Trizivir Information
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Indications And Usage
Trizivir (Abacavir sulfate,lamivudine,zidovudine) is indicated in combination with other antiretrovirals or alone for the treatment of HIV-1 infection.
Additional important information on the use of Trizivir (Abacavir sulfate,lamivudine,zidovudine) for treatment of HIV-1 infection:
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Dosage And Administration
The recommended oral dose of Trizivir (Abacavir sulfate,lamivudine,zidovudine) is one tablet twice daily.
Trizivir (Abacavir sulfate,lamivudine,zidovudine) is not recommended in adolescents who weigh less than 40 kg because it is a fixed-dose tablet and cannot be dose adjusted.
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Dosage Forms And Strengths
Trizivir (Abacavir sulfate,lamivudine,zidovudine) 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.
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Contraindications
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Tablets are contraindicated in patients with:
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Warnings And Precautions
Serious and sometimes fatal hypersensitivity reactions have been associated with Trizivir (Abacavir sulfate,lamivudine,zidovudine) and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.
HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue Trizivir (Abacavir sulfate,lamivudine,zidovudine) if hypersensitivity cannot be ruled out, even when other diagnoses are possible.
Important information on signs and symptoms of hypersensitivity, as well as clinical management, is presented below.
Signs and Symptoms of Hypersensitivity:
Group 1: Fever
Group 2: Rash
Group 3: Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)
Group 4: Constitutional (including generalized malaise, fatigue, or achiness)
Group 5: Respiratory (including dyspnea, cough, or pharyngitis)
Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported infrequently.
Hypersensitivity to abacavir was reported in approximately 8% of 2,670 subjects (n = 206) in 9 clinical studies (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. The frequencies of symptoms are shown in Figure 1. Symptoms usually appeared within the first 6 weeks of treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset was 9 days; 89% appeared within the first 6 weeks; 95% of subjects reported symptoms from 2 or more of the 5 groups listed above.
A study with ZIAGEN (abacavir sulfate) used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the study, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.
Figure 1. Hypersensitivity-Related Symptoms Reported With ≥10% Frequency in Clinical Studies (n = 206 Subjects
Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and death have occurred in association with hypersensitivity reactions.
Physical findings associated with hypersensitivity to abacavir in some subjects include lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports of erythema multiforme. Hypersensitivity reactions have occurred without rash.
Laboratory abnormalities associated with hypersensitivity to abacavir in some subjects include elevated liver function tests, elevated creatinine phosphokinase, elevated creatinine, and lymphopenia.
Clinical Management of Hypersensitivity:
Following a hypersensitivity reaction to abacavir, NEVER restart Trizivir (Abacavir sulfate,lamivudine,zidovudine) or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.
When therapy with Trizivir (Abacavir sulfate,lamivudine,zidovudine) has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of abacavir is under consideration, carefully evaluate the reason for discontinuation to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of Trizivir (Abacavir sulfate,lamivudine,zidovudine) .
If hypersensitivity cannot be ruled out, DO NOT reintroduce Trizivir (Abacavir sulfate,lamivudine,zidovudine) or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of abacavir and that abacavir reintroduction needs to be undertaken only if medical care can be readily accessed by the patient or others.
CNA106030 (PREDICT-1), a randomized, double-blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.
Screening for carriage of the HLA-B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.
Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity.
In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
Abacavir Hypersensitivity Reaction Registry:
Zidovudine, a component of Trizivir (Abacavir sulfate,lamivudine,zidovudine) , has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. Trizivir (Abacavir sulfate,lamivudine,zidovudine) should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells/mm or hemoglobin less than 9.5 g/dL.
Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with Trizivir (Abacavir sulfate,lamivudine,zidovudine) . Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.
Posttreatment Exacerbations of Hepatitis:
Emergence of Lamivudine-Resistant HBV:
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In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV-1/HCV co-infected subjects , hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected subjects receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and Trizivir (Abacavir sulfate,lamivudine,zidovudine) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. Discontinuation of Trizivir (Abacavir sulfate,lamivudine,zidovudine) 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 the complete 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 (Abacavir sulfate,lamivudine,zidovudine) is not advised.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Trizivir (Abacavir sulfate,lamivudine,zidovudine) . 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 infection, cytomegalovirus, 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.
In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI). In a sponsor-conducted pooled analysis of clinical studies, no excess risk of myocardial infarction was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical studies 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, and smoking).
Trizivir (Abacavir sulfate,lamivudine,zidovudine) is a fixed-dose combination of abacavir, lamivudine, and zidovudine and is intended only for patients whose regimen would otherwise include these 3 components. Trizivir (Abacavir sulfate,lamivudine,zidovudine) should not be administered concomitantly with other abacavir-, lamivudine-, or zidovudine-containing products including ZIAGEN (abacavir) Tablets and Oral Solution, EPIVIR (lamivudine) Tablets and Oral Solution, EPIVIR-HBV (lamivudine) Tablets and Oral Solution, RETROVIR (zidovudine) Tablets, Capsules, Syrup, and IV Infusion, COMBIVIR (lamivudine and zidovudine) Tablets, EPZICOM (abacavir sulfate and lamivudine) Tablets; or emtricitabine-containing products, including ATRIPLA (efavirenz, emtricitabine, and tenofovir disoproxil fumarate) Tablets, EMTRIVA (emtricitabine) Capsules and Oral Solution, TRUVADA (emtricitabine and tenofovir) Tablets, or COMPLERA™ (rilpivirine/emtricitabine/tenofovir).
