A-METHAPRED (methylprednisolone sodium succinate) Injection, Powder, Lyophilized, for Solution For Intravenous or Intramuscular Administration DESCRIPTION A-Methapred (methylprednisolone sodium succinate for injection, USP) sterile powder contains methylprednisolone sodium succinate as the active ingredient. Methylprednisolone sodium succinate, USP, occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in chloroform and is very slightly soluble in acetone. The chemical name for methylprednisolone sodium succinate is pregna-1,4-diene-3,20-dione,21-(3-carboxy-1-oxo-propoxy)-11,17-dihydroxy-6-methyl-monosodium salt, (6a, 11ß), and the molecular weight is 496.53. The structural formula is represented below: Methylprednisolone sodium succinate is so extremely soluble in water that it may be administered in a small volume of diluent and is especially well suited for intravenous use in situations in which high blood levels of methylprednisolone are required rapidly. A-Methapred (methylprednisolone sodium succinate) is available in several strengths and packages for intravenous or intramuscular administration. 40 mg Single-Dose Vial- Each mL (when mixed) contains methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate anhydrous; 25 mg lactose anhydrous; 8.8 mg benzyl alcohol added as preservative. 125 mg Single-Dose Vial- Each 2 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.4 mg dibasic sodium phosphate anhydrous; 17.6 mg benzyl alcohol added as preservative. When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8 and the tonicities are, for the 40 mg per mL solution, 0.50 osmolar; for the 125 mg per 2 mL, 0.40 osmolar; (Isotonic saline = 0.28 osmolar). IMPORTANT- Use only Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting A-Methapred (methylprednisolone sodium succinate) . Use within 48 hours after mixing.

SIDE EFFECTS Fluid and Electrolyte Disturbances Sodium retention, Fluid retention, Congestive heart failure in susceptible patients, Potassium loss, Hypokalemic alkalosis, Hypertension Musculoskeletal Muscle weakness, Steroid myopathy, Loss of muscle mass, Severe arthralgia, Vertebral compression fractures, Aseptic necrosis of femoral and humeral heads, Pathologic fracture of long bones, Osteoporosis Gastrointestinal Peptic ulcer with possible perforation and hemorrhage, Pancreatitis, Abdominal distention, and Ulcerative esophagitis Dermatologic Impaired wound healing, Thin fragile skin, Petechiae and ecchymoses, Facial erythema, Increased sweating, May suppress reactions to skin tests Neurological Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment, Convulsions, Vertigo, Headache Endocrine Development of Cushingoid state, Suppression of growth in children, Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness, Menstrual irregularities, Decreased carbohydrate tolerance, Manifestations of latent diabetes mellitus, Increased requirements for insulin or oral hypoglycemic agents in diabetics Ophthalmic Posterior subcapsular cataracts, Increased intraocular pressure, Glaucoma, Exophthalmos Metabolic Negative nitrogen balance due to protein catabolism The following additional adverse reactions are related to parenteral corticosteroid therapy: Hyperpigmentation or hypopigmentation, Subcutaneous and cutaneous atrophy, Sterile abscess, Anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm, Urticaria, Nausea and vomiting, Cardiac arrhythmias; hypotension or hypertension DRUG INTERACTIONS The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin.

OVERDOSE No information provided. CONTRAINDICATIONS The use of A-Methapred (methylprednisolone sodium succinate) sterile powder is contraindicated in premature infants because the reconstitution diluent contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. A-Methapred (methylprednisolone sodium succinate) sterile powder is also contraindicated in systemic fungal infections and patients with known hypersensitivity to the product and its constituents.

INDICATIONS ZIAGEN tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting ZIAGEN Screen for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adult Patients The recommended dosage of ZIAGEN for adults is 600 mg daily, administered orally as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents. Recommended Dosage For Pediatric Patients The recommended dosage of ZIAGEN oral solution in HIV-1-infected pediatric patients aged 3 months and older is 8 mg per kg orally twice daily or 16 mg per kg orally once-daily (up to a maximum of 600 mg daily) in combination with other antiretroviral agents. ZIAGEN is also available as a scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing ZIAGEN tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow ZIAGEN tablets, the oral solution formulation should be prescribed. The recommended oral dosage of ZIAGEN tablets for HIV-1-infected pediatric patients is presented in Table 1. Table 1: Dosing Recommendations for ZIAGEN Scored Tablets in Pediatric Patients Weight (ks) Once-Daily Dosing Regimena Twice-Daily Dosing Regimen AM Dose PM Dose Total Daily Dose 14 to < 20 1 tablet (300 mg) ½tablet (150 mg) ½tablet (150 mg) 300 mg ≥ 20 to < 25 1½tablets (450 mg) ½tablet (150 mg) 1 tablet (300 mg) 450 mg ≥ 25 2 tablets (600 mg) 1 tablet (300 mg) 1 tablet (300 mg) 600 mg a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies]. Recommended Dosage For Patients With Hepatic Impairment The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child-Pugh Class A) is 200 mg twice daily. To enable dose reduction, ZIAGEN oral solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients. HOW SUPPLIED Dosage Forms And Strengths ZIAGEN tablets contain 300 mg of abacavir as abacavir sulfate. The tablets are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides. ZIAGEN oral solution contains 20 mg per mL of abacavir as abacavir sulfate. The solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Storage And Handling ZIAGEN tablets, containing abacavir sulfate equivalent to 300 mg abacavir are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides. They are packaged as follows: Bottles of 60 tablets (NDC 49702-221-18). Unit dose blister packs of 60 tablets (NDC 49702-221-44). Each pack contains 6 blister cards of 10 tablets each. Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP). ZIAGEN oral solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows: Bottles of 240 mL (NDC 49702-222-48) with child-resistant closure. This product does not require reconstitution. Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP). DO NOT FREEZE. May be refrigerated. Manufactured For:ViiV Healthecare, Research Triangle Park, NC 27709. by: Research Triangle Park, NC 27709. Revised: Mar 2017

