PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics in AdultsIn single-dose, 3-way crossover bioavailability trial of TRIZIVIR tablet versus ZIAGEN tablet (300 mg), EPIVIR tablet (150 mg), plus RETROVIR tablet (300 mg) administered simultaneously in healthy subjects (n 24), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of all components. One TRIZIVIR tablet was bioequivalent to ZIAGEN tablet (300 mg), EPIVIR tablet (150 mg), plus RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n 24).Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 +- 0.89 mcg per mL (mean +- SD) and AUC(0-12 h) was 6.02 +- 1.73 mcgohour 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.Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. 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 minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 (CYP) enzymes.The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.Table 3. Pharmacokinetic Parametersa for Abacavir, Lamivudine, and Zidovudine in AdultsParameterAbacavirLamivudineZidovudineOral bioavailability (%)86 +- 25n 686 +- 16n 1264 +- 10n 5Apparent volume of distribution (L/kg)0.86 +- 0.15n 61.3 +- 0.4n 201.6 +- 0.6n 8Systemic clearance (L/h/kg)0.80 +- 0.24n 60.33 +- 0.06n 201.6 +- 0.6n 6Renal clearance (L/h/kg)0.007 +- 0.008n 60.22 +- 0.06n 200.34 +- 0.05n 9Elimination half-life (h)1.45 +- 0.32n 2013 to 19b 0.5 to 3b Data presented as mean +- standard deviation except where noted.b Approximate range.Effect of Food on Absorption of TRIZIVIR Administration with food in single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with high-fat meal, compared with administration under fasted conditions. Administration of TRIZIVIR with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n 24) [see Dosage and Administration (2.2)].Specific Populations Patients with Renal Impairment: TRIZIVIR: The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).Patients with Hepatic Impairment: TRIZIVIR: The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).Pregnant Women: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery. Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Zidovudine: Zidovudine pharmacokinetics have been studied in Phase trial of women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.Although data are limited, methadone maintenance therapy in pregnant women did not appear to alter zidovudine pharmacokinetics.Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components.Racial Groups: Abacavir and Lamivudine: There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.Drug Interaction StudiesThe drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using TRIZIVIR. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine. Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K. Riociguat: Coadministration of single dose of riociguat (0.5 mg) to HIV-1-infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC() compared with riociguat AUC() reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see Drug Interactions (7.1)].Effect of Other Agents on the Pharmacokinetics of Abacavir, Lamivudine, or Zidovudine: Abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. In vitro, abacavir is not substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in clinically relevant impact on abacavir concentrations.Lamivudine is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.Lamivudine is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.Glucuronyl Transferase: Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in crossover 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.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 trial of 19 healthy male subjects.Methadone: In 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 (7.1)]. 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 multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions (5.6)].Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received single 300-mg dose of lamivudine oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.Table 4. Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUCa CoadministeredDrug and DoseDrug and DosenConcentrations of Abacavir, Lamivudine, or ZidovudineConcentration of CoadministeredDrugAUCVariabilityEthanol0.7 g/kg Abacavir single 600 mg2441%90% CI:35% to 48%<->b Nelfinavir750 mg every h 7 to 10 daysLamivudine single 150 mg1110%95% CI:1% to 20%<->Trimethoprim 160 mg/Sulfamethoxazole 800 mg daily 5 daysLamivudine single 300 mg 1443%90% CI:32% to 55%<->Atovaquone750 mg every 12 hwith foodZidovudine 200 mg every h1431%Range:23% to 78%c <->Clarithromycin500 mg twice dailyZidovudine 100 mg every h 7 days412%Range:34% to 14%Not ReportedFluconazole400 mg dailyZidovudine 200 mg every h1274%95% CI:54% to 98%Not ReportedMethadone30 to 90 mg dailyZidovudine 200 mg every h943%Range:16% to 64%c <->Nelfinavir750 mg every h 7 to 10 daysZidovudine single 200 mg1135%Range:28% to 41%<->Probenecid 500 mg every h 2 daysZidovudine mg/kg every h 3 days3106%Range:100% to 170%c Not AssessedRifampin600 mg daily 14 daysZidovudine 200 mg every h 14 days847%90% CI: 41% to 53%Not AssessedRitonavir300 mg every h 4 daysZidovudine 200 mg every h 4 days925%95% CI:15% to 34%<->Valproic acid250 mg or 500 mgevery h 4 daysZidovudine 100 mg every h 4 days680%Range:64% to 130%c Not Assessed Increase; Decrease; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval.a See Drug Interactions (7) for additional information on drug interactions.b The drug-drug interaction was only evaluated in males.c Estimated range of percent difference.