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Triumeq

Generic Name: abacavir sulfate, dolutegravir sodium, lamivudine
Dosage Form: tablet, film coated

WARNING: HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of Triumeq® (abacavir, dolutegravir, and lamivudine). Patients who carry the HLAB*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLAB*5701 allele [see Warnings and Precautions (5.1)].

Triumeq is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLAB*5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLAB*5701 allele prior to initiating therapy with Triumeq or reinitiation of therapy with Triumeq, unless patients have a previously documented HLAB*5701 allele assessment. Discontinue Triumeq immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)].

Following a hypersensitivity reaction to Triumeq, NEVER restart Triumeq or any other abacavircontaining product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1)].

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 alone or in combination, including abacavir, lamivudine, and other antiretrovirals. Discontinue Triumeq if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.2)].

Exacerbations of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of Triumeq. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue Triumeq and are co-infected with HIV-1 and HBV. If appropriate, initiation of antihepatitis B therapy may be warranted [see Warnings and Precautions (5.3)].

Indications and Usage for Triumeq

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.

Triumeq Dosage and Administration

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)].

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.

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

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.

Not Recommended Due to Lack of Dosage Adjustment

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)].

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)].

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.
receiving dofetilide, due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir [see Drug Interactions (7)].
with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].

Warnings and Precautions

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 HLAB*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLAB*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 HLAB*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 HLAB*5701 allele prior to initiating therapy with Triumeq or reinitiation of therapy with Triumeq, unless patients have a previously documented HLAB*5701 allele assessment.
Triumeq is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLAB*5701positive 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 HLAB*5701 status.
To reduce the risk of a lifethreatening hypersensitivity reaction, regardless of HLAB*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, 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.

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).

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 LamivudineResistant 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).

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).

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.

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.

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).

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.

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)].

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) (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 Trials

The following adverse reactions occurred in less than 2% of treatment-naïve or treatment-experienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship.

Gastrointestinal Disorders: Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting.

General Disorders: Fever, lethargy.

Hepatobiliary Disorders: Hepatitis.

Metabolism and Nutrition Disorders: Anorexia, hypertriglyceridemia.

Musculoskeletal Disorders: Arthralgia, myositis.

Nervous: Somnolence.

Psychiatric: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder.

Renal and Urinary Disorders: Renal impairment.

Skin and Subcutaneous Tissue Disorders: Pruritus.

Laboratory Abnormalities

Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4.

Table 3. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naïve Subjects in SINGLE (Week 144 Analysis)

Laboratory Abnormality

TIVICAY + EPZICOM

Once Daily

(n = 414)

ATRIPLA

Once Daily

(n = 419)

ALT

Grade 2 (>2.5-5.0 x ULN)

3%

5%

Grade 3 to 4 (>5.0 x ULN)

1%

<1%

AST

Grade 2 (>2.5-5.0 x ULN)

3%

4%

Grade 3 to 4 (>5.0 x ULN)

1%

3%

Creatine kinase

Grade 2 (6.0-9.9 x ULN)

5%

3%

Grade 3 to 4 (≥10.0 x ULN)

7%

8%

Hyperglycemia

Grade 2 (126-250 mg/dL)

9%

6%

Grade 3 (>250 mg/dL)

2%

<1%

Lipase

Grade 2 (>1.5-3.0 x ULN)

11%

11%

Grade 3 to 4 (>3.0 ULN)

5%

4%

Total neutrophils

Grade 2 (0.75-0.99 x 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-infection

In SINGLE, the pivotal Phase 3 trial, subjects with hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with hepatitis B co-infection were excluded. Overall, the safety profile in subjects with hepatitis C virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis C virus co-infection for both treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV mono-infected subjects receiving Triumeq were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively [see Warnings and Precautions (5.3)]. See also full prescribing information for TIVICAY.

Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.25 mg per dL to 0.81 mg per dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects.

Abacavir and Lamivudine

Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other antiretroviral treatment) were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. 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)].

