INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Hypersensitivity Reactions Inform patients: that 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 abacavir and lamivudine tablets, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about abacavir and lamivudine tablets. The complete text of the Medication Guide is reprinted at the end of this document.to carry the Warning Card with them.how to identify hypersensitivity reaction [see Warnings and Precautions 5.1), Medication Guide] that if they develop symptoms consistent with hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking abacavir and lamivudine tablets.that hypersensitivity reaction can worsen and lead to hospitalization or death if abacavir and lamivudine tablets are not immediately discontinued.to not restart abacavir and lamivudine tablets 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.that if they have hypersensitivity reaction, they should dispose of any unused abacavir and lamivudine tablets to avoid restarting abacavir.that hypersensitivity reaction is usually reversible if it is detected promptly and abacavir and lamivudine tablets are stopped right away.that if they have interrupted abacavir and lamivudine tablets 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.to not restart abacavir and lamivudine tablets or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.Lactic Acidosis/Hepatomegaly with Steatosis Advise 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 abacavir and lamivudine tablets if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions 5.2)] Patients with Hepatitis or Co-infection Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see Warnings and Precautions 5.3)] Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions 5.4)]. Immune Reconstitution Syndrome Advise 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 abacavir and lamivudine tablets are started [see Warnings and Precautions 5.5)]. Redistribution/Accumulation of Body FatInform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions 5.6)] Pregnancy Registry Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir and lamivudine tablets during pregnancy [see Use in Specific Populations 8.1)]. Lactation Instruct 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 Dose Instruct patients that if they miss dose of abacavir and lamivudine tablets, 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 Guide Instruct patients to read the Medication Guide before starting abacavir and lamivudine tablets 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.All brand names listed are the registered trademarks of their respective owners and are not trademarks of AvKARE, Inc.Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 03/17 AV 02/18 (P) that 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 abacavir and lamivudine tablets, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about abacavir and lamivudine tablets. The complete text of the Medication Guide is reprinted at the end of this document.. to carry the Warning Card with them.. how to identify hypersensitivity reaction [see Warnings and Precautions 5.1), Medication Guide] . that if they develop symptoms consistent with hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking abacavir and lamivudine tablets.. that hypersensitivity reaction can worsen and lead to hospitalization or death if abacavir and lamivudine tablets are not immediately discontinued.. to not restart abacavir and lamivudine tablets 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.. that if they have hypersensitivity reaction, they should dispose of any unused abacavir and lamivudine tablets to avoid restarting abacavir.. that hypersensitivity reaction is usually reversible if it is detected promptly and abacavir and lamivudine tablets are stopped right away.. that if they have interrupted abacavir and lamivudine tablets 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.. to not restart abacavir and lamivudine tablets or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions 5.1)] Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions 5.2)] Exacerbations of hepatitis [see Boxed Warning, Warnings and Precautions 5.3)] Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis [see Warnings and Precautions 5.4)] Immune reconstitution syndrome [see Warnings and Precautions 5.5)] Fat redistribution [see Warnings and Precautions 5.6)] Myocardial infarction [see Warnings and Precautions 5.7)] . Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions 5.1)] . Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions 5.2)] . Exacerbations of hepatitis [see Boxed Warning, Warnings and Precautions 5.3)] . Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis [see Warnings and Precautions 5.4)] . Immune reconstitution syndrome [see Warnings and Precautions 5.5)] . Fat redistribution [see Warnings and Precautions 5.6)] . Myocardial infarction [see Warnings and Precautions 5.7)] . The most commonly reported adverse reactions of at least moderate intensity (incidence greater than 5%) in an adult HIV-1 clinical trial were drug hypersensitivity, insomnia, depression/depressed mood, headache/migraine, fatigue/malaise, dizziness/vertigo, nausea, and diarrhea. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience in Adult Subjects. 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 Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, component of abacavir and lamivudine tablets [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 Abacavir and Lamivudine TabletsTherapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 5% frequency during therapy with ZIAGEN (R) 600 mg once daily or ZIAGEN (R) 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily, are listed in Table 1. Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades to 4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30021) through 48 Weeks of Treatment Adverse Event ZIAGEN(R) 600 mg q.d. plus EPIVIR(R) plus Efavirenz (n 384) ZIAGEN(R) 300 mg b.i.d. plus EPIVIR(R) plus Efavirenz (n 386) Drug hypersensitivitySubjects receiving ZIAGEN (R) 600 mg once daily, experienced significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN (R) 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN (R) 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN (R) 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN (R) 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN (R) 300 mg twice daily had this event. ,CNA30024 was multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (R) (300 mg twice daily), EPIVIR (R) (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (R) (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group. 9% 7% Insomnia 7% 9% Depression/Depressed mood 7% 7% Headache/Migraine 7% 6% Fatigue/Malaise 6% 8% Dizziness/Vertigo 6% 6% Nausea 5% 6% Diarrhea 5% 6% Rash 5% 5% Pyrexia 5% 3% Abdominal pain/gastritis 4% 5% Abnormal dreams 4% 5% Anxiety 3% 5% Laboratory Abnormalities: Laboratory abnormalities observed in clinical trials of ZIAGEN (R) were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR (R) were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT. 6.2 Clinical Trials Experience in Pediatric Subjects. The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as abacavir and lamivudine tablets, was assessed in the ARROW trial (n 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade and Grade adverse events. The frequency of Grade and adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade or adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults [see Adverse Reactions 6.1)]. 6.3 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. Abacavir Cardiovascular: 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 and Lamivudine Body as Whole: Redistribution/accumulation of body fat [see Warnings and Precautions 5.6)]. Digestive: Stomatitis. Endocrine and Metabolic: Hyperglycemia. General: Weakness. Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic: Lactic acidosis and hepatic steatosis [see Warnings and Precautions 5.2)], posttreatment exacerbations of hepatitis [see Warnings and Precautions 5.3)]. Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis. Nervous: Paresthesia, peripheral neuropathy, seizures. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafetyavkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.

WARNING: HYPERSENSITIVITY REACTIONS, 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 abacavir and lamivudine tablets. 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)] Abacavir and lamivudine tablets are 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 abacavir and lamivudine tablets or reinitiation of therapy with abacavir and lamivudine tablets, unless patients have previously documented HLA-B5701 allele assessment. Discontinue abacavir and lamivudine tablets 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 abacavir and lamivudine tablets, NEVER restart abacavir and lamivudine tablets 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)]. 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 and other antiretrovirals. Discontinue abacavir and lamivudine tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions 5.2)]. Exacerbations of Hepatitis Severe 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, which is component of abacavir and lamivudine tablets. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue abacavir and lamivudine tablets and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis therapy may be warranted [see Warnings and Precautions 5.3)] . WARNING: HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B. See full prescribing information for complete boxed warning. Hypersensitivity ReactionsSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. 5.1) Hypersensitivity to abacavir is multi-organ clinical syndrome. 5.1) Patients who carry the HLA-B5701 allele are at higher risk of experiencing hypersensitivity reaction to abacavir. 5.1) Abacavir and lamivudine tablets are contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. 4) Discontinue abacavir and lamivudine tablets as soon as hypersensitivity reaction is suspected. Regardless of HLA-B5701 status, permanently discontinue abacavir and lamivudine tablets if hypersensitivity cannot be ruled out, even when other diagnoses are possible. 5.1) Following hypersensitivity reaction to abacavir and lamivudine tablets, NEVER restart abacavir and lamivudine tablets or any other abacavir-containing product. 5.1) 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. 5.2) Exacerbations of Hepatitis BSevere 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 abacavir and lamivudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. 5.3) Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. 5.1) Hypersensitivity to abacavir is multi-organ clinical syndrome. 5.1) Patients who carry the HLA-B5701 allele are at higher risk of experiencing hypersensitivity reaction to abacavir. 5.1) Abacavir and lamivudine tablets are contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. 4) Discontinue abacavir and lamivudine tablets as soon as hypersensitivity reaction is suspected. Regardless of HLA-B5701 status, permanently discontinue abacavir and lamivudine tablets if hypersensitivity cannot be ruled out, even when other diagnoses are possible. 5.1) Following hypersensitivity reaction to abacavir and lamivudine tablets, NEVER restart abacavir and lamivudine tablets or any other abacavir-containing product. 5.1) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. 5.2) Severe 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 abacavir and lamivudine tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. 5.3).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Abacavir and lamivudine tablets are an antiretroviral agent [see Microbiology 12.4)] . 12.3 Pharmacokinetics. Pharmacokinetics in Adults In single-dose, 3-way crossover bioavailability trial of abacavir and lamivudine tablets versus ZIAGEN (R) tablets (2 300 mg) and EPIVIR (R) tablets (2 150 mg) administered simultaneously in healthy subjects (n 25), 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 (C max), of each component. Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of single dose of 600 mg of abacavir in 20 subjects, max was 4.26 +- 1.19 mcg per mL (mean +- SD) and AUC was 11.95 +- 2.51 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. After multiple-dose oral administration of lamivudine 300 mg once daily for days to 60 healthy subjects, steady-state max (C max,ss) was 2.04 +- 0.54 mcg per mL (mean +- SD) and the 24-hour steady-state AUC (AUC 24,ss) was 8.87 +- 1.83 mcgohour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes. The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.Table 2. Pharmacokinetic Parameters Data presented as mean +- standard deviation except where noted. for Abacavir and Lamivudine in Adults Parameter Abacavir Lamivudine Oral bioavailability (%) 86 +- 25 = 86 +- 16 = 12 Apparent volume of distribution (L/kg) 0.86 +- 0.15 = 1.3 +- 0.4 = 20 Systemic clearance (L/h/kg) 0.80 +- 0.24 = 0.33 +- 0.06 = 20 Renal clearance (L/h/kg) 0.007 +- 0.008 = 0.22 +- 0.06 = 20 Elimination half-life (h) 1.45 +- 0.32 = 20 to Approximate range. Effect of Food on Absorption of Abacavir and Lamivudine Tablets Abacavir and lamivudine tablets may be administered with or without food. Administration with high-fat meal in single-dose bioavailability trial resulted in no change in AUC last, AUC and max for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC ), but the rate of absorption (C max) was decreased approximately 24% compared with fasted conditions (n 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately. Specific Populations Renal Impairment: Abacavir and Lamivudine Tablets: The effect of renal impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components). Hepatic Impairment: Abacavir and Lamivudine Tablets: The effect of hepatic impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components). Pregnancy: 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. Pediatric Patients: Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine following administration of abacavir and lamivudine tablets in pediatric subjects weighing 25 kg and above are limited. The dosing recommendations in this population are based on the safety and efficacy established in controlled trial conducted using either the combination of EPIVIR (R) and ZIAGEN (R) or abacavir and lamivudine tablets. Refer to the EPIVIR (R) and ZIAGEN (R) USPI for pharmacokinetic information on the individual products in pediatric patients [see Dosage and Administration 2.3), Adverse Reactions 6.1), Clinical Studies 14.2)]. Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age. Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components. Race: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components. Drug InteractionsThe drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with abacavir and lamivudine tablets. Cytochrome P450 Enzymes: In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Abacavir: Lamivudine and/or Zidovudine: Fifteen HIV-1-infected subjects were enrolled in crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir. Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 h). Other Interactions Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Methadone: In trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN (R) twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions 7)]. 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 5.4)]. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects. The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.Table 3. Effect of Coadministered Drugs on Abacavir or Lamivudine Coadministered Drug and DoseDrug and DosenConcentrations of Abacavir or LamivudineConcentration of Coadministered DrugAUCVariabilityEthanol 0.7 g/kg Abacavir Single 600 mg 24 41% 90% CI: 35% to 48% <-> The drug-drug interaction was only evaluated in males. Nelfinavir 750 mg every h 7 to 10 days Lamivudine Single 150 mg 11 10% 95% CI: 1% to 20% <->Trimethoprim 160 mg/Sulfamethoxazole 800 mg daily 5 days Lamivudine Single 300 mg 14 43% 90% CI: 32% to 55% <-> Increase; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval.. 12.4 Microbiology. Mechanism of Action Abacavir: 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. Antiviral Activity Abacavir: 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). EC 50 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-1 IIIB and HIV-1 BaL, respectively, and the mean EC 50 value was 0.26 +- 0.18 microM against clinical isolates. The median EC 50 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 EC 50 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. EC 50 values were in the range of 0.003 to 15 microM (1 microM 0.23 mcg per mL). The median EC 50 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 EC 50 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. The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype isolates and HIV-2 isolates with equivalent antiviral activity as for subtype isolates. Neither abacavir, nor lamivudine, were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (R) (abacavir) and EPIVIR (R) (lamivudine). Ribavirin, used in the treatment of HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2- to 6-fold in cell culture. Resistance 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. Cross-Resistance Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (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 thymidine analog mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with progressive reduction in abacavir susceptibility.