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:oSerious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].oHematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.2)].oSymptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.3)].oLactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.4)].oExacerbations of hepatitis [see Boxed Warning, Warnings and Precautions (5.5)].oHepatic decompensation in patients co-infected with HIV-1 and hepatitis [see Warnings and Precautions (5.6)].oExacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)].oImmune reconstitution syndrome [see Warnings and Precautions (5.7)].oLipoatrophy [see Warnings and Precautions (5.8)].oMyocardial infarction [see Warnings and Precautions (5.9)].. oSerious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].. oHematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.2)].. oSymptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.3)].. oLactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.4)].. oExacerbations of hepatitis [see Boxed Warning, Warnings and Precautions (5.5)].. oHepatic decompensation in patients co-infected with HIV-1 and hepatitis [see Warnings and Precautions (5.6)].. oExacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)].. oImmune reconstitution syndrome [see Warnings and Precautions (5.7)].. oLipoatrophy [see Warnings and Precautions (5.8)].. oMyocardial infarction [see Warnings and Precautions (5.9)].. 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.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Serious and Fatal Abacavir-Associated Hypersensitivity ReactionsIn clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, component of TRIZIVIR [see Boxed Warning, Warnings and Precautions (5.1)]. These reactions have been characterized by 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 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 TRIZIVIRTreatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with 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 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1.Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of TreatmentAdverse ReactionZIAGEN plus Lamivudine/Zidovudine(n 262)Indinavir plus Lamivudine/Zidovudine(n 264)Nausea19%17%Headache13%9%Malaise and fatigue12%12%Nausea and vomiting10%10%Hypersensitivity reaction8%2%Diarrhea7%5%Fever and/or chills6%3%Depressive disorders6%4%Musculoskeletal pain5%7%Skin rashes5%4%Ear/nose/throat infections5%4%Viral respiratory infections5%5%Anxiety5%3%Renal signs/symptoms<1%5%Pain (non-site-specific)<1%5%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 treatment arms.Laboratory Abnormalities Laboratory abnormalities in CNA3005 are listed in Table 2.Table 2. Treatment-Emergent Laboratory Abnormalities (Grades 3/4) in CNA3005Laboratory ParameterZIAGEN plus Lamivudine/Zidovudine(n 262)Indinavir plus Lamivudine/Zidovudine(n 264)Elevated CPK (>4 ULN)18 (7%)18 (7%)ALT (>5.0 ULN)16 (6%)16 (6%)Neutropenia (<750/mm3)13 (5%)13 (5%)Hypertriglyceridemia (>750 mg/dL)5 (2%)3 (1%)Hyperamylasemia (>2.0 ULN)5 (2%)1 (<1%)Hyperglycemia (>13.9 mmol/L)2 (<1%)2 (<1%)Anemia (Hgb <=6.9 g/dL)0 (0%)3 (1%)ULN Upper limit of normal.n Number of subjects assessed.Other Adverse Events In addition to adverse reactions in Tables and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. AbacavirCardiovascular: Myocardial infarction.Skin: 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. There have also been reports of erythema multiforme with abacavir use [see Adverse Reactions (6.1)].Abacavir, Lamivudine, and/or ZidovudineBody as Whole: Redistribution/accumulation of body fat.Cardiovascular: Cardiomyopathy.Digestive: Stomatitis.Endocrine and Metabolic: Gynecomastia.Gastrointestinal: Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation.General: Vasculitis, weakness.Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.Hepatic: Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.4)], elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis [see Warnings and Precautions (5.5)].Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.Musculoskeletal: Arthralgia, myalgia, muscle weakness, rhabdomyolysis.Nervous: Dizziness, paresthesia, peripheral neuropathy, seizures.Psychiatric: Insomnia and other sleep disorders.Respiratory: Abnormal breath sounds/wheezing.Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

BOXED WARNING SECTION.

WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B. Hypersensitivity ReactionsSerious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, component of TRIZIVIR (abacavir, lamivudine, and zidovudine). Patients who carry the HLA-B5701 allele are at higher risk of hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B5701 allele [see Warnings and Precautions (5.1)]. TRIZIVIR is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLA-B5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have previously documented HLA-B5701 allele assessment. Discontinue TRIZIVIR immediately if hypersensitivity reaction is suspected, regardless of HLA-B5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)]. Following hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavir-containing 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)]. Hematologic ToxicityZidovudine, component of TRIZIVIR, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see Warnings and Precautions (5.2)]. MyopathyProlonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.3)].Lactic Acidosis and Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)].Exacerbations of Hepatitis BSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and HIV-1 and have discontinued lamivudine, component of TRIZIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIZIVIR and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis therapy may be warranted [see Warnings and Precautions (5.5)]. WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS BSee full prescribing information for complete boxed warning.Hypersensitivity ReactionsoSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. (5.1)oHypersensitivity to abacavir is multi-organ clinical syndrome. (5.1)oPatients who carry the HLA-B5701 allele are at higher risk of experiencing hypersensitivity reaction to abacavir. (5.1)oTRIZIVIR is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. (4)oDiscontinue TRIZIVIR as soon as hypersensitivity reaction is suspected. Regardless of HLA-B5701 status, permanently discontinue TRIZIVIR if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1)oFollowing hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavir-containing product. (5.1)Hematologic ToxicityoHematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, component of TRIZIVIR. (5.2)MyopathyoSymptomatic myopathy associated with prolonged use of zidovudine. (5.3)Lactic Acidosis and Severe Hepatomegaly with SteatosisoLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.4)Exacerbations of Hepatitis BoSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, component of TRIZIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.5). oSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. (5.1). oHypersensitivity to abacavir is multi-organ clinical syndrome. (5.1). oPatients who carry the HLA-B5701 allele are at higher risk of experiencing hypersensitivity reaction to abacavir. (5.1). oTRIZIVIR is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. (4). oDiscontinue TRIZIVIR as soon as hypersensitivity reaction is suspected. Regardless of HLA-B5701 status, permanently discontinue TRIZIVIR if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1). oFollowing hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavir-containing product. (5.1). oHematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, component of TRIZIVIR. (5.2). oSymptomatic myopathy associated with prolonged use of zidovudine. (5.3). oLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. (5.4). oSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, component of TRIZIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.5).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityAbacavir: Abacavir was administered orally at 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 to 32 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 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.Zidovudine: Zidovudine was administered orally at dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.In mice, late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, squamous cell papilloma, and squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of middle-dose animal. No vaginal tumors were found at the lowest dose.In rats, late-appearing (after 20 months), non-metastasizing 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 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every hours.It is not known how predictive the results of rodent carcinogenicity studies may be for humans.Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from Gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately times the estimated human exposure at the recommended doses. After 24 months at the 40-mg-per-kg-per-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. second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per 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.MutagenicityAbacavir: 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 cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in cytogenetic study in rats given single dose.Impairment of FertilityAbacavir: Abacavir did not affect male or female fertility in rats at dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. TRIZIVIR is an antiretroviral agent [see Microbiology (12.4)].. 12.3 Pharmacokinetics. Pharmacokinetics in AdultsIn single-dose, 3-way crossover bioavailability trial of TRIZIVIR tablet versus ZIAGEN tablet (300 mg), EPIVIR tablet (150 mg), plus RETROVIR tablet (300 mg) administered simultaneously in healthy subjects (n 24), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of all components. One TRIZIVIR tablet was bioequivalent to ZIAGEN tablet (300 mg), EPIVIR tablet (150 mg), plus RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n 24).Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 +- 0.89 mcg per mL (mean +- SD) and AUC(0-12 h) was 6.02 +- 1.73 mcgohour 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.Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. 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 minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. second metabolite, 3-amino-3-deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 (CYP) enzymes.The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.Table 3. Pharmacokinetic Parametersa for Abacavir, Lamivudine, and Zidovudine in AdultsParameterAbacavirLamivudineZidovudineOral bioavailability (%)86 +- 25n 686 +- 16n 1264 +- 10n 5Apparent volume of distribution (L/kg)0.86 +- 0.15n 61.3 +- 0.4n 201.6 +- 0.6n 8Systemic clearance (L/h/kg)0.80 +- 0.24n 60.33 +- 0.06n 201.6 +- 0.6n 6Renal clearance (L/h/kg)0.007 +- 0.008n 60.22 +- 0.06n 200.34 +- 0.05n 9Elimination half-life (h)1.45 +- 0.32n 2013 to 19b 0.5 to 3b Data presented as mean +- standard deviation except where noted.b Approximate range.Effect of Food on Absorption of TRIZIVIR Administration with food in single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with high-fat meal, compared with administration under fasted conditions. Administration of TRIZIVIR with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n 24) [see Dosage and Administration (2.2)].Specific Populations Patients with Renal Impairment: TRIZIVIR: The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).Patients with Hepatic Impairment: TRIZIVIR: The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).Pregnant Women: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery. Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Zidovudine: Zidovudine pharmacokinetics have been studied in Phase trial of women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.Although data are limited, methadone maintenance therapy in pregnant women did not appear to alter zidovudine pharmacokinetics.Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components.Racial Groups: Abacavir and Lamivudine: There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.Drug Interaction StudiesThe drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using TRIZIVIR. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine. Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K. Riociguat: Coadministration of single dose of riociguat (0.5 mg) to HIV-1-infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC() compared with riociguat AUC() reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see Drug Interactions (7.1)].Effect of Other Agents on the Pharmacokinetics of Abacavir, Lamivudine, or Zidovudine: Abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. In vitro, abacavir is not substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in clinically relevant impact on abacavir concentrations.Lamivudine is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.Lamivudine is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.Glucuronyl Transferase: Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in crossover 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.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 trial of 19 healthy male subjects.Methadone: In 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 (7.1)]. 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 multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions (5.6)].Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received single 300-mg dose of lamivudine oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.Table 4. Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUCa CoadministeredDrug and DoseDrug and DosenConcentrations of Abacavir, Lamivudine, or ZidovudineConcentration of CoadministeredDrugAUCVariabilityEthanol0.7 g/kg Abacavir single 600 mg2441%90% CI:35% to 48%<->b Nelfinavir750 mg every h 7 to 10 daysLamivudine single 150 mg1110%95% CI:1% to 20%<->Trimethoprim 160 mg/Sulfamethoxazole 800 mg daily 5 daysLamivudine single 300 mg 1443%90% CI:32% to 55%<->Atovaquone750 mg every 12 hwith foodZidovudine 200 mg every h1431%Range:23% to 78%c <->Clarithromycin500 mg twice dailyZidovudine 100 mg every h 7 days412%Range:34% to 14%Not ReportedFluconazole400 mg dailyZidovudine 200 mg every h1274%95% CI:54% to 98%Not ReportedMethadone30 to 90 mg dailyZidovudine 200 mg every h943%Range:16% to 64%c <->Nelfinavir750 mg every h 7 to 10 daysZidovudine single 200 mg1135%Range:28% to 41%<->Probenecid 500 mg every h 2 daysZidovudine mg/kg every h 3 days3106%Range:100% to 170%c Not AssessedRifampin600 mg daily 14 daysZidovudine 200 mg every h 14 days847%90% CI: 41% to 53%Not AssessedRitonavir300 mg every h 4 daysZidovudine 200 mg every h 4 days925%95% CI:15% to 34%<->Valproic acid250 mg or 500 mgevery h 4 daysZidovudine 100 mg every h 4 days680%Range:64% to 130%c Not Assessed Increase; Decrease; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval.a See Drug Interactions (7) for additional information on drug interactions.b The drug-drug interaction was only evaluated in males.c Estimated range of percent difference.. 12.4 Microbiology. Mechanism of ActionAbacavir: Abacavir is 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 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. Zidovudine: Zidovudine is synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Antiviral ActivityAbacavir: The antiviral activity of abacavir against HIV-1 was assessed in number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (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 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 viruses (n 3 except = 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 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: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B), respectively. The EC50 values against HIV-2 isolates (n 4) ranged 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.Zidovudine: The antiviral activity of zidovudine against HIV-1 was assessed in number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM 0.27 mcg per mL) and 0.1 to microM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.Neither abacavir, lamivudine, nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), RETROVIR (zidovudine).ResistanceHIV-1 isolates with reduced susceptibility to abacavir, lamivudine, or zidovudine have been selected in cell culture and were also recovered from subjects treated with abacavir, lamivudine, and zidovudine, or the combinations of the individual components.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 emerging in HIV-1 RT. M184V or substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or conferred 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.Zidovudine: Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analogue mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Cross-Resistance Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with TAM substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with progressive reduction in abacavir susceptibility.TAMs are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir. Cross-resistance between lamivudine and zidovudine has not been reported.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk SummaryAvailable data from the APR show no difference in the overall risk of birth defects for abacavir, lamivudine, or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data).In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data). DataHuman Data: Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.Lamivudine pharmacokinetics were studied in pregnant women during clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)-fold greater compared with paired maternal serum concentration (n 8). Zidovudine: Based on prospective reports to the APR of exposures to zidovudine during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 9,700 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.1%) following second/third trimester exposure to zidovudine-containing regimens.A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug. See full prescribing information for RETROVIR (zidovudine) and COMBIVIR (lamivudine and zidovudine).Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.Animal Data: Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days through 17 and through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately times the human exposure at the recommended dose. Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days through 16 [rat] and through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine. Zidovudine: study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on Gestation Days through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on Gestation Days through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.

SPL MEDGUIDE SECTION.