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with ZIAGEN (abacavir). These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with ZIAGEN (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see ADVERSE REACTIONS]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with ZIAGEN: All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment. ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting ZIAGEN, review medical history for prior exposure to any abacavir-containing product. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue ZIAGEN immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). If a hypersensitivity reaction cannot be ruled out, do not restart ZIAGEN or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours. If a hypersensitivity reaction is ruled out, patients may restart ZIAGEN. 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 ZIAGEN 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. 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. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering ZIAGEN to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with ZIAGEN 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). Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZIAGEN. 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-Barr syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reactions Inform patients: that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of ZIAGEN, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about ZIAGEN. The complete text of the Medication Guide is reprinted at the end of this document. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking ZIAGEN. that a hypersensitivity reaction can worsen and lead to hospitalization or death if ZIAGEN is not immediately discontinued. to not restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death. that if they have a hypersensitivity reaction, they should dispose of any unused ZIAGEN to avoid restarting abacavir. that a hypersensitivity reaction is usually reversible if it is detected promptly and ZIAGEN is stopped right away. that if they have interrupted ZIAGEN for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir. to not restart ZIAGEN 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 ZIAGEN if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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 ZIAGEN is started [see WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation Of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy [see Use in Specific Populations]. 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]. Missed Dose Instruct patients that if they miss a dose of ZIAGEN, 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]. Availability of Medication Guide Instruct patients to read the Medication Guide before starting ZIAGEN 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg. Mutagenicity Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation. Impairment Of Fertility Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose. Use In Specific Populations Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy. Healthcare Providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for abacavir 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 a 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 9 times the human exposure (AUC) at the recommended clinical dose [see Data]. Data Human Data: 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]. Animal Data: 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 6 through 17 and 6 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 a 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 4 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 9 times the human exposure at the recommended dose. 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 is present in human milk. There is no information on the effects of abacavir 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 a breastfed infant, instruct mothers not to breastfeed if they are receiving ZIAGEN. Pediatric Use The safety and effectiveness of ZIAGEN have been established in pediatric patients aged 3 months and older. Use of ZIAGEN is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of ZIAGEN in adults and pediatric subjects [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies]. Geriatric Use Clinical trials of ZIAGEN 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 ZIAGEN in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Patients With Impaired Hepatic Function A dose reduction is required for patients with mild hepatic impairment (Child-Pugh Class A) [see DOSAGE AND ADMINISTRATION]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate or severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients [see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].

