE (Week 144 Analysis a ) Lipid TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Cholesterol (mg/dL) 24.0 26.7 HDL cholesterol (mg/dL) 5.4 7.2 LDL cholesterol (mg/dL) 16.0 14.6 Triglycerides (mg/dL) 13.6 31.9 a Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (TIVICAY + EPZICOM n = 36 and ATRIPLA: n = 36). Treatment-Experienced Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve trials. Hepatitis C Virus Co-infection In SINGLE, the pivotal Phase 3 trial, subjects with hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with hepatitis B co-infection were excluded. Overall, the safety profile in subjects with hepatitis C virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis C virus co-infection for both treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV mono-infected subjects receiving Triumeq were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively [see Warnings and Precautions (5.3)] . See also full prescribing information for TIVICAY. Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)] . Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.25 mg per dL to 0.81 mg per dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects. Abacavir and Lamivudine Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other antiretroviral treatment) were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use with one or more of the components of Triumeq. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Digestive Stomatitis. Gastrointestinal Pancreatitis. General Weakness. Blood and Lymphatic Systems Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Hypersensitivity Sensitization reactions (including anaphylaxis), urticaria [see Warnings and Precautions (5.1), Adverse Reactions (6.1)] . Metabolism and Nutrition Disorders Hyperlactemia. Musculoskeletal CPK elevation, muscle weakness, myalgia, rhabdomyolysis. Nervous Paresthesia, peripheral neuropathy, seizures. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, erythema multiforme. Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases [see Adverse Reactions (6.1)] . Drug Interactions Effect of Dolutegravir on the Pharmacokinetics of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC 50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC 50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin) [see Contraindications (4), Drug Interactions (7.3)]. In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC 50 = 2.12 microM) and OAT3 (IC 50 = 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 (IC 50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, 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. In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: daclatasvir, tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir. Effect of Other Agents on the Pharmacokinetics of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (Table 5) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)] . In vitro, dolutegravir was not a substrate of OATP1B1, or OATP1B3. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. Established and Other Potentially Significant Drug Interactions There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets. Information regarding potential drug interactions with dolutegravir (Table 5) and abacavir are provided below. 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 Clinical Pharmacology (12.3).] Table 5. Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment HIV-1 Antiviral Agents Non-nucleoside reverse transcriptase inhibitor: Etravirine a Dolutegravir Use of Triumeq with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Efavirenz a Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from Triumeq. Non-nucleoside reverse transcriptase inhibitor: Nevirapine Dolutegravir Avoid coadministration with Triumeq because there are insufficient data to make dosing recommendations. Protease inhibitor: Fosamprenavir/ritonavir a Tipranavir/ritonavir a Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from Triumeq. Other Agents Carbamazepine a Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from Triumeq. Oxcarbazepine Phenytoin Phenobarbital St. John s wort ( Hypericum perforatum ) Dolutegravir Avoid coadministration with Triumeq because there are insufficient data to make dosing recommendations. Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids a or laxatives Sucralfate Buffered medications Dolutegravir Administer Triumeq 2 hours before or 6 hours after taking medications containing polyvalent cations. Oral calcium and iron supplements, including multivitamins containing calcium or iron a Dolutegravir Administer Triumeq 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, Triumeq and supplements containing calcium or iron can be taken together with food. Metformin a Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or Triumeq. When stopping Triumeq, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of Triumeq is recommended. Rifampin a Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from Triumeq. a See Clinical Pharmacology (12.3) Table 8 or Table 9 for magnitude of interaction. Methadone Abacavir: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3)] . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no adequate and well controlled trials in pregnant women. Reproduction studies with the components of Triumeq have been performed in animals (see Dolutegravir, Abacavir, and Lamivudine sections below). Animal reproduction studies are not always predictive of human response. Triumeq should be used during pregnancy only if the potential benefit outweigh the risks. Antiretroviral Pregnancy Registry To monitor maternal fetal outcomes of pregnant women exposed to Triumeq or other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1 800 258 4263. Animal Data Dolutegravir: Reproduction studies performed in rats and rabbits at doses up to 50 times the human dose of 50 mg once daily have revealed no evidence of impaired fertility or harm to the fetus due to dolutegravir. Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 50 times the 50-mg once-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity. Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.74 times the 50-mg once-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg. Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown rump length) were observed in rats at a dose which produced 28 times the human exposure for a dose of 600 mg based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 7 times the human exposure at the recommended dose based on AUC. Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 32 times the human exposure for a dose of 300 mg. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at plasma levels up to 32 times those in humans. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV 1 infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV 1 infection. Because of both the potential for HIV 1 transmission and the potential for serious adverse reactions in nursing infants, instruct mothers not to breastfeed. Dolutegravir Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human breast milk. Abacavir Abacavir is excreted in the milk of lactating rats. Lamivudine Lamivudine is excreted in human breast milk. Pediatric Use Safety and effectiveness of Triumeq in pediatric patients have not been established [see Clinical Pharmacology (12.3)] . Geriatric Use Clinical trials of abacavir, dolutegravir, or lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Triumeq in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. Patients with Impaired Renal Function Triumeq is not recommended for patients with creatinine clearance less than 50 mL per min because Triumeq is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of Triumeq, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used [see Clinical Pharmacology (12.3)] . Patients with Impaired Hepatic Function Triumeq is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of Triumeq, is required for patients with mild hepatic impairment (Child-Pugh Score A), then the individual components should be used [see Clinical Pharmacology (12.3)] . The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Score B) or severe (Child-Pugh Score C) hepatic impairment; therefore, Triumeq is contraindicated in these patients [see Contraindications (4)]. Overdosage There is no known specific treatment for overdose with Triumeq. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Dolutegravir As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. Abacavir It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis. Lamivudine Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. Triumeq Description Triumeq Triumeq contains an INSTI (dolutegravir) and 2 nucleoside analogues (abacavir and lamivudine) with inhibitory activity against HIV. Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine. Triumeq tablets are purple, biconvex, oval, debossed with 572 Trı on one side and contain the inactive ingredients D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film-coating (OPADRY II Purple 85F90057) contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide. Abacavir Sulfate The chemical name of abacavir sulfate is ( 1 S,cis)- 4-[2-amino-6-(cyclopropylamino)-9 H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). It has a molecular formula of (C 14 H 18 N 6 O) 2 H 2 SO 4 and a molecular weight of 670.76 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white solid and is soluble in water. Dolutegravir The chemical name of dolutegravir sodium is sodium (4 R ,12a S )-9-[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2 H -pyrido[1',2':4,5]pyrazino[2,1- b ][1,3]oxazin-7-olate. The empirical formula is C 20 H 18 F 2 N 3 NaO 5 and the molecular weight is 441.36 g per mol. It has the following structural formula: Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water. Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2 ,3 -dideoxy, 3 -thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine is a white to off-white crystalline solid and is soluble in water. Triumeq - Clinical Pharmacology Mechanism of Action Triumeq is an HIV-1 antiviral agent [see Microbiology (12.4)]. Pharmacodynamics Effects on Electrocardiogram A thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated. In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250 mg suspension (exposures approximately 3 fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose. Effects on Renal Function The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo. Pharmacokinetics Pharmacokinetics in Adults One Triumeq tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n = 62). Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, C max was 4.26 1.19 mcg per mL (mean SD) and AUC was 11.95 2.51 mcg hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5 -carboxylic acid and glucuronyl transferase to form the 5 -glucuronide. In single-dose trials, the observed elimination half-life (t 1/2 ) was 1.54 0.63 hours. After intravenous administration, total clearance was 0.80 0.24 L per hour per kg (mean SD). Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, C max , and C 24 h ranging from 1.2 to 1.5. Dolutegravir is a P-glycoprotein substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis. Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [ 14 C] dolutegravir, 53% of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was less than 1% of the dose. Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses. The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV 1 infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV 1 infected subjects. Table 6. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1 Infected Adults Parameter 50 mg Once Daily Geometric Mean (%CV) AUC (0-24) (mcg h/mL) 53.6 (27) C max (mcg/mL) 3.67 (20) C min (mcg/mL) 1.11 (46) Cerebrospinal Fluid (CSF): In 11 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng per mL (range: 4 ng per mL to 23.2 ng per mL) 2 to 6 hours postdose after 2 weeks of treatment. The clinical relevance of this finding has not been established. Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state C max (C max,ss ) was 2.04 0.54 mcg per mL (mean SD) and the 24-hour steady-state AUC (AUC 24,ss ) was 8.87 1.83 mcg hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials in HIV 1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t ) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398.5 69.1 mL per min (mean SD). Effect of Food on Oral Absorption Triumeq may be taken with or without food. Overall, when compared with fasted conditions, administration of Triumeq to healthy adult subjects with a high-fat meal (53% fat, 869 calories) resulted in decreased C max for abacavir and increased C max and AUC for dolutegravir. Lamivudine exposures were not affected by food. With a high-fat meal, the C max of abacavir decreased 23% and the C max and AUC of dolutegravir increased 37% and 48%, respectively. Special Populations Renal Impairment: The effect of renal impairment on the combination of abacavir, dolutegravir, and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, dolutegravir and lamivudine components). Hepatic Impairment: The effect of hepatic impairment on the combination of abacavir, dolutegravir, and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, dolutegravir and lamivudine components). Pediatric Patients: The pharmacokinetics of the combination of abacavir, dolutegravir, and lamivudine in pediatric subjects have not been established. Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years. Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components. Race: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components. Drug Interactions The drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine. Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir or abacavir are provided in Section 7.3 [see Drug Interactions (7)] . Table 7. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs Coadministered Drug(s) and Dose(s) Dose of Dolutegravir n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00 C max AUC C τ or C 24 Daclatasvir 60 mg once daily 50 mg once daily 12 1.03 (0.84 to 1.25) 0.98 (0.83 to 1.15) 1.06 (0.88 to 1.29) Ethinyl estradiol 0.035 mg 50 mg twice daily 15 0.99 (0.91 to 1.08) 1.03 (0.96 to 1.11) 1.02 (0.93 to 1.11) Metformin 500 mg twice daily 50 mg once daily 15 a 1.66 (1.53 to 1.81) 1.79 (1.65 to 1.93) Metformin 500 mg twice daily 50 mg twice daily 15 a 2.11 (1.91 to 2.33) 2.45 (2.25 to 2.66) Methadone 16 to 150 mg 50 mg twice daily 11 1.00 (0.94 to 1.06) 0.98 (0.91 to 1.06) 0.99 (0.91 to 1.07) Midazolam 3 mg 25 mg once daily 10 0.95 (0.79 to 1.15) Norelgestromin 0.25 mg 50 mg twice daily 15 0.89 (0.82 to 0.97) 0.98 (0.91 to 1.04) 0.93 (0.85 to 1.03) Rilpivirine 25 mg once daily 50 mg once daily 16 1.10 (0.99 to 1.22) 1.06 (0.98 to 1.16) 1.21 (1.07 to 1.38) Tenofovir disoproxil fumarate 300 mg once daily 50 mg once daily 15 1.09 (0.97 to 1.23) 1.12 (1.01 to 1.24) 1.19 (1.04 to 1.35) a The number of subjects represents the maximum number of subjects that were evaluated. Table 8. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir Coadministered Drug(s) and Dose(s) Dose of Dolutegravir n Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 C max AUC C τ or C 24 Atazanavir 400 mg once daily 30 mg once daily 12 1.50 (1.40 to 1.59) 1.91 (1.80 to 2.03) 2.80 (2.52 to 3.11) Atazanavir/ritonavir 300/100 mg once daily 30 mg once daily 12 1.34 (1.25 to 1.42) 1.62 (1.50 to 1.74) 2.21 (1.97 to 2.47) Darunavir/ritonavir 600/100 mg twice daily 30 mg once daily 15 0.89 (0.83 to 0.97) 0.78 ( do business from home
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