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部份中文固定剂量复方制剂Triumeq处方资料（仅供参考）
TRIUMEQ, a combination of dolutegravir (integrase strand transfer inhibitor [INSTI]), abacavir, and lamivudine (both nucleoside analogue reverse transcriptase inhibitors) is indicated for the treatment of HIV-1 infection. (1) Limitations of Use: • TRIUMEQ alone is not recommended for use in patients with current or past history of resistance to any components of TRIUMEQ. ( 12.4) • TRIUMEQ alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in TRIUMEQ is insufficient in these subpopulations. See the dolutegravir prescribing information. ( 1) DOSAGE AND ADMINISTRATION • Before initiating TRIUMEQ, screen for the HLA‑B*5701 allele because TRIUMEQ contains abacavir. ( 2.1) . • Adults: One tablet daily. May be taken with or without food. ( 2.2) • If dosing with certain UGT1A or CYP3A inducers, then the recommended dolutegravir dosage regimen is 50 mg twice daily. An additional 50-mg dose of dolutegravir, separated by 12 hours from TRIUMEQ, should be taken. ( 2.3) • Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in patients requiring dosage adjustment or patients with hepatic impairment. ( 2.4, 4) DOSAGE FORMS AND STRENGTHS Tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. (3) CONTRAINDICATIONS • Presence of HLA-B*5701 allele. ( 4) • Prior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine. ( 4) • Coadministration with dofetilide. ( 4) • Moderate or severe hepatic impairment. ( 4, 8.7) WARNINGS AND PRECAUTIONS • Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TRIUMEQ is recommended in patients with underlying hepatic disease such as hepatitis B or C. ( 5.3) • Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co‑infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue TRIUMEQ as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.4) • Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. ( 5.5, 5.6) • Administration of TRIUMEQ is not recommended in patients receiving other products containing abacavir or lamivudine. ( 5.8) ADVERSE REACTIONS The most commonly reported adverse reactions of at least moderate intensity and incidence at least 2% (in those receiving TRIUMEQ) were insomnia, headache and fatigue. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Coadministration of TRIUMEQ with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of TRIUMEQ. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3) USE IN SPECIFIC POPULATIONS • Nursing mothers: Breastfeeding is not recommended due to the potential for HIV transmission. ( 8.3) • TRIUMEQ is not recommended in patients with creatinine clearance less than 50 mL per min. ( 8.6) • If a dose reduction of abacavir, a component of TRIUMEQ, is required for patients with mild hepatic impairment, then the individual components should be used. ( 8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 9/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations of Use: • TRIUMEQ alone is not recommended for use in patients with current or past history of resistance to any components of TRIUMEQ [see Microbiology (12.4)]. • TRIUMEQ alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in TRIUMEQ is insufficient in these subpopulations. See full prescribing information for dolutegravir. 2 DOSAGE AND ADMINISTRATION 2.1 Screening for HLA-B*5701 Allele prior to Starting TRIUMEQ Screen for the HLA‑B*5701 allele prior to initiating therapy with TRIUMEQ [see Boxed Warning, Warnings and Precautions (5.1)]. 2.2 Recommended Dosage TRIUMEQ 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. 2.3 Dosage Recommendation with Certain Concomitant Medications The 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
Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in: • patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations (8.6)]. • patients with mild hepatic impairment. TRIUMEQ is contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7)]. 3 DOSAGE FORMS AND STRENGTHS TRIUMEQ tablets are purple, biconvex, oval, and debossed with “572 Trı” 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 [see Description (11)]. 4 CONTRAINDICATION TRIUMEQ is contraindicated in patients: • who have the HLA-B*5701 allele [see Warnings and Precautions (5.1)]. • with prior hypersensitivity reaction to abacavir, dolutegravir [see Warnings and Precautions (5.1)], or lamivudine. • r eceiving 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 [see Drug Interactions (7)]. • with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)]. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ. Abacavir Serious 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 [see Adverse Reactions (6.1)]. 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: • All patients should be screened for the HLA‑ B*5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have a previously documented HLA‑ B*5701 allele assessment. • TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA‑ B*5701‑ positive patients. • Before starting TRIUMEQ, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA‑ B*5701 status. • To reduce the risk of a life‑ threatening hypersensitivity reaction, regardless of HLA‑ B*5701 status, discontinue TRIUMEQ immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). Clinical status, including liver chemistries, should be monitored and appropriate therapy initiated. • If a hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. • 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. • If a hypersensitivity reaction is ruled out, patients may restart TRIUMEQ. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIUMEQ, or any other abacavir-containing product, reintroduction of TRIUMEQ or any other abacavir-containing product is recommended only if medical care can be readily accessed. • A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill. Dolutegravir 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. 5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic 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). 5.3 Patients with Hepatitis B or C Virus Co-infection Effects on Serum Liver Biochemistries Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ [see Adverse Reactions (6.1)]. 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 Hepatitis Clinical 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 HBV Safety 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). 5.4 Use with Interferon- and Ribavirin-based Regimens Patients 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). 5.5 Immune Reconstitution Syndrome Immune 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. 5.6 Fat Redistribution Redistribution/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. 5.7 Myocardial Infarction In 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). 5.8 Related Products that are Not Recommended TRIUMEQ 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. 6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Serious and sometimes fatal hypersensitivity reaction [see Boxed Warning, Warnings and Precautions (5.1)]. • Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.2)]. • Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see Warnings and Precautions (5.3)]. • Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3)]. • Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.4)]. • Immune reconstitution syndrome [see Warnings and Precautions (5.5)]. • Fat redistribution [see Warnings and Precautions (5.6)]. • Myocardial infarction [see Warnings and Precautions (5.7)]. 6.1 Clinical Trials Experience 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 Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ [see Boxed Warning, Warnings and Precautions (5.1)]. 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 Reactions In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ [see Warnings and Precautions (5.1)]. 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 TRIUMEQ The 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). Through 96 weeks, the rate of adverse events leading to discontinuation was 3% in subjects receiving TIVICAY + EPZICOM and 12% 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 96 Analysis)
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 96 Analysis)
Table 4. Mean Change from Baseline in Fasted Lipid Values in Treatment-naïve Subjects in SINGLE (Week 96 Analysisa)
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), 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 24 to 96 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.32 mg per dL to 0.59 mg per dL) was observed after 96 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. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. 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. Abacavir and/or Lamivudine: 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: Muscle weakness, CPK elevation, 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)]. 7 DRUG INTERACTIONS 7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin) [see Contraindications (4), Drug Interactions (7.3)]. In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, 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: 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. 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma 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, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. 7.3 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
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. 8 USE IN SPECIFIC POPULATIONS 8.1 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. 8.3 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. 8.4 Pediatric Use Safety and effectiveness of TRIUMEQ in pediatric patients have not been established [see Clinical Pharmacology (12.3)]. 8.5 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)]. 8.6 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)]. 8.7 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)]. 10 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. 11 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 (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). It has a molecular formula of (C14H18N6O)2•H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula:
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 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 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. 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
Table 8. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir
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%) [see Drug Interactions (7.3)]. 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 [see Warnings and Precautions (5.4)]. 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 h). 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