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adults One abacavir and lamivudine tablet given once daily is an alternative regimen to EPIVIR (R) tablets 300 mg once daily plus ZIAGEN (R) tablets x 300 mg once daily as component of antiretroviral therapy. The following trial was conducted with the individual components of abacavir and lamivudine tablets. Therapy-Naive Adults CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (R) 600 mg once daily or ZIAGEN (R) 300 mg twice daily, both in combination with EPIVIR (R) 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm (range: 21 to 918 cells per mm 3) and the median baseline plasma HIV-1 RNA was 4.89 log 10 copies per mL (range: 2.60 to 6.99 log 10 copies per mL). The outcomes of randomized treatment are provided in Table 4. Table 4. Outcomes of Randomized Treatment through Week 48 (CNA30021) OutcomeZIAGEN (R) 600 mg q.d. plus EPIVIR (R) plus Efavirenz (n 384) ZIAGEN (R) 300 mg b.i.d. plus EPIVIR (R) plus Efavirenz (n 386) Responder Subjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR (R) standard test version 1.0). 64% (71%)65% (72%)Virologic failure Includes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response. 11% (5%)11% (5%)Discontinued due to adverse reactions13%11%Discontinued due to other reasons Includes consent withdrawn, lost to follow-up, protocol violations, clinical progression, and other. 11%13%After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm in the group receiving ZIAGEN (R) 600 mg once daily and 200 cells per mm in the group receiving ZIAGEN (R) 300 mg twice daily. Through Week 48, subjects (2%) in the group receiving ZIAGEN (R) 600 mg once daily (4 CDC classification events and deaths) and 10 subjects (3%) in the group receiving ZIAGEN (R) 300 mg twice daily (7 CDC classification events and deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications. 14.2 Pediatric Subjects ARROW (COL105677) was 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1-infected, treatment-naive subjects aged months to 17 years were enrolled and treated with first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not requirement for participation at baseline for Randomization 3. At baseline for Randomization (following minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Subjects randomized to receive once-daily dosing (n 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as abacavir and lamivudine tablets. The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 5. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age. Table 5. Virologic Outcome of Randomized Treatment at Week 96Analyses were based on the last observed viral load data within the Week 96 window. (ARROW Randomization 3)OutcomeAbacavir plus Lamivudine Twice-Daily Dosing (n 333) Abacavir plus Lamivudine Once-Daily Dosing (n 336) HIV-1 RNA 80 copies/mLRisk difference (95% CI) of response rate is -2.4% (-9% to 5%) at Week 96.70%67%HIV-1 RNA >= 80 copies/mLIncludes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had viral load value of greater than or equal to 80 copies per mL, or subjects who had switch in background regimen that was not permitted by the protocol.28%31%No virologic dataDiscontinued due to adverse event or death 1%< 1%Discontinued study for other reasons Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing). 0%< 1%Missing data during window but on study 1%1%.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics in Adults In single-dose, 3-way crossover bioavailability trial of abacavir and lamivudine tablets versus ZIAGEN (R) tablets (2 300 mg) and EPIVIR (R) tablets (2 150 mg) administered simultaneously in healthy subjects (n 25), 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 (C max), of each component. Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of single dose of 600 mg of abacavir in 20 subjects, max was 4.26 +- 1.19 mcg per mL (mean +- SD) and AUC was 11.95 +- 2.51 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. After multiple-dose oral administration of lamivudine 300 mg once daily for days to 60 healthy subjects, steady-state max (C max,ss) was 2.04 +- 0.54 mcg per mL (mean +- SD) and the 24-hour steady-state AUC (AUC 24,ss) was 8.87 +- 1.83 mcgohour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes. The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.Table 2. Pharmacokinetic Parameters Data presented as mean +- standard deviation except where noted. for Abacavir and Lamivudine in Adults Parameter Abacavir Lamivudine Oral bioavailability (%) 86 +- 25 = 86 +- 16 = 12 Apparent volume of distribution (L/kg) 0.86 +- 0.15 = 1.3 +- 0.4 = 20 Systemic clearance (L/h/kg) 0.80 +- 0.24 = 0.33 +- 0.06 = 20 Renal clearance (L/h/kg) 0.007 +- 0.008 = 0.22 +- 0.06 = 20 Elimination half-life (h) 1.45 +- 0.32 = 20 to Approximate range. Effect of Food on Absorption of Abacavir and Lamivudine Tablets Abacavir and lamivudine tablets may be administered with or without food. Administration with high-fat meal in single-dose bioavailability trial resulted in no change in AUC last, AUC and max for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC ), but the rate of absorption (C max) was decreased approximately 24% compared with fasted conditions (n 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately. Specific Populations Renal Impairment: Abacavir and Lamivudine Tablets: The effect of renal impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components). Hepatic Impairment: Abacavir and Lamivudine Tablets: The effect of hepatic impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components). Pregnancy: 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. Pediatric Patients: Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine following administration of abacavir and lamivudine tablets in pediatric subjects weighing 25 kg and above are limited. The dosing recommendations in this population are based on the safety and efficacy established in controlled trial conducted using either the combination of EPIVIR (R) and ZIAGEN (R) or abacavir and lamivudine tablets. Refer to the EPIVIR (R) and ZIAGEN (R) USPI for pharmacokinetic information on the individual products in pediatric patients [see Dosage and Administration 2.3), Adverse Reactions 6.1), Clinical Studies 14.2)]. Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age. Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components. Race: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components. Drug InteractionsThe drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with abacavir and lamivudine tablets. Cytochrome P450 Enzymes: In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Abacavir: Lamivudine and/or Zidovudine: Fifteen HIV-1-infected subjects were enrolled in crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir. Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 h). Other Interactions Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Methadone: In trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN (R) twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions 7)]. 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 5.4)]. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects. The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.Table 3. Effect of Coadministered Drugs on Abacavir or Lamivudine Coadministered Drug and DoseDrug and DosenConcentrations of Abacavir or LamivudineConcentration of Coadministered DrugAUCVariabilityEthanol 0.7 g/kg Abacavir Single 600 mg 24 41% 90% CI: 35% to 48% <-> The drug-drug interaction was only evaluated in males. Nelfinavir 750 mg every h 7 to 10 days Lamivudine Single 150 mg 11 10% 95% CI: 1% to 20% <->Trimethoprim 160 mg/Sulfamethoxazole 800 mg daily 5 days Lamivudine Single 300 mg 14 43% 90% CI: 32% to 55% <-> Increase; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir and lamivudine tablets 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 or lamivudine 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. 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 (C max) 35 times the recommended clinical dose [see Data]. Data Human Data: Abacavir: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first 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 the U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) 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 over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first 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 the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5%, 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). 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 (C max) 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 (C max) 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 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 gestation Day through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Abacavir (a-BAK-a-vir) and Lamivudine (la-MIV-ue-deen) Tablets USPWhat is the most important information should know about abacavir and lamivudine tablets Abacavir and lamivudine tablets can cause serious side effects, including:Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with abacavir and lamivudine tablets 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 abacavir and lamivudine tablets, call your healthcare provider right away to find out if you should stop taking abacavir and lamivudine tablets.Symptoms(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 abacavir and lamivudine tablets because of an allergic reaction, never take abacavir and lamivudine tablets or any other abacavir-containing medicine (TRIUMEQ (R), TRIZIVIR (R) or ZIAGEN (R)) again. If you have an allergic reaction, dispose of any unused abacavir and lamivudine tablets. Ask your pharmacist how to properly dispose of medicines.If you take abacavir and lamivudine tablets 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. If you stop abacavir and lamivudine tablets for any other reason, even for few days, and you are not allergic to abacavir and lamivudine tablets, talk with your healthcare provider before taking them again. Taking abacavir and lamivudine tablets again can cause serious allergic or life-threatening reaction, even if you never had an allergic reaction to them before.If your healthcare provider tells you that you can take abacavir and lamivudine tablets again, start taking them when you are around medical help or people who can call healthcare provider if you need one.Build up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take abacavir and lamivudine tablets. Lactic acidosis is serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: feel very weak or tiredunusual (not normal) muscle paintrouble breathingstomach pain with nausea and vomitingfeel cold, especially in your arms and legsfeel dizzy or light-headedhave fast or irregular heartbeatSerious liver problems can happen in people who take abacavir and lamivudine tablets. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: your skin or the white part of your eyes turns yellow (jaundice)dark or tea-colored urinelight-colored stools (bowel movements)loss of appetite for several days or longernauseapain, 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, very overweight (obese), or have been taking nucleoside analogue medicines for long time. Worsening of hepatitis virus in people who have HIV-1 infection. If you have HIV-1 and hepatitis virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking abacavir and lamivudine tablets. flare-up is when your HBV infection suddenly returns in worse way than before. Worsening liver disease can be serious and may lead to death. Do not run out of abacavir and lamivudine tablets. Refill your prescription or talk to your healthcare provider before your abacavir and lamivudine tablets are all gone.Do not stop abacavir and lamivudine tablets without first talking to your healthcare provider.If you stop taking abacavir and lamivudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.Resistant Hepatitis Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis virus can change (mutate) during your treatment with abacavir and lamivudine tablets and become harder to treat (resistant). Use 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 antiretroviral medicines and are also being treated for hepatitis with interferon with or without ribavirin. If you are taking abacavir and lamivudine tablets and interferon with or without ribavirin tell your healthcare provider if you have any new symptoms. What are abacavir and lamivudine tablets Abacavir and lamivudine tablets are prescription HIV-1 (Human Immunodeficiency Virus-type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). Abacavir and lamivudine tablets contain prescription medicines, abacavir (ZIAGEN (R)) and lamivudine (EPIVIR (R)). Abacavir and lamivudine tablets should not be used in children weighing less than 55 pounds (25 kg).When used with other antiretroviral medicines to treat HIV-1 infection, abacavir and lamivudine tablets may help: reduce the amount of HIV-1 in your blood. This is called viral load.increase the number of CD4+ (T) cells in your blood, that help fight off other infections.Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).Abacavir and lamivudine tablets do not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses. Who should not take abacavir and lamivudine tablets Do not take abacavir and lamivudine tablets if you:have certain type of gene variation called the HLA-B5701 allele. Your healthcare provider will test you for this before prescribing treatment with abacavir and lamivudine tablets.are allergic to abacavir or any of the ingredients in abacavir and lamivudine tablets. See the end of this Medication Guide for complete list of ingredients in abacavir and lamivudine tablets.have liver problems.What should tell my healthcare provider before taking abacavir and lamivudine tablets Before you take abacavir and lamivudine tablets tell your healthcare provider if you:have been tested and know whether or not you have particular gene variation called HLA-B5701.have or have had liver problems, including hepatitis or virus infection.have kidney problems.have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.drink alcohol or take medicines that contain alcohol.are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Pregnancy Registry. There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take abacavir and lamivudine tablets. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with abacavir and lamivudine tablets. Keep list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for list of medicines that interact with abacavir and lamivudine tablets. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take abacavir and lamivudine tablets with other medicines. Tell your healthcare provider if you take:any other medicine to treat HIV-1medicines to treat hepatitis viruses such as interferon or ribavirinmethadoneHow should take abacavir and lamivudine tablets Take abacavir and lamivudine tablets exactly as your healthcare provider tells you. Do not change your dose or stop taking abacavir and lamivudine tablets without talking with your healthcare provider. If you miss dose of abacavir and lamivudine tablets, take it as soon as you remember. Do not take doses at the same time. If you are not sure about your dosing, call your healthcare provider.Stay under the care of healthcare provider while taking abacavir and lamivudine tablets.Abacavir and lamivudine tablets may be taken with or without food.Tell your healthcare provider if your child has trouble swallowing abacavir and lamivudine tablets.Do not run out of abacavir and lamivudine tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.If you take too many abacavir and lamivudine tablets, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of abacavir and lamivudine tablets Abacavir and lamivudine tablets can cause serious side effects including: See What is the most important information should know about abacavir and lamivudine tabletsChanges 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 abacavir and lamivudine tablets. Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. Heart attack (myocardial infarction). Some HIV-1 medicines including abacavir and lamivudine tablets may increase your risk of heart attack. The most common side effects of abacavir and lamivudine tablets include: trouble sleepingdepressionheadachetirednessdizzinessnauseadiarrhearashfeverTell 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 abacavir and lamivudine tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store abacavir and lamivudine tablets Store abacavir and lamivudine tablets between 68 to 77F (20 to 25C).Keep abacavir and lamivudine tablets and all medicines out of the reach of children. General information for safe and effective use of abacavir and lamivudine tablets.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use abacavir and lamivudine tablets for condition for which they were not prescribed. Do not give abacavir and lamivudine tablets to other people, even if they have the same symptoms that you have. They may harm them.If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information about abacavir and lamivudine tablets that is written for health professionals.For more information call 1-855-361-3993.What are the ingredients in abacavir and lamivudine tablets USP Active ingredients: abacavir sulfate, USP and lamivudine, USPInactive ingredients: FD&C yellow 6, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 03/17 AV 02/18 (P) Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with abacavir and lamivudine tablets 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 have an allergic reaction, dispose of any unused abacavir and lamivudine tablets. Ask your pharmacist how to properly dispose of medicines.. If you take abacavir and lamivudine tablets 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. If you stop abacavir and lamivudine tablets for any other reason, even for few days, and you are not allergic to abacavir and lamivudine tablets, talk with your healthcare provider before taking them again. Taking abacavir and lamivudine tablets again can cause serious allergic or life-threatening reaction, even if you never had an allergic reaction to them before.. Build up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take abacavir and lamivudine tablets. Lactic acidosis is serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: feel very weak or tired. unusual (not normal) muscle pain. trouble breathing. stomach pain with nausea and vomiting. feel cold, especially in your arms and legs. feel dizzy or light-headed. have fast or irregular heartbeat. Serious liver problems can happen in people who take abacavir and lamivudine tablets. