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.
DolutegravirAs dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
AbacavirIt is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
LamivudineBecause 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 is contraindicated in patients:
The following adverse reactions are discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Serious And Fatal Abacavir-Associated Hypersensitivity ReactionsIn clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.
Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized).
Serious Dolutegravir Hypersensitivity ReactionsIn clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ. These hypersensitivity reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury.
Additional Treatment-Emergent Adverse Drug Reactions (ADRs) With Use Of TRIUMEQThe safety assessment of TRIUMEQ is primarily based on the analyses of data from a randomized, international, multicenter, double-blind, active-controlled trial, SINGLE (ING114467) and supported by data in treatment-experienced, INSTI-naïve subjects from SAILING (ING111762) and by data from other treatment-naïve trials. See full prescribing information for TIVICAY.
Treatment-Naïve Subjects: In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir and lamivudine (EPZICOM®) once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA®) once daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rate of adverse events leading to discontinuation was 4% in subjects receiving TIVICAY + EPZICOM and 14% in subjects receiving ATRIPLA once daily.
Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm of SINGLE are provided in Table 2.
Table 2: Treatment-Emergent Adverse Drug Reactions of
at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in
Treatment-Naïve Subjects in SINGLE (Week 144 Analysis)
| Adverse Reaction | TIVICAY + EPZICOM Once Daily (n = 414) |
ATRIPLA Once Daily (n = 419) |
| Psychiatric | ||
| Insomnia | 3% | 3% |
| Depression | 1% | 2% |
| Abnormal dreams | < 1% | 2% |
| Nervous System | ||
| Dizziness | < 1% | 5% |
| Headache | 2% | 2% |
| Gastrointestinal | ||
| Nausea | < 1% | 3% |
| Diarrhea | < 1% | 2% |
| General Disorders | ||
| Fatigue | 2% | 2% |
| Skin and Subcutaneous Tissue | ||
| Rasha | < 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 TrialsThe 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 AbnormalitiesTreatment-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 ( > 15-3.0 x ULN) | 11% | 11% |
| Grade 3 to 4 ( > 3.0 ULN) | 5% | 4% |
| Total neutrophils | ||
| Grade 2 (0.75-0.99 x 109) | 4% | 5% |
| Grade 3 to 4 ( < 0.75 x 109) | 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 Analysisa)
| 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-infectionIn 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 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. 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 LamivudineLaboratory 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 ExperienceIn 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.
DigestiveStomatitis.
GastrointestinalPancreatitis.
GeneralWeakness.
Blood and Lymphatic SystemsAplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.
HypersensitivitySensitization reactions (including anaphylaxis), urticaria.
Metabolism and Nutrition DisordersHyperlactemia.
MusculoskeletalCPK elevation, muscle weakness, myalgia, rhabdomyolysis.
NervousParesthesia, peripheral neuropathy, seizures.
RespiratoryAbnormal breath sounds/wheezing.
SkinAlopecia, 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.
TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.
Limitations Of UseA 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 FunctionThe 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.
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, Cmax 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 (t½) 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, Cmax, and C24 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 [14C] 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) |
| Cmax (mcg/mL) | 3.67 (20) |
| Cmin (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 Cmax (Cmax,ss) was 2.04 ± 0.54 mcg per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,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 (t½) 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 AbsorptionTRIUMEQ 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 Cmax for abacavir and increased Cmax and AUC for dolutegravir.
Lamivudine exposures were not affected by food. With a high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively.
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 RegistryTo 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 DataDolutegravir: 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.
TRIUMEQ tablets are purple, biconvex, oval, and debossed with “572 Tr1” on one side. 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.
Storage And HandlingTRIUMEQ tablets, 600 mg of abacavir as abacavir sulfate, 50 mg of dolutegravir as dolutegravir sodium, and 300 mg lamivudine, are purple, oval, film-coated, biconvex tablets debossed with “572 Tr1” on one side.
Bottle of 30 with 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 25°C (77°F); excursions permitted 15° to 30°C (59° to 86°F)..
Manufactured for: ViiV Healthcare Research Triangle Park, NC 27709. by: GlaxoSmithKline Research Triangle Park, NC 27709 Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc, Basingstoke, UK Revised: Mar 2017
Included as part of the PRECAUTIONS section.
PRECAUTIONS Hypersensitivity ReactionsHypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ.
AbacavirSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir containing regimens. See full prescribing information for ZIAGEN® (abacavir).
Abacavir hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.
Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:
Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY® in Phase 3 clinical trials. Discontinue TRIUMEQ 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 TRIUMEQ or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.
Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir-or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to a hypersensitivity reaction.
Lactic Acidosis And Severe Hepatomegaly With SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for ZIAGEN (abacavir) and EPIVIR® (lamivudine). Treatment with TRIUMEQ should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Patients With Hepatitis B Or C Virus Co-infection Effects On Serum Liver BiochemistriesPatients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ. See full prescribing information for TIVICAY® (dolutegravir). 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. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TRIUMEQ are recommended in patients with underlying hepatic disease such as hepatitis B or C.
Posttreatment Exacerbations Of HepatitisClinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
Emergence Of Lamivudine-Resistant HBVSafety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR-HBV® (lamivudine).
Use With Interferon-And Ribavirin-Based RegimensPatients receiving interferon alfa with or without ribavirin and TRIUMEQ should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR (lamivudine). Discontinuation of TRIUMEQ should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).
Immune Reconstitution SyndromeImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIUMEQ. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Fat RedistributionRedistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Myocardial InfarctionIn a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).
Related Products That Are Not RecommendedTRIUMEQ contains fixed doses of an INSTI (dolutegravir) and 2 nucleoside analogue reverse transcriptase inhibitors (abacavir and lamivudine); concomitant administration of TRIUMEQ with other products containing abacavir or lamivudine is not recommended.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide).
Drug InteractionsDo not coadminister TRIUMEQ with dofetilide (TIKOSYN®) because the interaction between dofetilide and dolutegravir can result in potentially life-threatening adverse events. Patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.
Hypersensitivity ReactionInform patients:
Inform patients that they should not take TRIUMEQ with ATRIPLA, COMBIVIR® , COMPLERA®, DUTREBIS™, EMTRIVA®, EPIVIR, EPIVIR-HBV, EPZICOM, STRIBILD® , TRIZIVIR, TRUVADA®, or ZIAGEN.
Lactic Acidosis/HepatomegalyInform patients that some HIV medicines, including TRIUMEQ, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).
Patients With Hepatitis B Or C Co-infectionPatients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ and advise patients to have laboratory testing before and during therapy.
Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician.
Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.
Immune Reconstitution SyndromeIn some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection.
Redistribution/Accumulation Of Body FatInform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Information About HIV-1 InfectionTRIUMEQ is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Advise patients to remain under the care of a physician when using TRIUMEQ.
Advise patients to take all HIV medications exactly as prescribed.
Advise patients to avoid doing things that can spread HIV-1 infection to others.
Advise patients not to re-use or share needles or other injection equipment.
Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Female patients should be advised not to breastfeed because it is not known if TRIUMEQ can be passed to your baby in your breast milk and whether it could harm your baby. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Instruct patients to read the Medication Guide before starting TRIUMEQ and to reread it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 4 hours of the time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.
Instruct patients to store TRIUMEQ in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility CarcinogenicityDolutegravir: Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26-fold higher than those in humans at the recommended dose of 50 mg once daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17-fold and 30-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg once daily.
Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 7 to 28 times the human exposure at the recommended dose of 600 mg.
Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose of 300 mg.
MutagenicityDolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.
Abacavir: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.
Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.
Impairment Of FertilityDolutegravir, abacavir, or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44, 9, or 112 times (respectively) higher than the exposures in humans at the doses of 50 mg, 600 mg, and 300 mg (respectively).
Use In Specific Populations PregnancyPregnancy 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 RegistryTo 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 DataDolutegravir: 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 MothersThe 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.
DolutegravirStudies 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.
AbacavirAbacavir is excreted in the milk of lactating rats.
LamivudineLamivudine is excreted in human breast milk.
Pediatric UseSafety and effectiveness of TRIUMEQ in pediatric patients have not been established.
Geriatric UseClinical 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.
Patients With Impaired Renal FunctionTRIUMEQ 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.
Patients With Impaired Hepatic FunctionTRIUMEQ 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.
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.
Screen for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ.
Recommended DosageTRIUMEQ is a fixed-dose combination product 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.
Dosage Recommendation With Certain Concomitant MedicationsThe dolutegravir dose (50 mg) in TRIUMEQ is insufficient when coadministered with medications listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.
Table 1: Dosing Recommendations for TRIUMEQ with
Coadministered Medications
| Coadministered Drug | Dosing Recommendation |
| Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin | The recommended dolutegravir dosage regimen is 50 mg twice daily. An additional dolutegravir 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken. |
Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in:
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.