Drug Interactions

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: daclatasvir, tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir.

Effect of Other Agents on the Pharmacokinetics of Dolutegravir

Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir.

Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (Table 5) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

In vitro, dolutegravir was not a substrate of OATP1B1, or OATP1B3.

Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.

Established and Other Potentially Significant Drug Interactions

There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets.

Information regarding potential drug interactions with dolutegravir (Table 5) and abacavir are provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [See Clinical Pharmacology (12.3).]

Table 5. Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions

Concomitant Drug Class:
Drug Name

Effect on Concentration

Clinical Comment

HIV-1 Antiviral Agents

Non-nucleoside reverse transcriptase inhibitor:

Etravirinea

↓Dolutegravir

Use of Triumeq with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.

Non-nucleoside reverse transcriptase inhibitor:

Efavirenza

↓Dolutegravir

Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from Triumeq.

Non-nucleoside reverse transcriptase inhibitor:

Nevirapine

↓Dolutegravir

Avoid coadministration with Triumeq because there are insufficient data to make dosing recommendations.

Protease inhibitor:

Fosamprenavir/ritonavira
Tipranavir/ritonavira

↓Dolutegravir

Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from Triumeq.

Other Agents

Carbamazepinea

↓Dolutegravir

Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from Triumeq.

Oxcarbazepine
Phenytoin
Phenobarbital
St. John’s wort (Hypericum perforatum)

↓Dolutegravir

Avoid coadministration with Triumeq because there are insufficient data to make dosing recommendations.

Medications containing polyvalent cations
(e.g., Mg or Al):

Cation-containing antacidsa or laxatives
Sucralfate
Buffered medications

↓Dolutegravir

Administer Triumeq 2 hours before or 6 hours after taking medications containing polyvalent cations.

Oral calcium and iron supplements, including multivitamins containing calcium or irona

↓Dolutegravir

Administer Triumeq 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, Triumeq and supplements containing calcium or iron can be taken together with food.

Metformina

↑Metformin

With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or Triumeq. When stopping Triumeq, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of Triumeq is recommended.

Rifampina

↓Dolutegravir

Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from Triumeq.

aSee Clinical Pharmacology (12.3) Table 8 or Table 9 for magnitude of interaction.

Methadone

Abacavir: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3)]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. There are no adequate and well‑controlled trials in pregnant women. Reproduction studies with the components of Triumeq have been performed in animals (see Dolutegravir, Abacavir, and Lamivudine sections below). Animal reproduction studies are not always predictive of human response. Triumeq should be used during pregnancy only if the potential benefit outweigh the risks.

Antiretroviral Pregnancy Registry

To monitor maternal‑fetal outcomes of pregnant women exposed to Triumeq or other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1‑800‑258‑4263.

Animal Data

Dolutegravir: Reproduction studies performed in rats and rabbits at doses up to 50 times the human dose of 50 mg once daily have revealed no evidence of impaired fertility or harm to the fetus due to dolutegravir.

Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 50 times the 50-mg once-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity.

Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.74 times the 50-mg once-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg.

Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown‑rump length) were observed in rats at a dose which produced 28 times the human exposure for a dose of 600 mg based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 7 times the human exposure at the recommended dose based on AUC.

Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 32 times the human exposure for a dose of 300 mg. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at plasma levels up to 32 times those in humans.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV‑1 infection.

Because of both the potential for HIV‑1 transmission and the potential for serious adverse reactions in nursing infants, instruct mothers not to breastfeed.

Dolutegravir

Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human breast milk.

Abacavir

Abacavir is excreted in the milk of lactating rats.

Lamivudine

Lamivudine is excreted in human breast milk.

Pediatric Use

Safety and effectiveness of Triumeq in pediatric patients have not been established [see Clinical Pharmacology (12.3)].

Geriatric Use

Clinical trials of abacavir, dolutegravir, or lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of Triumeq in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

Patients with Impaired Renal Function

Triumeq is not recommended for patients with creatinine clearance less than 50 mL per min because Triumeq is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of Triumeq, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used [see Clinical Pharmacology (12.3)].