CLINICAL PHARMACOLOGY Mechanism Of Action Abacavir is an antiretroviral agent [see Microbiology]. Pharmacokinetics Pharmacokinetics In Adults The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day. Absorption and Bioavailability: Following oral administration, abacavir is rapidly absorbed and extensively distributed. The geometric mean absolute bioavailability of the tablet was 83%. Plasma abacavir AUC was similar following administration of the oral solution or tablets. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (Cmax) was 3.0 &plusmn; 0.89 mcg per mL (mean &plusmn; SD) and AUC(0-12 h) was 6.02 &plusmn; 1.73 mcg&bull;hour per mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 &plusmn; 1.19 mcg per mL (mean &plusmn; SD) and AUC&infin; was 11.95 &plusmn; 2.51 mcg&bull;hour per mL. Distribution: The apparent volume of distribution after IV administration of abacavir was 0.86 &plusmn; 0.15 L per kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC(0-6 h) to plasma abacavir AUC(0-6 h) ratio ranged from 27% to 33%. 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. Metabolism and Elimination: In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. 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. The metabolites do not have antiviral activity. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations. Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5'-carboxylic acid metabolite, 36% as the 5'-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose. In single-dose trials, the observed elimination half-life (t&frac12;) was 1.54 &plusmn; 0.63 hours. After intravenous administration, total clearance was 0.80 &plusmn; 0.24 L per hour per kg (mean &plusmn; SD). Effects Of Food On Oral Absorption Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC&infin;); therefore, ZIAGEN tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of ZIAGEN oral solution and ZIAGEN tablets. Therefore, these products may be used interchangeably. Specific Populations Renal Impairment: The pharmacokinetic properties of ZIAGEN have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans. Hepatic Impairment: The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see CONTRAINDICATIONS, Use in Specific Populations]. 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. Pediatric Patients: The pharmacokinetics of abacavir have been studied after either single or repeat doses of ZIAGEN in 169 pediatric subjects. Subjects receiving abacavir oral solution according to the recommended dosage regimen achieved plasma concentrations of abacavir similar to adults. Subjects receiving abacavir oral tablets achieved higher plasma concentrations of abacavir than subjects receiving oral solution. The pharmacokinetics of abacavir dosed once daily in HIV-1-infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice- versus once-daily dosing of abacavir and lamivudine. For the oral solution as well as the tablet formulation, these 3 trials demonstrated that once-daily dosing provides comparable AUC0-24 to twice-daily dosing of abacavir at the same total daily dose. The mean Cmax was approximately 1.6- to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing. Geriatric Patients: The pharmacokinetics of ZIAGEN have not been studied in subjects older than 65 years. Gender: A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight. Race: There are no significant or clinically relevant racial differences between blacks and whites in abacavir pharmacokinetics. Drug Interactions In human liver microsomes, abacavir did not inhibit cytochrome P450 isoforms (2C9, 2D6, 3A4). Based on these data, it is unlikely that clinically significant drug interactions will occur between abacavir and drugs metabolized through these pathways. Lamivudine and/or Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir. Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Due to the common metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was studied in 24 HIV-1-infected male subjects. Each subject received the following treatments on separate occasions: a single 600-mg dose of abacavir, 0.7 g per kg ethanol (equivalent to 5 alcoholic drinks), and abacavir 600 mg plus 0.7 g per kg ethanol. Coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC&infin; and a 26% increase in abacavir t&frac12;. Abacavir had no effect on the pharmacokinetic properties of ethanol, so no clinically significant interaction is expected in men. This interaction has not been studied in females. Methadone: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients [see DRUG INTERACTIONS]. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir. Microbiology Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Antiviral Activity The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 &plusmn; 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. Ribavirin (50 microM) used in the treatment of chronic HCV infection had no effect on the anti-HIV-1 activity of abacavir in cell culture. Resistance HIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture. Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I emerged in HIV-1 RT. M184V or I substitutions resulted in an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility. Thirty-nine percent (7 of 18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a greater than 2.5-fold mean decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5 of 17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13). Cross-Resistance Cross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, and tenofovir in cell culture and in subjects. An increasing number of thymidine analogue mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility. Animal Toxicology And/Or Pharmacology Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined. Clinical Studies Adult Trials Therapy-Naive Adults CNA30024 was a multicenter, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Trial participants were male (81%), white (51%), black (21%), and Hispanic (26%). The median age was 35 years; the median pretreatment CD4+ cell count was 264 cells per mm&sup3;, and median plasma HIV-1 RNA was 4.79 log10 copies per mL. The outcomes of randomized treatment are provided in Table 7. Table 7: Outcomes of Randomized Treatment through Week 48 (CNA30024) Outcome ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Respondera 69% (73%) 69% (71%) Virologic failuresb 6% 4% Discontinued due to adverse reactions 14% 16% Discontinued due to other reasonsc 10% 11% a Subjects achieved and maintained confirmed HIV-1 RNA less than or equal to 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR&reg; standard test 1.0 PCR). b Includes viral rebound, insufficient viral response according to the investigator, and failure to achieve confirmed less than or equal to 50 copies per mL by Week 48. c Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other. After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells per mm&sup3; in the group receiving ZIAGEN and 155 cells per mm&sup3; in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving ZIAGEN (5 CDC classification C events and 3 deaths) and 5 subjects (2%) on the zidovudine arm (3 CDC classification C events and 2 deaths) experienced clinical disease progression. CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR&reg; (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), white (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells per mm&sup3;, and median baseline plasma HIV-1 RNA was 4.8 log10 copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8. Table 8. Outcomes of Randomized Treatment through Week 48 (CNA3005) Outcome ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 265) Respondera 49% 50% Virologic failureb 31% 28% Discontinued due to adverse reactions 10% 12% Discontinued due to other reasonsc 11% 10% a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL. b Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48. c Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other. Treatment response by plasma HIV-1 RNA strata is shown in Table 9. Table 9: Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005) Screening HIV-1 RNA (copies/mL) ZIAGEN plus Lamivudine/ Zidovudine (n = 262) Indinavir plus Lamivudine/ Zidovudine (n = 265) < 400 copies/mL n < 400 copies/mL n &ge; 10,000 - &le; 100,000 50% 166 48% 165 > 100,000 48% 96 52% 100 In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir versus 45% in the group receiving indinavir. Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm&sup3; was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression. CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a 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&sup3; (range: 21 to 918 cells per mm&sup3;) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.60 to 6.99 log10 copies per mL). The outcomes of randomized treatment are provided in Table 10. Table 10: Outcomes of Randomized Treatment through Week 48 (CNA30021) Outcome ZIAGEN 600 mg q.d. plus EPIVIR&reg; plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Respondera 64% (71%) 65% (72%) Virologic failureb 11% (5%) 11% (5%) Discontinued due to adverse reactions 13% 11% Discontinued due to other reasonsc 11% 13% a 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 standard test version 1.0). b 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. c Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other. After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm&sup3; in the group receiving abacavir 600 mg once daily and 200 cells per mm&sup3; in the group receiving abacavir 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications. Pediatric Trials Therapy-Experienced Pediatric Subjects CNA3006 was a randomized, double-blind trial comparing ZIAGEN 8 mg per kg twice daily plus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m&sup2; twice daily versus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m&sup2; twice daily. Two hundred and five therapy-experienced pediatric subjects were enrolled: female (56%), white (17%), black (50%), Hispanic (30%), median age of 5.4 years, baseline CD4+ cell percent greater than 15% (median = 27%), and median baseline plasma HIV-1 RNA of 4.6 log10 copies per mL. Eighty percent and 55% of subjects had prior therapy with zidovudine and lamivudine, respectively, most often in combination. The median duration of prior nucleoside analogue therapy was 2 years. At 16 weeks the proportion of subjects responding based on plasma HIV-1 RNA less than or equal to 400 copies per mL was significantly higher in subjects receiving ZIAGEN plus lamivudine plus zidovudine compared with subjects receiving lamivudine plus zidovudine, 13% versus 2%, respectively. Median plasma HIV-1 RNA changes from baseline were -0.53 log10 copies per mL in the group receiving ZIAGEN plus lamivudine plus zidovudine compared with -0.21 log10 copies per mL in the group receiving lamivudine plus zidovudine. Median CD4+ cell count increases from baseline were 69 cells per mm&sup3; in the group receiving ZIAGEN plus lamivudine plus zidovudine and 9 cells per mm&sup3; in the group receiving lamivudine plus zidovudine. Once-Daily Dosing ARROW (COL105677) was a 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 3 months to 17 years were enrolled and treated with a first-line regimen containing ZIAGEN and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of ZIAGEN and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation at baseline for Randomization 3 (following a 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. The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 11. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age. Table 11: Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3) Outcome ZIAGEN plus Lamivudine Twice-Daily Dosing (n = 333) ZIAGEN plus Lamivudine Once-Daily Dosing (n = 336) HIV-1 RNA < 80 copies/mLb 70% 67% HIV-1 RNA &ge; 80 copies/mLc 28% 31% No virologic data Discontinued due to adverse event or death 1% < 1% Discontinued study for other reasonsd 0% < 1% Missing data during window but on study 1% 1% a Analyses were based on the last observed viral load data within the Week 96 window. b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96. c Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol. d 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).