The complete prescribing information for all agents being considered for use with Trizivir (Abacavir sulfate,lamivudine,zidovudine) should be consulted before combination therapy with Trizivir (Abacavir sulfate,lamivudine,zidovudine) is initiated.
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared with rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
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 study 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:
Other Adverse Events:
In addition to adverse reactions reported from clinical studies, the following reactions have been identified during postmarketing use of abacavir, lamivudine, and/or zidovudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to abacavir, lamivudine and/or zidovudine.
Abacavir:
Cardiovascular:
Skin:
There have also been reports of erythema multiforme with abacavir use.
Abacavir, Lamivudine, and/or Zidovudine:
Cardiovascular:
Digestive:
Endocrine and Metabolic:
Gastrointestinal:
General:
Hemic and Lymphatic:
Hypersensitivity:
Musculoskeletal:
Nervous:
Psychiatric:
Respiratory:
Skin:
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Drug Interactions
Nucleoside Analogues Affecting DNA Replication:
Zidovudine:
Abacavir:
[see Clinical Pharmacology (12.3)]
Zidovudine:
Lamivudine:
[see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)]
Abacavir:
[see Clinical Pharmacology (12.3)]
Lamivudine:
[see Clinical Pharmacology (12.3)]
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Use In Specific Populations
Trizivir (Abacavir sulfate,lamivudine,zidovudine) :
Abacavir:
Lamivudine:
Antiretroviral Pregnancy Registry:
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV infection.
Abacavir, Lamivudine, and Zidovudine:
Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Trizivir (Abacavir sulfate,lamivudine,zidovudine) .
Trizivir (Abacavir sulfate,lamivudine,zidovudine) is not intended for use in pediatric patients and is not recommended in adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations.
Therapy-Experienced Pediatric Patients:
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Description
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY green 03B11434) that is made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.
Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled water at 25°C.
In vivo, abacavir sulfate dissociates to its free base, abacavir. In this insert, all dosages for ZIAGEN (abacavir sulfate) are expressed in terms of abacavir.
Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.
Zidovudine is a white to beige, crystalline solid with a solubility of 20.1 mg/mL in water at 25°C.
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Clinical Pharmacology
max
Abacavir:
Lamivudine:
Zidovudine:
In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes.
The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.
Pregnancy: See Use in Specific Populations (8.1)
Abacavir and Lamivudine:
Nursing Mothers: See Use in Specific Populations (8.3).
Abacavir:
Lamivudine:
Pediatric Patients:
Geriatric Patients:
Gender:
Abacavir:
Lamivudine and Zidovudine:
Race:
Abacavir:
Lamivudine:
Zidovudine:
Drug Interactions:
Cytochrome P450:
Glucuronyl Transferase:
Lamivudine and Zidovudine:
The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.
Lamivudine:
Zidovudine:
Lamivudine:
Zidovudine:
Resistance:
Abacavir:
Lamivudine:
Zidovudine:
Cross-Resistance:
Abacavir:
Lamivudine:
Zidovudine:
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Nonclinical Toxicology
Carcinogenicity:
Abacavir:
Lamivudine:
Zidovudine:
In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.
At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.
Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately 3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg/kg/day dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1,000 mg/kg nonpregnant body weight or ~450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
Mutagenicity:
Abacavir:
Lamivudine:
Zidovudine:
Impairment of Fertility:
Abacavir:
Lamivudine:
Zidovudine:
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Clinical Studies
The following study was conducted with the individual components of Trizivir (Abacavir sulfate,lamivudine,zidovudine)
Treatment response by plasma HIV-1 RNA strata is shown in Table 6.
In subjects with baseline viral load >100,000 copies/mL, percentages of subjects with HIV-1 RNA levels
Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells/mm was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir sulfate (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.
Trizivir (Abacavir sulfate,lamivudine,zidovudine) How Supplied/storage And Handling
Trizivir (Abacavir sulfate,lamivudine,zidovudine) is available as tablets. Each tablet contains 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. They are packaged as follows:
Bottles of 60 Tablets (NDC 49702-217-18).
Trizivir (Abacavir sulfate,lamivudine,zidovudine) Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
Patients should be informed to take all HIV medications exactly as prescribed.
COMBIVIR, EPIVIR, EPZICOM, RETROVIR, Trizivir (Abacavir sulfate,lamivudine,zidovudine) , and ZIAGEN are registered trademarks of ViiV Healthcare.
Other brands are trademarks of their respective owners and are not trademarks of ViiV Healthcare. The makers of these brands are not affiliated with and do not endorse ViiV Healthcare 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
Basingstoke, UK
©2011, ViiV Healthcare. All rights reserved.
November 2011
TRZ:4PI
Trizivir (Abacavir sulfate,lamivudine,zidovudine)
Trizivir (Abacavir sulfate,lamivudine,zidovudine)