Patients with Impaired Hepatic Function

Triumeq is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of Triumeq, is required for patients with mild hepatic impairment (Child-Pugh Score A), then the individual components should be used [see Clinical Pharmacology (12.3)].

The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Score B) or severe (Child-Pugh Score C) hepatic impairment; therefore, Triumeq is contraindicated in these patients [see Contraindications (4)].

Overdosage

There is no known specific treatment for overdose with Triumeq. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Dolutegravir

As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Abacavir

It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Lamivudine

Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Triumeq Description

Triumeq

Triumeq contains an INSTI (dolutegravir) and 2 nucleoside analogues (abacavir and lamivudine) with inhibitory activity against HIV.

Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine. Triumeq tablets are purple, biconvex, oval, debossed with “572 Trı” on one side and contain the inactive ingredients D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film-coating (OPADRY® II Purple 85F90057) contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide.

Abacavir Sulfate

The chemical name of abacavir sulfate is (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:

Abacavir sulfate is a white to off-white solid and is soluble in water.

Dolutegravir

The chemical name of dolutegravir sodium is sodium (4R,12aS) - 9 - {[(2,4 - difluorophenyl)methyl]carbamoyl} - 4 - methyl - 6,8 - dioxo - 3,4,6,8,12,12a - hexahydro - 2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 g per mol. It has the following structural formula:

Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.

Lamivudine

The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid and is soluble in water.

Triumeq - Clinical Pharmacology

Mechanism of Action

Triumeq is an HIV-1 antiviral agent [see Microbiology (12.4)].

Pharmacodynamics

Effects on Electrocardiogram

A thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated.

In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250‑mg suspension (exposures approximately 3–fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.

Effects on Renal Function

The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

Pharmacokinetics

Pharmacokinetics in Adults

One Triumeq tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n = 62).

Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, 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 (t1/2) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L per hour per kg (mean ± SD).

Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, 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 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

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%) [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 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.

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 = 11 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies per mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of Triumeq, was observed in the arm receiving dolutegravir + EPZICOM in the SINGLE trial through Week 144.

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.

Nonclinical Toxicology

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).

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.

Clinical Studies

Adult Subjects

The efficacy of Triumeq is supported by data from a randomized, controlled trial (double-blind through 96 weeks and open-label phase from 96 to 144 weeks) 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 144 (open-label-phase analysis which followed the Week 96 double-blind phase) outcomes for SINGLE are provided in Table 10.

Table 10. Virologic Outcomes of Randomized Treatment in SINGLE at 144 Weeks (Snapshot Algorithm)

TIVICAY + EPZICOM Once Daily

(n = 414)

ATRIPLA

Once Daily

(n = 419)

HIV1 RNA <50 copies/mL

71%

63%

Treatment differencea

8.3% (95% CI: 2.0%, 14.6%)d

Virologic nonresponse

10%

7%

Data in window not <50 copies/mL

4%

<1%

Discontinued for lack of efficacy

3%

3%

Discontinued for other reasons while not suppressed

3%

4%

No virologic data

18%

30%

Reasons

Discontinued study/study drug due to adverse event or deathb

4%

14%

Discontinued study/study drug for other reasonsc

12%

13%

Missing data during window but on study

2%

3%

Proportion (%) of Subjects with HIV1 RNA <50 copies/mL by Baseline Category

Plasma viral load (copies/mL)

≤100,000

73%

64%

>100,000

69%

61%

Gender

Male

72%

66%

Female

69%

48%

Race

White

72%

71%

African-American/African Heritage/Other

71%

47%

Adjusted for pre-specified stratification factors.

Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window.

Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.

The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%).

Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race. The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm3 in the group receiving TIVICAY + EPZICOM and 332 cells per mm3 for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm3 (15.6 cells per mm3, 78.2 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV‑1 RNA, and baseline CD4+ cell count).

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%]).