Find Lowest Prices on Brand Names: Ziagen Generic Name: abacavir (Pronunciation: a BAK a veer) What is abacavir (Ziagen)? What are the possible side effects of abacavir (Ziagen)? What is the most important information I should know about abacavir (Ziagen)? What should I discuss with my healthcare provider before taking abacavir (Ziagen)? How should I take abacavir (Ziagen)? What happens if I miss a dose (Ziagen)? What happens if I overdose (Ziagen)? What should I avoid while taking abacavir (Ziagen)? What other drugs will affect abacavir (Ziagen)? Where can I get more information? What is abacavir (Ziagen)? Abacavir is an antiviral medication that prevents human immunodeficiency virus (HIV) cells from multiplying in your body.Abacavir is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). Abacavir is not a cure for HIV or AIDS.Abacavir may also be used for purposes not listed in this medication guide. What are the possible side effects of abacavir (Ziagen)? Stop using abacavir and call your doctor at once if you have symptoms of an allergic reaction from two or more of these specific side effect groups:Group 1 - fever;Group 2 - rash;Group 3 - nausea, vomiting, diarrhea, stomach pain;Group 4 - general ill feeling, extreme tiredness, body aches;Group 5 - shortness of breath, cough, sore throat.Once you have had an allergic reaction to abacavir, you must never use it again. If you stop taking abacavir for any reason, talk to your doctor before you start taking the medication again.Abacavir may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Abacavir can cause other serious side effects that may not be signs of an allergic reaction. Call your doctor at once if you have:the first sign of any skin rash, no matter how mild;signs of a new infection such as flu symptoms, chills, easy bruising or unusual bleeding, loss of appetite, mouth sores;severe pain in your upper stomach spreading to your back;itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);increased sweating, tremors in your hands, anxiety, feeling irritable, sleep problems (insomnia);diarrhea, unexplained weight loss, menstrual changes, impotence, loss of interest in sex;swelling in your neck or throat (enlarged thyroid);weakness or prickly feeling in your fingers or toes;problems with walking, breathing, speech, swallowing, or eye movement; orsevere lower back pain, loss of bladder or bowel control.Less serious side effects may include:strange dreams;headache, ear pain;cold symptoms such as stuffy nose, sneezing, sinus pain; orchanges in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and trunk).This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is the most important information I should know about abacavir (Ziagen)? Stop using abacavir and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.Once you have had an allergic reaction to abacavir, you must never use it again.Read the Warning Card that comes with this medication, and carry it with you at all times so you will know the symptoms of allergic reaction to watch for.Some people develop lactic acidosis while taking abacavir. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired. Abacavir can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have any of these symptoms while taking abacavir: pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).Do not allow this medicine to run out completely before you get your prescription refilled. It is important that you not stop taking abacavir once you have started. If you miss several doses in a row, you may have a dangerous or even fatal allergic reaction once you start taking abacavir again. If you stop taking abacavir for any reason, talk to your doctor before you start taking the medication again.

INDICATIONS EPZICOM, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting EPZICOM Screen for the HLA-B*5701 allele prior to initiating therapy with EPZICOM [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adult Patients The recommended dosage of EPZICOM for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food. Recommended Dosage For Pediatric Patients The recommended oral dose of EPZICOM for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents [see Clinical Studies]. Before prescribing EPZICOM tablets, pediatric patients should be assessed for the ability to swallow tablets. Not Recommended Due To Lack of Dosage Adjustment Because EPZICOM is a fixed-dose tablet and cannot be dose adjusted, EPZICOM is not recommended for: patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations]. patients with mild hepatic impairment. EPZICOM is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS, Use in Specific Populations]. Use of EPIVIR&reg; (lamivudine) oral solution or tablets and ZIAGEN&reg; (abacavir) oral solution may be considered. HOW SUPPLIED Dosage Forms And Strengths EPZICOM tablets contain 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are modified capsule-shaped, orange, film-coated, and debossed with &ldquo;GS FC2&rdquo; on one side with no markings on the reverse side. Storage And Handling EPZICOM is available as tablets. Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are orange, film-coated, modified capsule-shaped, and debossed with GS FC2 on one side with no markings on the reverse side. They are packaged as follows: Bottles of 30 tablets (NDC 49702-206-13). Store at 25&deg;C (77&deg;F); excursions permitted to 15&deg; to 30&deg;C (59&deg; to 86&deg;F) (see USP Controlled Room Temperature). Manufactured for : ViiV Healthcare, Research Triangle Park, NC 27709. by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised: September 2015