MEDICATION GUIDETRIZIVIR (TRY-zih-veer)(abacavir, lamivudine, and zidovudine tablets)What is the most important information should know about TRIZIVIRTRIZIVIR can cause serious side effects, including:oSerious allergic reactions (hypersensitivity reaction) that can cause death have happened with TRIZIVIR and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have gene variation called HLA-B5701. Your healthcare provider can determine with blood test if you have this gene variation. If you get symptom from or more of the following groups while taking TRIZIVIR, call your healthcare provider right away to find out if you should stop taking TRIZIVIR.Symptom(s)Group 1FeverGroup 2RashGroup 3Nausea, vomiting, diarrhea, abdominal (stomach area) painGroup 4Generally ill feeling, extreme tiredness, or achinessGroup 5Shortness of breath, cough, sore throatA 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 TRIZIVIR because of an allergic reaction, never take TRIZIVIR (abacavir, lamivudine and zidovudine) or any other abacavir-containing medicine (EPZICOM, TRIUMEQ, or ZIAGEN) again. oIf you have an allergic reaction, dispose of any unused TRIZIVIR. Ask your pharmacist how to properly dispose of medicines.oIf you take TRIZIVIR or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death. oIf you stop TRIZIVIR for any other reason, even for few days, and you are not allergic to TRIZIVIR, talk with your healthcare provider before taking it again. Taking TRIZIVIR again can cause 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 TRIZIVIR again, start taking it when you are around medical help or people who can call healthcare provider if you need one.oBlood problems. Zidovudine, one of the medicines in TRIZIVIR, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). These blood cell problems are especially likely to happen in people with advanced human immunodeficiency virus-1 (HIV-1) infection or Acquired Immune Deficiency Syndrome (AIDS). Your healthcare provider should check your blood cell counts regularly during treatment with TRIZIVIR. oMuscle pain or weakness can happen during treatment with TRIZIVIR. Zidovudine, one of the medicines in TRIZIVIR, can cause muscle pain or weakness when used for long time.oToo much lactic acid in your blood (lactic acidosis). Lactic acidosis is serious medical emergency that can lead to death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: ofeel very weak or tiredounusual (not normal) muscle pain otrouble breathing ostomach pain with nausea and vomitingofeel cold, especially in your arms and legsofeel dizzy or light-headedohave fast or irregular heartbeatoSevere liver problems. In some cases, severe 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: oyour skin or the white part of your eyes turns yellow (jaundice) odark or tea-colored urineolight colored stools (bowel movements)oloss of appetite for several days or longeronauseaopain, aching, or tenderness on the right side of your stomach areaYou may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).oWorsening of hepatitis virus (HBV) infection. If you have HBV infection and take TRIZIVIR, your HBV may get worse (flare-up) if you stop taking TRIZIVIR. flare-up is when your HBV infection suddenly returns in worse way than before. oDo not run out of TRIZIVIR. Refill your prescription or talk to your healthcare provider before your TRIZIVIR is all gone.oDo not stop TRIZIVIR without first talking to your healthcare provider.oIf you stop taking TRIZIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIZIVIR. oResistant HBV. If you have HIV-1 and HBV, the HBV can change (mutate) during your treatment with TRIZIVIR and become harder to treat (resistant). oUse with interferon and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis virus who are taking HIV-1 medicines, and are also being treated for hepatitis with interferon alfa with or without ribavirin. If you are taking TRIZIVIR and interferon alfa with or without ribavirin, tell your healthcare provider if you have any new symptoms.oFor more information about side effects, see What are the possible side effects of TRIZIVIRWhat is TRIZIVIRTRIZIVIR is prescription medicine used alone or with other HIV-1 medicines to treat HIV-1 infection. HIV-1 is the virus that causes AIDS. TRIZIVIR contains the prescription medicines abacavir, lamivudine, and zidovudine.TRIZIVIR should not be used in children weighing less than 88 pounds (40 kg).Do not take TRIZIVIR if you:ohave certain type of gene variation called the HLA-B5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIZIVIR.oare allergic to abacavir, lamivudine, zidovudine, or any of the ingredients in TRIZIVIR. See the end of this Medication Guide for complete list of ingredients in TRIZIVIR.ohave certain liver problems.Before you take TRIZIVIR, tell your healthcare provider about all of your medical conditions, including if you:ohave been tested and know whether or not you have particular gene variation called HLA-B5701.ohave or have had liver problems, including hepatitis or virus infection.ohave kidney problems.ohave low blood cell counts (bone marrow problem). Ask your healthcare provider if you are not sure.ohave heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.oare pregnant or plan to become pregnant. Pregnancy Registry. There is pregnancy registry for women who take HIV-1 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.oare breastfeeding or plan to breastfeed. Do not breastfeed if you take TRIZIVIR.oYou 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 TRIZIVIR. Keep list of your medicines to show your healthcare provider and pharmacist when you get new medicine. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with TRIZIVIR. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TRIZIVIR with other medicines.How should take TRIZIVIRoTake TRIZIVIR exactly as your healthcare provider tells you to take it.oDo not change your dose or stop taking TRIZIVIR without talking with your healthcare provider.oIf you miss dose of TRIZIVIR, take it as soon as you remember. Do not take doses at the same time or take more than your healthcare provider tells you to take.oStay under the care of healthcare provider during treatment with TRIZIVIR.oTRIZIVIR may be taken with or without food.oDo not run out of TRIZIVIR. 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.oIf you take too much TRIZIVIR, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of TRIZIVIRoTRIZIVIR can cause serious side effects including:oSee What is the most important information should know about TRIZIVIRoChanges 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 long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIZIVIR.oLoss of body fat can happen in people who take HIV-1 medicines that contain zidovudine. This loss of fat may occur in the legs, arms, buttocks, and face. The loss of fat may be permanent and long-term health effects are not known.oHeart attack. Some HIV-1 medicines including TRIZIVIR may increase your risk of heart attack.The most common side effects of TRIZIVIR include:onauseaoheadacheoweakness or tirednessovomitingTell 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 TRIZIVIR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TRIZIVIRoStore TRIZIVIR at room temperature.Keep TRIZIVIR and all medicines out of the reach of children.General information for safe and effective use of TRIZIVIR.