a The drug-drug interaction was only evaluated in males. 12.4 Microbiology Mechanism of Action Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM. Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity in Cell Culture Dolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of drug necessary to effect viral replication by 50 percent (EC50) values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a median EC50 value of 0.54 nM (range: 0.41 to 0.60 nM) in a viral susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV‑1 clinical isolates with median EC50 values of 0.18 nM (n = 3, range: 0.09 to 0.5 nM), 0.08 nM (n = 5, range: 0.05 to 2.14 nM) 0.12 nM (n = 4, range: 0.05 to 0.51 nM), 0.17 nM (n = 3, range: 0.16 to 0.35 nM), 0.24 nM (n = 3, range: 0.09 to 0.32 nM), 0.17 nM (range: 0.07 to 0.44 nM), 0.2 nM (n = 3, range: 0.02 to 0.87 nM), and 0.42 nM (n = 3, range: 0.41 to 1.79 nM) for clades A, B, C, D, E, F, and G, and group O viruses, respectively. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM. Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including in primary monocytes/macrophages and PBMCs. EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV‑1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV‑2 isolates (n = 4), ranged from 0.024 to 0.49 microM. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV‑1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV‑2 isolates (n = 4) from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells. Antiviral Activity in Combination with Other Antiviral Agents Neither dolutegravir, abacavir, nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir), TIVICAY (dolutegravir), and EPIVIR (lamivudine). Resistance in Cell Culture Dolutegravir: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV‑1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Abacavir and Lamivudine: HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility. Resistance in Clinical Subjects Dolutegravir: No subjects in the treatment arm receiving dolutegravir + EPZICOM of SINGLE (treatment-naïve trial) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 8 with HIV-1 RNA greater than 400 copies per mL at failure or last visit through Week 96 and having resistance data). One subject in SINGLE with 275 copies per mL HIV-1 RNA had a treatment-emergent integrase substitution (E157Q/P) detected at Week 24, but no corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of TRIUMEQ, was observed in the arm receiving dolutegravir + EPZICOM in the SINGLE trial. Cross-resistance Dolutegravir: The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively. Abacavir and Lamivudine: Cross‑resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Dolutegravir: 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. Mutagenicity Dolutegravir: 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 Fertility Dolutegravir, 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). 13.2 Animal Toxicology and/or Pharmacology Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 21 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined. 14 CLINICAL STUDIES 14.1 Adult Subjects The efficacy of TRIUMEQ is supported by data from a randomized, controlled trial in antiretroviral treatment-naïve subjects, SINGLE (ING114467) and other trials in treatment-naïve subjects. See full prescribing information for TIVICAY. The efficacy of dolutegravir, in combination with at least two active background regimens in treatment-experienced, INSTI-naïve subjects is supported by data from SAILING (ING111762) (refer to the prescribing information for TIVICAY). Treatment-naïve Subjects In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV‑1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups. Week 96 outcomes for SINGLE are provided in Table 10. Table 10. Virologic Outcomes of Randomized Treatment in SINGLE at 96 Weeks (Snapshot Algorithm)
b Includes subjects who discontinued prior to Week 96 for lack or loss of efficacy, and subjects who were HIV-1 RNA greater than or equal to 50 copies per mL in the Week 96 window. c Includes subjects who discontinued due to an adverse event or death at any time point from Day 1 through the Week 96 window if this resulted in no virologic data on treatment during the Week 96 window. d Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation. e The proportion of subjects who had no virologic data due to reasons such as withdrew consent, lost to follow-up, moved, and protocol deviation was 10% (TIVICAY + EPZICOM) and 6% (ATRIPLA) in the greater than 100,000–copies-per- mL group and 8% and 9% (respectively) in the less than or equal to 100,000–copies-per-mL group. Treatment differences were maintained across baseline characteristics including CD4+ cell count, age, gender, and race. The adjusted mean changes in CD4+ cell counts from baseline were 325 cells per mm3 in the group receiving TIVICAY + EPZICOM and 281 cells per mm3 for the ATRIPLA group at 96 weeks. The adjusted difference between treatment arms and 95% CI was 44.0 cells per mm3 (14.3 cells per mm3, 73.6 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV‑1 RNA, baseline CD4+ cell count, and multiplicity). Treatment-experienced In SAILING, there were 715 subjects included in the efficacy and safety analyses (see full prescribing information for TIVICAY). At Week 48, 71% of subjects randomized to TIVICAY plus background regimen versus 64% of subjects randomized to raltegravir plus background regimen had HIV‑1 RNA less than 50 copies per mL (treatment difference and 95% CI: 7.4% [0.7%, 14.2%]). 16 HOW SUPPLIED/STORAGE AND HANDLING TRIUMEQ 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 Trı” 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). [See USP Controlled Room Temperature]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2997739a-aa91-42aa-a206-a70e2db7b84f
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