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see ADVERSE REACTIONS]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with EPZICOM or reinitiation of therapy with EPZICOM, unless patients have a previously documented HLA-B*5701 allele assessment. EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting EPZICOM, review medical history for prior exposure to any abacavircontaining product. NEVER restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue EPZICOM immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). If a hypersensitivity reaction cannot be ruled out, do not restart EPZICOM or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. If a hypersensitivity reaction is ruled out, patients may restart EPZICOM. 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 EPZICOM 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. Lactic Acidosis And Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with EPZICOM should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Patients With Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Emergence of Lamivudine-resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine). Use With Interferon-And Ribavirin-Based Regimens Patients receiving interferon alfa with or without ribavirin and EPZICOM should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR (lamivudine). Discontinuation of EPZICOM should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin). Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPZICOM. 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-Barr&eacute; syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &ldquo;cushingoid appearance&rdquo; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Related Products That Are Not Recommended EPZICOM contains fixed doses of 2 nucleoside analogue reverse transcriptase inhibitors (abacavir and lamivudine); concomitant administration of EPZICOM with other products containing abacavir or lamivudine is not recommended. In addition, do not administer EPZICOM in combination with products containing emtricitabine. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reactions Inform patients: that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of EPZICOM, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about EPZICOM. The complete text of the Medication Guide is reprinted at the end of this document. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking EPZICOM. that a hypersensitivity reaction can worsen and lead to hospitalization or death if EPZICOM is not immediately discontinued. to not restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death. that a hypersensitivity reaction is usually reversible if it is detected promptly and EPZICOM is stopped right away. that if they have interrupted EPZICOM for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir. to not restart EPZICOM or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others. Related Products that are Not Recommended Inform patients that they should not take EPZICOM with ATRIPLA&reg;, COMBIVIR&reg;, COMPLERA&reg;, DUTREBIS&trade;, EMTRIVA&reg;, EPIVIR, EPIVIR-HBV&reg;, STRIBILD&reg;, TRIUMEQ&reg;, TRIZIVIR, TRUVADA&reg;, or ZIAGEN. Lactic Acidosis/Hepatomegaly Inform patients that some HIV medicines, including EPZICOM, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see WARNINGS AND PRECAUTIONS]. Patients with Hepatitis B or C 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]. 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]. Immune Reconstitution Syndrome In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Information about HIV-1 Infection EPZICOM is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Advise patients to remain under the care of a physician when using EPZICOM. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others. Advise patients not to re-use or share needles or other injection equipment. Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Instruct patients to read the Medication Guide before starting EPZICOM and to reread it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Mutagenicity Abacavir: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation. Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Impairment of Fertility Abacavir or lamivudine did not affect male or female fertility in rats at a dose associated with exposures approximately 8 or 130 times, respectively, higher than the exposures in humans at the doses of 600 mg and 300 mg (respectively). Use In Specific Populations Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPZICOM during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for abacavir or lamivudine compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Abacavir produced fetal malformations and other embryonic and fetal toxicities in rats at 35 times the human exposure at the recommended clinical dose. Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures to the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. Data Human Data: Abacavir: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 900 exposed in the first trimester), there was no difference between abacavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of defects in the first trimester was 3.0% (95% CI: 2.0% to 4.4%). Lamivudine: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%). Lamivudine pharmacokinetics were studied in pregnant women during 2 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 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. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily). Animal Data: Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC. Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed. Pediatric Use The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Clinical Studies]. In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing. 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 EPZICOM 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, Use In Specific Populations]. Patients With Impaired Renal Function EPZICOM is not recommended for patients with creatinine clearance less than 50 mL per min because EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of EPZICOM, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used [see CLINICAL PHARMACOLOGY]. Patients With Impaired Hepatic Function EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of EPZICOM, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see CLINICAL PHARMACOLOGY]. 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, EPZICOM is contraindicated in these patients [see CONTRAINDICATIONS].