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TRIZIVIR for condition for which it was not prescribed. Do not give TRIZIVIR to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for the information about TRIZIVIR that is written for health professionals.What are the ingredients in TRIZIVIRActive ingredients: abacavir, lamivudine, and zidovudineInactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolateTablet film coating contains: OPADRY green 03B11434 made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.Manufactured for:ViiV HealthcareResearch Triangle Park, NC 27709EPZICOM, TRIUMEQ, TRIZIVIR, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.The other brand listed is trademark owned by or licensed to its respective owner and is not trademark owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not affiliated with and does not endorse the ViiV Healthcare group of companies or its products.(C)2021 ViiV Healthcare group of companies or its licensor.TRZ:13MGFor more information go to www.TRIZIVIR.com or call 1-877-844-8872.This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 02/2021. oSerious allergic reactions (hypersensitivity reaction) that can cause death have happened with TRIZIVIR and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have gene variation called HLA-B5701. Your healthcare provider can determine with blood test if you have this gene variation.. If you get symptom from or more of the following groups while taking TRIZIVIR, call your healthcare provider right away to find out if you should stop taking TRIZIVIR.. oIf you have an allergic reaction, dispose of any unused TRIZIVIR. Ask your pharmacist how to properly dispose of medicines.. oIf you take TRIZIVIR or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death. oIf you stop TRIZIVIR for any other reason, even for few days, and you are not allergic to TRIZIVIR, talk with your healthcare provider before taking it again. Taking TRIZIVIR again can cause serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.. oBlood problems. Zidovudine, one of the medicines in TRIZIVIR, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). These blood cell problems are especially likely to happen in people with advanced human immunodeficiency virus-1 (HIV-1) infection or Acquired Immune Deficiency Syndrome (AIDS). Your healthcare provider should check your blood cell counts regularly during treatment with TRIZIVIR. oMuscle pain or weakness can happen during treatment with TRIZIVIR. Zidovudine, one of the medicines in TRIZIVIR, can cause muscle pain or weakness when used for long time.. oToo much lactic acid in your blood (lactic acidosis). Lactic acidosis is serious medical emergency that can lead to death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: ofeel very weak or tired. ounusual (not normal) muscle pain otrouble breathing ostomach pain with nausea and vomiting. ofeel cold, especially in your arms and legs. ofeel dizzy or light-headed. ohave fast or irregular heartbeat. oSevere liver problems. In some cases, severe 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: oyour skin or the white part of your eyes turns yellow (jaundice) odark or tea-colored urine. olight colored stools (bowel movements). oloss of appetite for several days or longer. onausea. opain, aching, or tenderness on the right side of your stomach area. oWorsening of hepatitis virus (HBV) infection. If you have HBV infection and take TRIZIVIR, your HBV may get worse (flare-up) if you stop taking TRIZIVIR. flare-up is when your HBV infection suddenly returns in worse way than before. oDo not run out of TRIZIVIR. Refill your prescription or talk to your healthcare provider before your TRIZIVIR is all gone.oDo not stop TRIZIVIR without first talking to your healthcare provider.oIf you stop taking TRIZIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIZIVIR. oDo not run out of TRIZIVIR. Refill your prescription or talk to your healthcare provider before your TRIZIVIR is all gone.. oDo not stop TRIZIVIR without first talking to your healthcare provider.. oIf you stop taking TRIZIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIZIVIR.. oResistant HBV. If you have HIV-1 and HBV, the HBV can change (mutate) during your treatment with TRIZIVIR and become harder to treat (resistant). oUse with interferon and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis virus who are taking HIV-1 medicines, and are also being treated for hepatitis with interferon alfa with or without ribavirin. If you are taking TRIZIVIR and interferon alfa with or without ribavirin, tell your healthcare provider if you have any new symptoms.. oFor more information about side effects, see What are the possible side effects of TRIZIVIR. ohave certain type of gene variation called the HLA-B5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIZIVIR.. oare allergic to abacavir, lamivudine, zidovudine, or any of the ingredients in TRIZIVIR. See the end of this Medication Guide for complete list of ingredients in TRIZIVIR.. ohave certain liver problems.. ohave been tested and know whether or not you have particular gene variation called HLA-B5701.. ohave or have had liver problems, including hepatitis or virus infection.. ohave kidney problems.. ohave low blood cell counts (bone marrow problem). Ask your healthcare provider if you are not sure.. ohave heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.. oare pregnant or plan to become pregnant.. Pregnancy Registry. There is pregnancy registry for women who take HIV-1 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.. oare breastfeeding or plan to breastfeed. Do not breastfeed if you take TRIZIVIR.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with TRIZIVIR. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TRIZIVIR with other medicines.. oTake TRIZIVIR exactly as your healthcare provider tells you to take it.. oDo not change your dose or stop taking TRIZIVIR without talking with your healthcare provider.. oIf you miss dose of TRIZIVIR, take it as soon as you remember. Do not take doses at the same time or take more than your healthcare provider tells you to take.. oStay under the care of healthcare provider during treatment with TRIZIVIR.. oTRIZIVIR may be taken with or without food.. oDo not run out of TRIZIVIR. 