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 | ||
| Cmax | AUC | Cτ or C24 | |||
| Daclatasvir 60 mg once daily | 50 mg once daily | 12 | 1.03 (0.84 to 1.25) |
0.98 (0.83 to 1.15) |
1.06 (0.88 to 1.29) |
| 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 | 15a | 1.66 (1.53 to 1.81) |
1.79 (1.65 to 1.93) |
_ |
| Metformin 500 mg twice daily | 50 mg twice daily | 15a | 2.11 (1.91 to 2.33) |
2.45 (2.25 to 2.66) |
_ |
| Methadone 16 to 150 mg | 50 mg twice daily | 11 | 1.00 (0. 94 to 1.06) |
0.98 (0.91 to 1.06) |
0.99 (0.91 to 1.07) |
| Midazolam 3 mg | 25 mg once daily | 10 | _ | 0.95 (0.79 to 1.15) |
_ |
| Norelgestromin 0.25 mg | 50 mg twice daily | 15 | 0.89 (0.82 to 0.97) |
0.98 (0.91 to 1.04) |
0.93 (0.85 to 1.03) |
| Rilpivirine 25 mg once daily | 50 mg once daily | 16 | 1.10 (0.99 to 1.22) |
1.06 (0.98 to 1.16) |
1.21 (1.07 to 1.38) |
| 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 | ||
| Cmax | AUC | Cτ or C24 | |||
| Atazanavir 400 mg once daily | 30 mg once daily | 12 | 1.50 (1.40 to 1.59) |
1.91 (1.80 to 2.03) |
2.80 (2.52 to 3.11) |
| Atazanavir/ritonavir 300/100 mg once daily | 30 mg once daily | 12 | 1.34 (1.25 to 1.42) |
1.62 (1.50 to 1.74) |
2.21 (1.97 to 2.47) |
| Darunavir/ritonavir 600/100 mg twice daily | 30 mg once daily | 15 | 0.89 (0.83 to 0.97) |
0.78 (0.72 to 0.85) |
0.62 (0.56 to 0.69) |
| Efavirenz 600 mg once daily | 50 mg once daily | 12 | 0.61 (0.51 to 0.73) |
0.43 (0.35 to 0.54) |
0.25 (0.18 to 0.34) |
| Etravirine 200 mg twice daily | 50 mg once daily | 16 | 0.48 (0.43 to 0.54) |
0.29 (0.26 to 0.34) |
0.12 (0.09 to 0.16) |
| Etravirine + darunavir/ritonavir 200 mg + 600/100 mg twice daily | 50 mg once daily | 9 | 0.88 (0.78 to 1.00) |
0.75 (0.69 to 0.81) |
0.63 (0.52 to 0.76) |
| Etravirine + lopinavir/ritonavir 200 mg + 400/100 mg twice daily | 50 mg once daily | 8 | 1.07 (1.02 to 1.13) |
1.11 (1.02 to 1.20) |
1.28 (1.13 to 1.45) |
| Fosamprenavir/ritonavir 700 mg /100 mg twice daily | 50 mg once daily | 12 | 0.76 (0.63 to 0.92) |
0.65 (0.54 to 0.78) |
0.51 (0.41 to 0.63) |
| Lopinavir/ritonavir 400/100 mg twice daily | 30 mg once daily | 15 | 1.00 (0.94 to 1.07) |
0.97 (0.91 to 1.04) |
0.94 (0.85 to 1.05) |
| Rilpivirine 25 mg once daily | 50 mg once daily | 16 | 1.13 (1.06 to 1.21) |
1.12 (1.05 to 1.19) |
1.22 (1.15 to 1.30) |
| Tenofovir 300 mg once daily | 50 mg once daily | 15 | 0.97 (0.87 to 1.08) |
1.01 (0.91 to 1.11) |
0.92 (0.82 to 1.04) |
| Tipranavir/ritonavir 500/200 mg twice daily | 50 mg once daily | 14 | 0.54 (0.50 to 0.57) |
0.41 (0.38 to 0.44) |
0.24 (0.21 to 0.27) |
| Antacid (Maalox®) simultaneous administration | 50 mg single dose | 16 | 0.28 (0.23 to 0.33) |
0.26 (0.22 to 0.32) |
0.26 (0.21 to 0.31) |
| Antacid (Maalox®) 2 h after dolutegravir | 50 mg single dose | 16 | 0.82 (0.69 to 0.98) |
0.74 (0.62 to 0.90) |
0.70 (0.58 to 0.85) |
| Boceprevir 800 mg every 8 h | 50 mg once daily | 13 | 1.05 (0.96 to 1.15) |
1.07 (0.95 to 1.20) |
1.08 (0.91 to 1.28) |
| Calcium carbonate 1,200 mg simultaneous administration (fasted) | 50 mg single dose | 12 | 0.63 (0.50 to 0.81) |
0.61 (0.47 to 0.80) |
0.61 (0.47 to 0.80) |