CLINICAL PHARMACOLOGY Mechanism Of Action EPZICOM is an antiretroviral agent [see Microbiology]. Pharmacokinetics Pharmacokinetics in Adults In a single-dose, 3-way crossover bioavailability trial of 1 EPZICOM tablet versus 2 ZIAGEN tablets (2 x 300 mg) and 2 EPIVIR tablets (2 x 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 (Cmax), of each component. Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 &plusmn; 1.19 mcg per mL (mean &plusmn; SD) and AUC&infin;was 11.95 &plusmn; 2.51 mcg&bull;hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide. Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 &plusmn; 0.54 mcg per mL (mean &plusmn; SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 &plusmn; 1.83 mcg&bull;hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In 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 Parametersa for Abacavir and Lamivudine in Adults Parameter Abacavir Lamivudine Oral bioavailability (%) 86 &plusmn; 25 n = 6 86 &plusmn; 16 n = 12 Apparent volume of distribution (L/kg) 0.86 &plusmn; 0.15 n = 6 1.3 &plusmn; 0.4 n = 20 Systemic clearance (L/h/kg) 0.80 &plusmn; 0.24 n = 6 0.33 &plusmn; 0.06 n = 20 Renal clearance (L/h/kg) 0.007 &plusmn; 0.008 n = 6 0.22 &plusmn; 0.06 n = 20 Elimination half-life (h) 1.45 &plusmn; 0.32 n = 20 5 to 7b aData presented as mean &plusmn;standard deviation except where noted. bApproximate range. Effect of Food on Absorption of EPZICOM EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability trial resulted in no change in AUClast, AUC&infin;, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC&infin;), but the rate of absorption (Cmax) 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. Special Populations Renal Impairment: EPZICOM: 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: EPZICOM: 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: No data are available on the pharmacokinetics of abacavir during pregnancy. Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 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 EPZICOM 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 a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM. Refer to the EPIVIR and ZIAGEN USPI for pharmacokinetic information on the individual products in pediatric patients [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Clinical Studies]. 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 Interactions The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with EPZICOM. 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 a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir. Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a 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 a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see DRUG INTERACTIONS]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see WARNINGS AND PRECAUTIONS]. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a 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 Dose Drug and Dose n Concentrations of Abacavir or Lamivudine Concentration of Coadministered Drug AUC Variability Ethanol 0.7 g/kg Abacavir Single 600 mg 24 &uarr;41% 90% CI: 35% to 48% &harr;a Nelfinavir 750 mg every 8 h x 7 to 10 days Lamivudine Single 150 mg 11 &uarr;10% 95% CI: 1% to 20% &harr; Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine Single 300 mg 14 &uarr;43% 90% CI: 32% to 55% &harr; &uarr; = Increase; &harr; = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. aThe drug-drug interaction was only evaluated in males. Microbiology Mechanism of Action Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 &plusmn; 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades AG and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 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 B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Neither abacavir, nor lamivudine, were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (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 I 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 I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility. 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 a 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 a progressive reduction in abacavir susceptibility. Animal Toxicology And/Or Pharmacology Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined. Clinical Studies Adults One EPZICOM tablet given once daily is an alternative regimen to EPIVIR tablets 300 mg once daily plus ZIAGEN tablets 2 x 300 mg once daily as a component of antiretroviral therapy. The following trial was conducted with the individual components of EPZICOM. Therapy-naive Adults CNA30021 was an international, multi-center, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a 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&sup3; (range: 21 to 918 cells per mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.60 to 6.99 log10 copies per mL). The outcomes of randomized treatment are provided in Table 4. Table 4: Outcomes of Randomized Treatment through Week 48 (CNA30021) Outcome ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Respondera 64% (71%) 65% (72%) Virologic failure b 11% (5%) 11% (5%) Discontinued due to adverse reactions 13% 11% Discontinued due to other reasonsc 11% 13% aSubjects 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&reg; standard test version 1.0). bIncludes 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. cIncludes consent withdrawn, lost to follow-up, protocol violations, clinical progression, and other. After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm&sup3; in the group receiving ZIAGEN 600 mg once daily and 200 cells per mm&sup3; in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications. Pediatric Subjects ARROW (COL105677) was a 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1&ndash;infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. At baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared to 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 EPZICOM. 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 96a (ARROW Randomization 3) Outcome Abacavir plus LamivudineTwice-daily Dosing (n = 333) Abacavir plus LamivudineOnce-daily Dosing (n = 336) HIV-1 RNA < 80 copies/mLb 70% 67% HIV-1 RNA &ge; 80 copies/mLc 28% 31% No virologic data Discontinued due to adverse event or death 1% < 1% Discontinued study for other reasonsd 0% < 1% Missing data during window but on study 1% 1% aAnalyses were based on the last observed viral load data within the Week 96 window. bRisk difference (95% CI) of response rate is -2.4% (-9% to 5%) at Week 96. cIncludes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol. dOther 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).

Find Lowest Prices on Brand Names: Epzicom Generic Name: abacavir and lamivudine (Pronunciation: a BAK a veer and la MIV yoo deen) What is abacavir and lamivudine (Epzicom)? What are the possible side effects of abacavir and lamivudine (Epzicom)? What is the most important information I should know about abacavir and lamivudine (Epzicom)? What should I discuss with my healthcare provider before taking abacavir and lamivudine (Epzicom)? How should I take abacavir and lamivudine (Epzicom)? What happens if I miss a dose (Epzicom)? What happens if I overdose (Epzicom)? What should I avoid while taking abacavir and lamivudine (Epzicom)? What other drugs will affect abacavir and lamivudine (Epzicom)? Where can I get more information? What is abacavir and lamivudine (Epzicom)? Abacavir and lamivudine are antiviral medications that prevent human immunodeficiency virus (HIV) cells from multiplying in your body.The combination of abacavir and lamivudine is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). This medication is not a cure for HIV or AIDS.Abacavir and lamivudine may also be used for purposes not listed in this medication guide. What are the possible side effects of abacavir and lamivudine (Epzicom)? Stop using this medication and call your doctor at once if you have symptoms of an allergic reaction from two or more of these specific side effect groups:Group 1 - fever;Group 2 - rash;Group 3 - nausea, vomiting, diarrhea, stomach pain;Group 4 - general ill feeling, extreme tiredness, body aches;Group 5 - shortness of breath, cough, sore throat.Once you have had an allergic reaction to this medication, you must never use it again. If you stop taking abacavir and lamivudine for any reason, talk to your doctor before you start taking it again.This medication may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Abacavir and lamivudine can cause serious side effects that may not be signs of an allergic reaction. Call your doctor at once if you have:the first sign of any skin rash, no matter how mild;signs of a new infection such as flu symptoms, easy bruising or unusual bleeding, loss of appetite, mouth sores;severe pain in your upper stomach spreading to your back;itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);increased sweating, tremors in your hands, anxiety, feeling irritable, sleep problems (insomnia);diarrhea, unexplained weight loss, menstrual changes, impotence, loss of interest in sex;swelling in your neck or throat (enlarged thyroid);weakness or prickly feeling in your fingers or toes;problems with walking, breathing, speech, swallowing, or eye movement; orsevere lower back pain, loss of bladder or bowel control.Less serious side effects include:strange dreams;headache, dizziness, depression, anxiety;mild nausea or diarrhea; orchanges in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and trunk).This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is the most important information I should know about abacavir and lamivudine (Epzicom)? Stop using this medication and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.Once you have had an allergic reaction to abacavir, you must never use it again.Read the Warning Card that comes with this medication, and carry it with you at all times so you will know the symptoms of allergic reaction to watch for.Some people develop lactic acidosis while taking abacavir and lamivudine. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Abacavir and lamivudine can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have any of these symptoms while taking this medication: pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).If you have hepatitis B you may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using abacavir and lamivudine. Visit your doctor regularly.Do not allow your medicine to run out completely before you get your prescription refilled. It is important that you not stop taking abacavir and lamivudine once you have started. If you miss several doses, you may have a dangerous or even fatal allergic reaction once you start taking the medicine again. If you stop taking abacavir and lamivudine for any reason, talk to your doctor before you start taking the medication again.