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.. oIf you take too much TRIZIVIR, call your healthcare provider or go to the nearest hospital emergency room right away.. oTRIZIVIR can cause serious side effects including:. oSee What is the most important information should know about TRIZIVIR. oChanges 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 long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIZIVIR.. oLoss of body fat can happen in people who take HIV-1 medicines that contain zidovudine. This loss of fat may occur in the legs, arms, buttocks, and face. The loss of fat may be permanent and long-term health effects are not known.. oHeart attack. Some HIV-1 medicines including TRIZIVIR may increase your risk of heart attack.. onausea. oheadache. oweakness or tiredness. ovomiting. oStore TRIZIVIR at room temperature.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oLactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. (8.2). oLactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. (8.2). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk SummaryAvailable data from the APR show no difference in the overall risk of birth defects for abacavir, lamivudine, or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see Data).In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see Data). DataHuman Data: Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.Lamivudine pharmacokinetics were studied in pregnant women during clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)-fold greater compared with paired maternal serum concentration (n 8). Zidovudine: Based on prospective reports to the APR of exposures to zidovudine during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 9,700 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.1%) following second/third trimester exposure to zidovudine-containing regimens.A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug. See full prescribing information for RETROVIR (zidovudine) and COMBIVIR (lamivudine and zidovudine).Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.Animal Data: Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days through 17 and through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately times the human exposure at the recommended dose. Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days through 16 [rat] and through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine. Zidovudine: study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on Gestation Days through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on Gestation Days through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.. 8.2 Lactation Risk SummaryThe Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIZIVIR.. 8.4 Pediatric Use. TRIZIVIR is not recommended in children who weigh less than 40 kg because it is fixed-dose tablet that cannot be adjusted for these patient populations [see Dosage and Administration (2.3)].Therapy-Experienced Pediatric Trial randomized, double-blind trial, CNA3006, compared ZIAGEN plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had limited response to abacavir.. 8.5 Geriatric Use. Clinical trials of abacavir, lamivudine, and zidovudine 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 TRIZIVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].. 8.6 Patients with Impaired Renal Function. TRIZIVIR is not recommended for patients with creatinine clearance less than 50 mL per min because TRIZIVIR is fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of the lamivudine or zidovudine components of TRIZIVIR is required for patients with renal impairment then the individual components should be used [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].. 8.7 Patients with Impaired Hepatic Function. TRIZIVIR is fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of abacavir, component of TRIZIVIR, is required for patients with mild hepatic impairment (Child-Pugh Class 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 Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, TRIZIVIR is contraindicated in these patients [see Contraindications (4)].Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHepatic 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)oExacerbation 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)oImmune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy. (5.7, 5.8). oHepatic 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). oExacerbation 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). oImmune reconstitution syndrome and lipoatrophy have been reported in patients treated with combination antiretroviral therapy. (5.7, 5.8). 5.1 Hypersensitivity Reactions. Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, component of TRIZIVIR. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first weeks of treatment with abacavir (median time to onset was days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1)]. Patients who carry the HLA-B5701 allele are at higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in clinical trials with abacavir-containing products where HLA-B5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B5701 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:oAll patients should be screened for the HLA-B5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have previously documented HLA-B5701 allele assessment.oTRIZIVIR is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients.oBefore starting TRIZIVIR, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIZIVIR or any other abacavir-containing product following hypersensitivity reaction to abacavir, regardless of HLA-B5701 status.oTo reduce the risk of life-threatening hypersensitivity reaction, regardless of HLA-B5701 status, discontinue TRIZIVIR immediately if 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).oIf 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.oIf 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.oA Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.. oAll patients should be screened for the HLA-B5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have previously documented HLA-B5701 allele assessment.. oTRIZIVIR is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients.. oBefore starting TRIZIVIR, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIZIVIR or any other abacavir-containing product following hypersensitivity reaction to abacavir, regardless of HLA-B5701 status.. oTo reduce the risk of life-threatening hypersensitivity reaction, regardless of HLA-B5701 status, discontinue TRIZIVIR immediately if 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).. oIf 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.. oIf 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.. oA 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, 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, including abacavir, lamivudine and zidovudine (components of TRIZIVIR). majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. 