| Calcium carbonate 1,200 mg simultaneous administration (fed) | 50 mg single dose | 11 | 1.07 (0.83 to 1.38) |
1.09 (0.84 to 1.43) |
1.08 (0.81 to 1.42) |
| Calcium carbonate 1,200 mg 2 h after dolutegravir | 50 mg single dose | 11 | 1.00 (0.78 to 1.29) |
0.94 (0.72 to 1.23) |
0.90 (0.68 to 1.19) |
| Carbamazepine 300 mg twice daily | 50 mg once daily | 16c | 0.67 (0.61 to 0.73) |
0.51 (0.48 to 0.55) |
0.27 (0.24 to 0.31) |
| Daclatasvir 60 mg once daily | 50 mg once daily | 12 | 1.29 (1.07 to 1.57) |
1.33 (1.11 to 1.59) |
1.45 (1.25 to 1.68) |
| Ferrous fumarate 324 mg simultaneous administration (fasted) | 50 mg single dose | 11 | 0.43 (0.35 to 0.52) |
0.46 (0.38 to 0.56) |
0.44 (0.36 to 0.54) |
| Ferrous fumarate 324 mg simultaneous administration (fed) | 50 mg single dose | 11 | 1.03 (0.84 to 1.26) |
0.98 (0.81 to 1.20) |
1.00 (0.81 to 1.23) |
| Ferrous fumarate 324 mg 2 h after dolutegravir | 50 mg single dose | 10 | 0.99 (0.81 to 1.21) |
0.95 (0.77 to 1.15) |
0.92 (0.74 to 1.13) |
| Multivitamin (One-A-Day®) simultaneous administration | 50 mg single dose | 16 | 0.65 (0.54 to 0.77) |
0.67 (0.55 to 0.81) |
0.68 (0.56 to 0.82) |
| Omeprazole 40 mg once daily | 50 mg single dose | 12 | 0.92 (0.75 to 1.11) |
0.97 (0.78 to 1.20) |
0.95 (0.75 to 1.21) |
| Prednisone 60 mg once daily with taper | 50 mg once daily | 12 | 1.06 (0.99 to 1.14) |
1.11 (1.03 to 1.20) |
1.17 (1.06 to 1.28) |
| Rifampina 600 mg once daily | 50 mg twice daily | 11 | 0.57 (0.49 to 0.65) |
0.46 (0.38 to 0.55) |
0.28 (0.23 to 0.34) |
| Rifampinb 600 mg once daily | 50 mg twice daily | 11 | 1.18 (1.03 to 1.37) |
1.33 (1.15 to 1.53) |
1.22 (1.01 to 1.48) |
| Rifabutin 300 mg once daily | 50 mg once daily | 9 | 1.16 (0.98 to 1.37) |
0.95 (0.82 to 1.10) |
0.70 (0.57 to 0.87) |
| a Comparison is rifampin taken with
dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. c The number of subjects represents the maximum number of subjects that were evaluated. |
Abacavir or Lamivudine: The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities.
Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.
Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.
Methadone: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%). The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.
Abacavir, Lamivudine, Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.
Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).
The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 9.
Table 9: Effect of Coadministered Drugs on Abacavir or
Lamivudine
| Coadministered Drug and Dose | Drug and Dose | n | Concentrations of Abacavir or Lamivudine | Concentration of Coadministered Drug | |
| AUC | Variability | ||||
| Ethanol 0.7 g/kg | Abacavir Single 600 mg | 24 | ↑41% | 90% CI: 35% to 48% | ↔a |
| Nelfinavir 750 mg every 8 h x 7 to 10 days | Lamivudine Single 150 mg | 11 | ↑10% | 95% CI: 1% to 20% | ↔ |
| Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days | Lamivudine Single 300 mg | 14 | ↑43% | 90% CI: 32% to 55% | ↔ |
| ↑ = Increase; ↔ = no significant change; AUC
= area under the concentration versus time curve; CI = Confidence interval. a The drug-drug interaction was only evaluated in males. |