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].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Drug Interactions

Do not coadminister Triumeq with dofetilide (TIKOSYN®) because the interaction between dofetilide and dolutegravir can result in potentially life-threatening adverse events [see Contraindications (4)]. Patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.

Hypersensitivity Reaction

Inform patients:

that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of Triumeq, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about Triumeq. The complete text of the Medication Guide is reprinted at the end of this document.
to carry the Warning Card with them.
how to identify a hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].
that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking Triumeq.
that a hypersensitivity reaction can worsen and lead to hospitalization or death if Triumeq is not immediately discontinued.
to not restart Triumeq or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life‑threatening hypotension and death.
that a hypersensitivity reaction is usually reversible if it is detected promptly and Triumeq is stopped right away.
that if they have interrupted Triumeq for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.
to not restart Triumeq or any other abacavir‑containing product without medical consultation and only if medical care can be readily accessed by the patient or others.
to not restart Triumeq or any other dolutegravir-containing product following a hypersensitivity reaction to Triumeq.

Related Products that are Not Recommended

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/Hepatomegaly

Inform patients that some HIV medicines, including Triumeq, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.2)].

Patients with Hepatitis B or C Co-infection

Patients 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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.4)].

Immune Reconstitution Syndrome

In 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 [see Warnings and Precautions (5.5)].

Redistribution/Accumulation of Body Fat

Inform 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 [see Warnings and Precautions (5.6)].

Information about HIV1 Infection

Triumeq 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.

COMBIVIR, EPIVIR, EPZICOM, TIVICAY, Triumeq, TRIZIVIR, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies.

EPIVIR-HBV is a registered trademark of the GSK group of companies.

The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

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

©2016 the ViiV Healthcare group of companies. All rights reserved.

TRM:4PI

MEDICATION GUIDE

Triumeq® (TRI-u-meck)

(abacavir, dolutegravir, and lamivudine)

tablets

What is the most important information I should know about Triumeq?

Triumeq can cause serious side effects, including:

Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with Triumeq and other abacavir-containing products. Your risk of this allergic reaction to abacavir is much higher if you have a gene variation called HLA‑B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.
 
If you get a symptom from 2 or more of the following groups while taking Triumeq, call your healthcare provider right away to find out if you should stop taking Triumeq.
 
                                                                                     Symptom

          Group 1                                     Fever

          Group 2                                     Rash

          Group 3                                     Nausea, vomiting, diarrhea, abdominal (stomach area) pain

          Group 4                                     Generally ill feeling, extreme tiredness, or achiness

          Group 5                                     Shortness of breath, cough, sore throat

 
A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times.
 
If you stop Triumeq because of an allergic reaction, never take Triumeq (abacavir, dolutegravir and lamivudine) or any other abacaviror dolutegravircontaining medicines (EPZICOM®, TIVICAY®, TRIZIVIR®, or ZIAGEN®) again.
 
If you take Triumeq or any other abacavir‑containing medicine again after you have had an allergic reaction, within hours you may get lifethreatening symptoms that may include very low blood pressure or death.
If you stop Triumeq for any other reason, even for a few days, and you are not allergic to Triumeq, talk with your healthcare provider before taking it again. Taking Triumeq again can cause a serious allergic or life‑threatening reaction, even if you never had an allergic reaction to it before.

If your healthcare provider tells you that you can take Triumeq again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.

Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take Triumeq. Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:

         •  feel very weak or tired                                            •  feel cold, especially in your arms and legs

         •  unusual (not normal) muscle pain                             •  feel dizzy or light-headed

         •  trouble breathing                                                     •  have a fast or irregular heartbeat

         •  stomach pain with nausea and vomiting   

Serious liver problems can happen in people who take Triumeq. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:

         •  your skin or the white part of your eyes                  •  loss of appetite for several days or longer

             turns yellow (jaundice)                                           •  nausea

         •  dark or “tea-colored” urine                                    •  pain, aching, or tenderness on the right side

         •  light-colored stools (bowel movements)                      of your stomach area

You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time.