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 Virus Co-infection. Posttreatment Exacerbations of HepatitisClinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.Emergence of Lamivudine-Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis 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 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 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 evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre 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 Lipoatrophy. Treatment with zidovudine, component of TRIZIVIR, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to non-zidovudine-containing regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy. 5.9 Myocardial Infarction. Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for causal relationship between abacavir treatment and the risk of MI is inconclusive.As 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 Therapy-Experienced 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Hypersensitivity ReactionInform patients:othat 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 TRIZIVIR, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIZIVIR. The complete text of the Medication Guide is reprinted at the end of this document.oto carry the Warning Card with them.ohow to identify hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].othat if they develop symptoms consistent with hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIZIVIR.othat hypersensitivity reaction can worsen and lead to hospitalization or death if TRIZIVIR is not immediately discontinued.oto not restart TRIZIVIR or any other abacavir-containing product following hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.othat if they have hypersensitivity reaction, they should dispose of any unused TRIZIVIR to avoid restarting abacavir.othat hypersensitivity reaction is usually reversible if it is detected promptly and TRIZIVIR is stopped right away.othat if they have interrupted TRIZIVIR for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.oto not restart TRIZIVIR or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.Neutropenia and AnemiaInform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV-1 disease [see Boxed Warning, Warnings and Precautions (5.2)].MyopathyInform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see Warnings and Precautions (5.3)].Lactic Acidosis/Hepatomegaly with SteatosisAdvise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking TRIZIVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.4)].Patients with Hepatitis or Co-infectionAdvise 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 healthcare provider [see Warnings and Precautions (5.5)]. 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 (5.6)]. Drug InteractionsAdvise patients that other medications may interact with TRIZIVIR and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, component of TRIZIVIR [see Drug Interactions (7.3)]. Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TRIZIVIR is started [see Warnings and Precautions (5.7)]. LipoatrophyAdvise patients that loss of subcutaneous fat may occur in patients receiving TRIZIVIR and that they will be regularly assessed during therapy [see Warnings and Precautions (5.8)].Pregnancy RegistryAdvise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy [see Use in Specific Populations (8.1)].LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].Missed DoseInstruct patients that if they miss dose of TRIZIVIR, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].Availability of Medication GuideInstruct patients to read the Medication Guide before starting TRIZIVIR and to re-read 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.COMBIVIR, EPIVIR, RETROVIR, TRIZIVIR, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.Other brands listed are trademarks owned by or licensed to their respective owners and are not trademarks owned by or licensed to 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 HealthcareResearch Triangle Park, NC 27709(C)2021 ViiV Healthcare group of companies or its licensor.TRZ:13PI. othat 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 TRIZIVIR, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIZIVIR. The complete text of the Medication Guide is reprinted at the end of this document.. oto carry the Warning Card with them.. ohow to identify hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].. othat if they develop symptoms consistent with hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIZIVIR.. othat hypersensitivity reaction can worsen and lead to hospitalization or death if TRIZIVIR is not immediately discontinued.. oto not restart TRIZIVIR or any other abacavir-containing product following hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.. othat if they have hypersensitivity reaction, they should dispose of any unused TRIZIVIR to avoid restarting abacavir.. othat hypersensitivity reaction is usually reversible if it is detected promptly and TRIZIVIR is stopped right away.. othat if they have interrupted TRIZIVIR for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.. oto not restart TRIZIVIR or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityAbacavir: Abacavir was administered orally at 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 to 32 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 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.Zidovudine: Zidovudine was administered orally at dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.In mice, late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, squamous cell papilloma, and squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of middle-dose animal. No vaginal tumors were found at the lowest dose.In rats, late-appearing (after 20 months), non-metastasizing 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 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every hours.It is not known how predictive the results of rodent carcinogenicity studies may be for humans.Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from Gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately times the estimated human exposure at the recommended doses. After 24 months at the 40-mg-per-kg-per-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. second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per 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.MutagenicityAbacavir: 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 cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in cytogenetic study in rats given single dose.Impairment of FertilityAbacavir: Abacavir did not affect male or female fertility in rats at dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.. 13.2 Animal Toxicology and/or Pharmacology. Myocardial degeneration was found in mice and rats following administration of abacavir for years. The systemic exposures were equivalent to to 24 times the expected systemic exposure in humans at dose of 600 mg. The clinical relevance of this finding has not been determined.