SIDE EFFECTS Fluid and Electrolyte Disturbances Sodium retention, Fluid retention, Congestive heart failure in susceptible patients, Potassium loss, Hypokalemic alkalosis, Hypertension Musculoskeletal Muscle weakness, Steroid myopathy, Loss of muscle mass, Severe arthralgia, Vertebral compression fractures, Aseptic necrosis of femoral and humeral heads, Pathologic fracture of long bones, Osteoporosis Gastrointestinal Peptic ulcer with possible perforation and hemorrhage, Pancreatitis, Abdominal distention, and Ulcerative esophagitis Dermatologic Impaired wound healing, Thin fragile skin, Petechiae and ecchymoses, Facial erythema, Increased sweating, May suppress reactions to skin tests Neurological Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment, Convulsions, Vertigo, Headache Endocrine Development of Cushingoid state, Suppression of growth in children, Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness, Menstrual irregularities, Decreased carbohydrate tolerance, Manifestations of latent diabetes mellitus, Increased requirements for insulin or oral hypoglycemic agents in diabetics Ophthalmic Posterior subcapsular cataracts, Increased intraocular pressure, Glaucoma, Exophthalmos Metabolic Negative nitrogen balance due to protein catabolism The following additional adverse reactions are related to parenteral corticosteroid therapy: Hyperpigmentation or hypopigmentation, Subcutaneous and cutaneous atrophy, Sterile abscess, Anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm, Urticaria, Nausea and vomiting, Cardiac arrhythmias; hypotension or hypertension DRUG INTERACTIONS The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin.

OVERDOSE No information provided. CONTRAINDICATIONS The use of A-Methapred (methylprednisolone sodium succinate) sterile powder is contraindicated in premature infants because the reconstitution diluent contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping Syndrome" in premature infants. A-Methapred (methylprednisolone sodium succinate) sterile powder is also contraindicated in systemic fungal infections and patients with known hypersensitivity to the product and its constituents.