Worsening of hepatitis B virus in people who have HIV-1 infection. If you have Human Immunodeficiency Virus type 1 (HIV-1) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking Triumeq. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death.
Do not run out of Triumeq. Refill your prescription or talk to your healthcare provider before your Triumeq is all gone.
Do not stop Triumeq without first talking to your healthcare provider.
If you stop taking Triumeq, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.
Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with Triumeq and become harder to treat (resistant).
Use with interferon and ribavirinbased regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who were taking antiretroviral medicines, and were also being treated for hepatitis C with interferon with or without ribavirin. If you are taking Triumeq and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms.

What is Triumeq?

Triumeq is a prescription HIV‑1 (Human Immunodeficiency Virus type 1) medicine used alone or with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). Triumeq contains 3 prescription medicines, abacavir (ZIAGEN), dolutegravir (TIVICAY) and lamivudine (EPIVIR®).

 
Triumeq is not for use by itself in people who have or have had resistance to abacavir, dolutegravir, or lamivudine.

Triumeq should not be used in children.

When used alone or with other antiretroviral medicines to treat HIV-1 infection, Triumeq may help:

reduce the amount of HIV-1 in your blood. This is called “viral load”.
increase the number of CD4+ (T) cells in your blood, which help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

Triumeq does not cure HIV-1 infection or AIDS. You must keep taking HIV‑1 medicines to control HIV‑1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others.

Do not share or re-use needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people.

Who should not take Triumeq?

Do not take Triumeq if you:

have a certain type of gene variation called the HLA‑B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with Triumeq.
are allergic to abacavir, dolutegravir, or any of the ingredients in Triumeq. See the end of this Medication Guide for a complete list of ingredients in Triumeq.
take dofetilide (TIKOSYN®). Taking Triumeq and dofetilide (TIKOSYN) can cause side effects that may be life-threatening.
have liver problems.

What should I tell my healthcare provider before taking Triumeq?

Before you take Triumeq, tell your healthcare provider if you:

have been tested and know whether or not you have a particular gene variation called HLA‑B*5701.
have or have had liver problems, including hepatitis B or C virus infection.
have kidney problems.
have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.
drink alcohol or take medicines that contain alcohol.
are pregnant or plan to become pregnant. It is not known if Triumeq will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
 
Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
are breastfeeding or plan to breastfeed. Do not breastfeed if you take Triumeq.
You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medicines interact with Triumeq. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with Triumeq. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take Triumeq with other medicines.

You should not take Triumeq if you also take:

abacavir (EPZICOM, TRIZIVIR, or ZIAGEN)
lamivudine (COMBIVIR®, DUTREBIS™, EPIVIR®, EPIVIR-HBV®, EPZICOM, or TRIZIVIR)
emtricitabine (ATRIPLA®, COMPLERA®, EMTRIVA®,STRIBILD®, or TRUVADA®)

Tell your healthcare provider if you take:

antacids, laxatives, or other medicines that contain aluminum, magnesium, sucralfate (CARAFATE®), or buffered medicines. Triumeq should be taken at least 2 hours before or 6 hours after you take these medicines.
anti-seizure medicines:
oxcarbazepine (TRILEPTAL®)
phenytoin (DILANTIN®, DILANTIN®-125, PHENYTEK®)
phenobarbital
carbamazepine (CARBATROL®, EQUETRO®, TEGRETOL®, TEGRETOL®-XR, TERIL®, EPITOL®)
any other medicine to treat HIV-1
iron or calcium supplements taken by mouth. Supplements containing calcium or iron may be taken at the same time with Triumeq if taken with food. Otherwise, Triumeq should be taken at least 2 hours before or 6 hours after you take these medicines.
medicines used to treat hepatitis virus infections, such as interferon or ribavirin
a medicine that contains metformin
methadone
rifampin (RIFATER®, RIFAMATE®, RIMACTANE®, RIFADIN®)
St. John’s wort (Hypericum perforatum)

How should I take Triumeq?