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: your skin or the white part of your eyes turns yellow (jaundice). dark or tea-colored urine. light-colored stools (bowel movements). loss of appetite for several days or longer. nausea. pain, aching, or tenderness on the right side of your stomach area. Worsening of hepatitis virus in people who have HIV-1 infection. If you have HIV-1 and hepatitis virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking abacavir and lamivudine tablets. flare-up is when your HBV infection suddenly returns in worse way than before. Worsening liver disease can be serious and may lead to death. Do not run out of abacavir and lamivudine tablets. Refill your prescription or talk to your healthcare provider before your abacavir and lamivudine tablets are all gone.. Do not stop abacavir and lamivudine tablets without first talking to your healthcare provider.. If you stop taking abacavir and lamivudine tablets, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.. Resistant Hepatitis Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis virus can change (mutate) during your treatment with abacavir and lamivudine tablets and become harder to treat (resistant). Use 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 antiretroviral medicines and are also being treated for hepatitis with interferon with or without ribavirin. If you are taking abacavir and lamivudine tablets and interferon with or without ribavirin tell your healthcare provider if you have any new symptoms. reduce the amount of HIV-1 in your blood. This is called viral load.. increase the number of CD4+ (T) cells in your blood, that help fight off other infections.. have certain type of gene variation called the HLA-B5701 allele. Your healthcare provider will test you for this before prescribing treatment with abacavir and lamivudine tablets.. are allergic to abacavir or any of the ingredients in abacavir and lamivudine tablets. See the end of this Medication Guide for complete list of ingredients in abacavir and lamivudine tablets.. have liver problems.. have been tested and know whether or not you have particular gene variation called HLA-B5701.. have or have had liver problems, including hepatitis or virus infection.. have kidney problems.. have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.. drink alcohol or take medicines that contain alcohol.. are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Pregnancy Registry. There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take abacavir and lamivudine tablets. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. any other medicine to treat HIV-1. medicines to treat hepatitis viruses such as interferon or ribavirin. methadone. Take abacavir and lamivudine tablets exactly as your healthcare provider tells you. Do not change your dose or stop taking abacavir and lamivudine tablets without talking with your healthcare provider. If you miss dose of abacavir and lamivudine tablets, take it as soon as you remember. Do not take doses at the same time. If you are not sure about your dosing, call your healthcare provider.. Stay under the care of healthcare provider while taking abacavir and lamivudine tablets.. Abacavir and lamivudine tablets may be taken with or without food.. Tell your healthcare provider if your child has trouble swallowing abacavir and lamivudine tablets.. Do not run out of abacavir and lamivudine tablets. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.. If you take too many abacavir and lamivudine tablets, call your healthcare provider or go to the nearest hospital emergency room right away.. Abacavir and lamivudine tablets can cause serious side effects including: See What is the most important information should know about abacavir and lamivudine tablets. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after you start taking abacavir and lamivudine tablets. Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. Heart attack (myocardial infarction). Some HIV-1 medicines including abacavir and lamivudine tablets may increase your risk of heart attack. trouble sleeping. depression. headache. tiredness. dizziness. nausea. diarrhea. rash. fever. Store abacavir and lamivudine tablets between 68 to 77F (20 to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. 8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 2/2018 Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. 8.2) 8.1 Pregnancy Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to abacavir and lamivudine tablets 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 or lamivudine 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. 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 (C max) 35 times the recommended clinical dose [see Data]. Data Human Data: Abacavir: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first 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 the U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) 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 over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first 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 the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5%, 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). 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 (C max) 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 (C max) 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 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 gestation Day through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir and lamivudine are present in human milk. There is no information on the effects of abacavir and lamivudine 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) serious adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving abacavir and lamivudine tablets.. 