HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TRIZIVIR safely and effectively. See full prescribing information for TRIZIVIR.
TRIZIVIR (abacavir, lamivudine, and zidovudine) tablets, for oral use
Initial U.S. Approval: 2000
WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B
See full prescribing information for complete boxed warning.
Hypersensitivity Reactions
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Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. (5.1)
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Hypersensitivity to abacavir is a multi-organ clinical syndrome. (5.1)
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Patients who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir. (5.1)
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TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. (4)
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Discontinue TRIZIVIR as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue TRIZIVIR if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1)
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Following a hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavir-containing product. (5.1)
Hematologic Toxicity
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Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, a component of TRIZIVIR. ( 5.2 )
Myopathy
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Symptomatic myopathy associated with prolonged use of zidovudine. (5.3)
Lactic Acidosis and Severe Hepatomegaly with Steatosis
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Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.4)
Exacerbations of Hepatitis B
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Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIZIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.5)
RECENT MAJOR CHANGES
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Boxed Warning
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09/2015
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Indications and Usage (1)
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09/2015
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Dosage and Administration (2.1, 2.3)
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09/2015
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Contraindications (4)
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09/2015
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Warnings and Precautions (5)
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09/2015
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INDICATIONS AND USAGE
TRIZIVIR, a combination of abacavir, lamivudine, and zidovudine, each nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection. (1)
DOSAGE AND ADMINISTRATION
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Before initiating TRIZIVIR, screen for the HLA‑B*5701 allele because TRIZIVIR contains abacavir. ( 2.1)
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Adults and pediatric patients weighing at least 40 kg: 1 tablet twice daily. ( 2.2)
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Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended in patients requiring dosage adjustment or patients with hepatic impairment. ( 2.3, 4)
DOSAGE FORMS AND STRENGTHS
Tablets: 300 mg abacavir, 150 mg lamivudine, and 300 mg zidovudine. (3)
CONTRAINDICATIONS
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Presence of HLA-B*5701 allele. ( 4)
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Prior hypersensitivity reaction to abacavir, lamivudine, or zidovudine ( 4)
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Moderate or severe hepatic impairment. ( 4, 8.7)
WARNINGS AND PRECAUTIONS
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Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue TRIZIVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. ( 5.6)
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Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. ( 5.6)
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Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. ( 5.7, 5.8)
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TRIZIVIR should not be administered with other products containing abacavir, lamivudine, or zidovudine; or with emtricitabine-containing products. ( 5.11)
ADVERSE REACTIONS
The most commonly reported adverse reactions (incidence at least 10%) in clinical trials were nausea, headache, malaise and fatigue, and nausea and vomiting. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
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Methadone: An increased methadone dose may be required in a small number of patients. ( 7.1)
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Agents antagonistic with zidovudine: Concomitant use should be avoided ( 7.2).
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Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. ( 7.2))
USE IN SPECIFIC POPULATIONS
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Lactation: Breastfeeding not recommended. ( 8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection.
Limitations of Use:
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Limited data exist on the use of TRIZIVIR alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2.1 Screening for HLA-B*5701 Allele prior to Starting TRIZIVIR
Screen for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR [see Boxed Warning, Warnings andPrecautions (5.1)].
2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg
The recommended dosage of TRIZIVIR is one tablet taken orally twice daily with or without food.
2.3 Not Recommended Due to Lack of Dosage Adjustment
Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended in:
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pediatric patients who weigh less than 40 kg [see Use in Specific Populations (8.4)].
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patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations (8.6)].
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patients with mild hepatic impairment. TRIZIVIR is contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7)].
3 DOSAGE FORMS AND STRENGTHS
TRIZIVIR tablets contain 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green, capsule-shaped, film-coated, and imprinted with “GX LL1” on one side with no markings on the reverse side.
4 CONTRAINDICATIONS
TRIZIVIR is contraindicated in patients:
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who have the HLA‑B*5701 allele [see Warnings and Precautions (5.1)].
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with prior hypersensitivity reaction to abacavir [see Warnings and Precautions (5.1)], lamivudine, or zidovudine.
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with moderate or severe hepatic impairment [see Use in Specific Populations(8.7)].
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1)]. Patients who carry the HLA‑B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA‑B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA‑B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA‑B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.
Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:
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All patients should be screened for the HLA‑B*5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLA‑B*5701 allele assessment.
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TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA‑B*5701-positive patients.
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Before starting TRIZIVIR, review medical history for prior exposure to any abacavir-containing product. NE VER restart TRIZIVIR or any other abacavir‑containing product following a hypersensitivity reaction to abacavir, regardless of HLA‑B*5701 status.
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To reduce the risk of a life‑threatening hypersensitivity reaction, regardless of HLA‑B*5701 status, discontinue TRIZIVIR 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).
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If a hypersensitivity reaction cannot be ruled out, do not restart TRIZIVIR or any other abacavir‑containing products because more severe symptoms, which may include life‑threatening hypotension and death, can occur within hours.
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If a hypersensitivity reaction is ruled out, patients may restart TRIZIVIR. 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 TRIZIVIR or any other abacavir-containing product is recommended only if medical care can be readily accessed.
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A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.
5.2 Hematologic Toxicity/Bone Marrow Suppression
Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. TRIZIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm3 or hemoglobin less than 9.5 grams per dL [see Adverse Reactions (6.1)].
Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with TRIZIVIR. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.
5.3 Myopathy
Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with TRIZIVIR.
5.4 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), EPIVIR® (lamivudine), and RETROVIR® (zidovudine). Treatment with TRIZIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
5.5 Patients with Hepatitis B Virus Co-infection
Posttreatment Exacerbations of Hepatitis
Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
Emergence of Lamivudine-resistant HBV
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).
5.6 Use with Interferon- and Ribavirin-based Regimens
Patients receiving interferon alfa with or without ribavirin and TRIZIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Discontinuation of TRIZIVIR 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).
Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and TRIZIVIR is not advised.
5.7 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIZIVIR. 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 eva luation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.8 Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
5.9 Myocardial Infarction
In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).
5.10 TherapyExperienced Patients
In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients [see Microbiology (12.4)].
5.11 Related Products that are Not Recommended
TRIZIVIR is a fixed‑dose combination of 3 nucleoside analogue reverse transcriptase inhibitors (abacavir, lamivudine, and zidovudine). Concomitant administration of TRIZIVIR with other products containing abacavir, lamivudine, or zidovudine is not recommended. In addition, do not administer TRIZIVIR in combination with products containing emtricitabine.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
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Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].
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Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.2)].
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Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.3)].
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Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.4)].
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Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.5)].
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Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.6)].
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Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)].
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Immune reconstitution syndrome [see Warnings and Precautions (5.7)].
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Fat redistribution [see Warnings and Precautions (5.8)].
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Myocardial infarction [see Warnings and Precautions (5.9)].
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Serious and Fatal Abacavir-associated Hypersensitivity Reactions
In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR [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).
Additional Adverse Reactions with Use of TRIZIVIR
Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1.
Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.
Laboratory Abnormalities
Laboratory abnormalities in CNA3005 are listed in Table 2.
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