Take Triumeq exactly as your healthcare provider tells you.
Do not change your dose or stop taking Triumeq without talking with your healthcare provider. If you miss a dose of Triumeq, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.
Stay under the care of a healthcare provider while taking Triumeq.
Triumeq may be taken with or without food.
Do not run out of Triumeq. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.
If you take too much Triumeq, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of Triumeq?

Triumeq can cause serious side effects including:
See “What is the most important information I should know about Triumeq?”
Changes in liver tests. People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver tests during treatment with Triumeq. Your healthcare provider may do tests to check your liver function before and during treatment with Triumeq.
Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking Triumeq.
Changes in body fat can happen in people who take HIV‑1 medicines. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
Heart attack (myocardial infarction). Some HIV-1 medicines including Triumeq may increase your risk of heart attack.

The most common side effects of Triumeq include:

         •  trouble sleeping                             •  tiredness

         •  headache

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Triumeq. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088.

How should I store Triumeq?

Store Triumeq at room temperature between 68°F to 77°F (20°C to 25°C).
Store Triumeq in the original bottle.
Keep the bottle of Triumeq tightly closed and protected from moisture.
The bottle of Triumeq contains a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the bottle. Do not remove the desiccant packet.

Keep Triumeq and all medicines out of the reach of children.

General information about the safe and effective use of Triumeq

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Triumeq for a condition for which it was not prescribed. Do not give Triumeq to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Triumeq that is written for health professionals.

For more information go to www.Triumeq.comor call 1-877-844-8872.

What are the ingredients in Triumeq?

Active ingredients: abacavir, dolutegravir, and lamivudine

Inactive ingredients: D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.

Tablet film‑coating contains: iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol–part hydrolyzed, talc, and titanium oxide.

  Manufactured for:                                              by:

  ViiV Healthcare                                                 GlaxoSmithKline

  Research Triangle Park, NC 27709                   Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc, Basingstoke, UK

COMBIVIR, EPIVIR, EPZICOM, TIVICAY, Triumeq, TRIZIVIR, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies.

EPIVIR-HBV is a registered trademark of the GSK group of companies.

The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

©2016 the ViiV Healthcare group of companies. All rights reserved.

TRM:4MG

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 04/2016

PRINICPAL DISPLAY PANEL

NDC 49702-231-13

Triumeq®

(abacavir, dolutegravir, and lamivudine)

600 mg/50 mg/300 mg

TABLETS

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.

Store in original package at controlled room temperature of 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)(See USP). Keep bottle tightly closed; protect from moisture. Do not remove desiccant.

Do not use if printed safety seal under cap is broken or missing.

See prescribing information for dosage information.

Notice to Authorized Dispenser:

Each time Triumeq is dispensed, give the patient a Medication Guide and Warning Card from the carton.

Rx only

30 Tablets

©2015 the ViiV Healthcare group of companies.

 
10000000137745 Rev. 11/15
Triumeq 
abacavir sulfate, dolutegravir sodium, lamivudine tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:49702-231
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOLUTEGRAVIR SODIUM (DOLUTEGRAVIR) DOLUTEGRAVIR 50 mg
ABACAVIR SULFATE (ABACAVIR) ABACAVIR 600 mg
LAMIVUDINE (LAMIVUDINE) LAMIVUDINE 300 mg
Inactive Ingredients
Ingredient Name Strength
MANNITOL  
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
POVIDONES  
SODIUM STARCH GLYCOLATE TYPE A CORN  
FERROSOFERRIC OXIDE  
FERRIC OXIDE RED  
POLYETHYLENE GLYCOLS  
POLYVINYL ALCOHOL  
TALC  
TITANIUM DIOXIDE  
Product Characteristics
Color PURPLE Score no score
Shape OVAL Size 22mm
Flavor Imprint Code 572;Tri
Contains         
Packaging
# Item Code Package Description
1 NDC:49702-231-13 30 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA205551 08/22/2014
Labeler - ViiV Healthcare Company (027295585)
Revised: 04/2016
 
ViiV Healthcare Company
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