8.4 Pediatric Use. The dosing recommendations in this population are based on the safety and efficacy established in controlled trial conducted using either the combination of EPIVIR (R) and ZIAGEN (R) or abacavir and lamivudine tablets [see Dosage and Administration 2.3), Adverse Reactions 6.2), Clinical Studies 14.2)]. In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing.. 8.5 Geriatric Use. Clinical trials of abacavir and lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of abacavir and lamivudine tablets in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration 2.4), Use in Specific Populations 8.6, 8.7)] . 8.6 Patients with Impaired Renal Function. Abacavir and lamivudine tablets are not recommended for patients with creatinine clearance less than 50 mL per min because abacavir and lamivudine tablets are fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of lamivudine, component of abacavir and lamivudine tablets, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used [see Clinical Pharmacology 12.3)]. 8.7 Patients with Impaired Hepatic Function. Abacavir and lamivudine tablets are fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of abacavir, component of abacavir and lamivudine tablets, 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, abacavir and lamivudine tablets are contraindicated in these patients [see Contraindications 4)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue abacavir and lamivudine tablets as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. 5.4) Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. 5.5, 5.6) Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue abacavir and lamivudine tablets as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. 5.4) Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. 5.5, 5.6) 5.1 Hypersensitivity Reactions. Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, component of abacavir and lamivudine tablets. 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: All patients should be screened for the HLA-B5701 allele prior to initiating therapy with abacavir and lamivudine tablets or reinitiation of therapy with abacavir and lamivudine tablets, unless patients have previously documented HLA-B5701 allele assessment. Abacavir and lamivudine tablets are contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. Before starting abacavir and lamivudine tablets, review medical history for prior exposure to any abacavir- containing product. NEVER restart abacavir and lamivudine tablets or any other abacavir-containing product following hypersensitivity reaction to abacavir, regardless of HLA-B5701 status. To reduce the risk of life-threatening hypersensitivity reaction, regardless of HLA-B5701 status, discontinue abacavir and lamivudine tablets 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). If hypersensitivity reaction cannot be ruled out, do not restart abacavir and lamivudine tablets or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. If hypersensitivity reaction is ruled out, patients may restart abacavir and lamivudine tablets. 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 abacavir and lamivudine tablets or any other abacavir-containing product is recommended only if medical care can be readily accessed. Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. All patients should be screened for the HLA-B5701 allele prior to initiating therapy with abacavir and lamivudine tablets or reinitiation of therapy with abacavir and lamivudine tablets, unless patients have previously documented HLA-B5701 allele assessment. Abacavir and lamivudine tablets are contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. Before starting abacavir and lamivudine tablets, review medical history for prior exposure to any abacavir- containing product. NEVER restart abacavir and lamivudine tablets or any other abacavir-containing product following hypersensitivity reaction to abacavir, regardless of HLA-B5701 status. To reduce the risk of life-threatening hypersensitivity reaction, regardless of HLA-B5701 status, discontinue abacavir and lamivudine tablets 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). If hypersensitivity reaction cannot be ruled out, do not restart abacavir and lamivudine tablets or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. If hypersensitivity reaction is ruled out, patients may restart abacavir and lamivudine tablets. 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 abacavir and lamivudine tablets or any other abacavir-containing product is recommended only if medical care can be readily accessed. A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. 5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for ZIAGEN (R) (abacavir) and EPIVIR (R) (lamivudine). Treatment with abacavir and lamivudine tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.3 Patients with Hepatitis Virus Co-infection. Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR(R) (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(R) (lamivudine). 5.4 Use with Interferon- and Ribavirin-based Regimens. Patients receiving interferon alfa with or without ribavirin and abacavir and lamivudine tablets should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR(R) (lamivudine). Discontinuation of abacavir and lamivudine tablets should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).. 5.5 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including abacavir and lamivudine tablets. 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.. 5.6 Fat Redistribution. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.. 5.7 Myocardial Infarction. In published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous months was correlated with an increased risk of MI. In sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. As 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).