SIDE EFFECTS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]. Fat redistribution [see WARNINGS AND PRECAUTIONS]. Myocardial infarction [see WARNINGS AND PRECAUTIONS]. Clinical Trials Experience In Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Serious And Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized). Additional Adverse Reactions With Use Of ZIAGEN Therapy-Naive Adults: Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2. Table 2: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024a) through 48 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plusLamivudine plus Efavirenz (n = 325) Dreams/sleep disorders 10% 10% Drug hypersensitivity 9% < 1%b Headaches/migraine 7% 11% Nausea 7% 11% Fatigue/malaise 7% 10% Diarrhea 7% 6% Rashes 6% 12% Abdominal pain/gastritis/gastrointestinal signs and symptoms 6% 8% Depressive disorders 6% 6% Dizziness 6% 6% Musculoskeletal pain 6% 5% Bronchitis 4% 5% Vomiting 2% 9% a This trial 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. b Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding. Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3. Table 3: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Nausea 19% 17% Headache 13% 9% Malaise and fatigue 12% 12% Nausea and vomiting 10% 10% Hypersensitivity reaction 8% 2% Diarrhea 7% 5% Fever and/or chills 6% 3% Depressive disorders 6% 4% Musculoskeletal pain 5% 7% Skin rashes 5% 4% Ear/nose/throat infections 5% 4% Viral respiratory infections 5% 5% Anxiety 5% 3% Renal signs/symptoms < 1% 5% Pain (non-site-specific) < 1% 5% Five subjects receiving ZIAGEN in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms. ZIAGEN Once Daily versus ZIAGEN Twice Daily (CNA30021): Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving ZIAGEN twice daily. However, subjects receiving ZIAGEN 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event. Laboratory Abnormalities: Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4. Table 4: Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment Grade 3/4 Laboratory Abnormalities ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Elevated CPK ( > 4 X ULN) 8% 8% Elevated ALT ( > 5 X ULN) 6% 6% Elevated AST ( > 5 X ULN) 6% 5% Hypertriglyceridemia ( > 750 mg/dL) 6% 5% Hyperamylasemia ( > 2 X ULN) 4% 5% Neutropenia (ANC < 750/mm&sup3;) 2% 4% Anemia (Hgb &le; 6.9 gm/dL) < 1% 2% Thrombocytopenia (Platelets < 50,000/mm&sup3;) 1% < 1% Leukopenia (WBC &le; 1,500/mm&sup3;) < 1% 2% ULN = Upper limit of normal. n = Number of subjects assessed. Laboratory abnormalities in CNA3005 are listed in Table 5. Table 5: Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005 Grade 3/4 Laboratory Abnormalities ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Elevated CPK ( > 4 x ULN) 18 (7%) 18 (7%) ALT ( > 5.0 x ULN) 16 (6%) 16 (6%) Neutropenia ( < 750/mm ) 13 (5%) 13 (5%) Hypertriglyceridemia ( > 750 mg/dL) 5 (2%) 3 (1%) Hyperamylasemia ( > 2.0 x ULN) 5 (2%) 1 ( < 1%) Hyperglycemia ( > 13.9 mmol/L) 2 ( < 1%) 2 ( < 1%) Anemia (Hgb &le; 6.9 g/dL) 0 (0%) 3 (1%) ULN = Upper limit of normal. n = Number of subjects assessed. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Clinical Trials Experience In Pediatric Subjects Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing) Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m&sup2; twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m&sup2; twice daily from CNA3006 are listed in Table 6. Table 6: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine plus Zidovudine (n = 102) Lamivudine plus Zidovudine (n = 103) Fever and/or chills 9% 7% Nausea and vomiting 9% 2% Skin rashes 7% 1% Ear/nose/throat infections 5% 1% Pneumonia 4% 5% Headache 1% 5% Laboratory Abnormalities: In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving ZIAGEN (CNA3006) as compared with adult subjects (CNA30024). Other Adverse Events In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT. Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-daily compared with twice-daily dosing of ZIAGEN was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. Postmarketing Experience The following adverse reactions have been identified during postmarketing use of ZIAGEN. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposures. Body as a Whole Redistribution/accumulation of body fat. Cardiovascular Myocardial infarction. Hepatic Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS]. 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]. DRUG INTERACTIONS Methadone In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see CLINICAL PHARMACOLOGY]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

SIDE EFFECTS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see WARNINGS AND PRECAUTIONS]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]. Fat redistribution [see WARNINGS AND PRECAUTIONS]. Myocardial infarction [see WARNINGS AND PRECAUTIONS]. Clinical Trials Experience In Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Serious And Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized). Additional Adverse Reactions With Use Of EPZICOM Therapy-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 600 mg once daily or ZIAGEN 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 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30021) through 48 Weeks of Treatment Adverse Event ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Drug hypersensitivitya, b 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% Diarrheaa 5% 6% Rash 5% 5% Pyrexia 5% 3% Abdominal pain/gastritis 4% 5% Abnormal dreams 4% 5% Anxiety 3% 5% a Subjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event. b CNA30024 was a multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (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. Laboratory Abnormalities: Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR 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. 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 EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 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]. Postmarketing Experience The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a 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]. Abacavir And Lamivudine Body as a Whole: Redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS]. 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], posttreatment exacerbations of hepatitis B [see WARNINGS AND PRECAUTIONS]. 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. DRUG INTERACTIONS Methadone In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see CLINICAL PHARMACOLOGY]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

INDICATIONS TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations of Use Limited data exist on the use of TRIZIVIR alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) [see Clinical Studies]. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting TRIZIVIR Screen for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adults And Pediatric Patients Weighing At Least 40 kg The recommended dosage of TRIZIVIR is one tablet taken orally twice daily with or without food. Not Recommended Due To Lack Of Dosage Adjustment Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended in: pediatric patients who weigh less than 40 kg [see Use in Specific Populations] patients with creatinine clearance less than 50 mL per minute [see Use In Specific Populations] patients with mild hepatic impairment. TRIZIVIR is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS, Use In Specific Populations]. HOW SUPPLIED Dosage Forms And Strengths TRIZIVIR tablets contain 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green, capsule-shaped, film-coated, and imprinted with &ldquo;GX LL1&rdquo; on one side with no markings on the reverse side. Storage And Handling TRIZIVIR is available as tablets. Each tablet contains 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green capsule-shaped, film-coated, and imprinted with GX LL1 on one side with no markings on the reverse side. They are packaged as follows: Bottles of 60 tablets (NDC 49702-217-18). Store at 25&deg;C (77&deg;F); excursions permitted to 15&deg; to 30&deg;C (59&deg; to 86&deg;F) (see USP Controlled Room Temperature). Manufactured for: ViiV Healthcare, Research Triangle Park, NC 27709 by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised: September 2015

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see ADVERSE REACTIONS]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLA-B*5701 allele assessment. TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting TRIZIVIR, review medical history for prior exposure to any abacavircontaining product. NEVER restart TRIZIVIR or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue TRIZIVIR immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). If a hypersensitivity reaction cannot be ruled out, do not restart TRIZIVIR or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. If a hypersensitivity reaction is ruled out, patients may restart TRIZIVIR. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIZIVIR or any other abacavir-containing product is recommended only if medical care can be readily accessed. A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill. Hematologic Toxicity/Bone Marrow Suppression Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. TRIZIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm&sup3; or hemoglobin less than 9.5 grams per dL [see ADVERSE REACTIONS]. Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with TRIZIVIR. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed. Myopathy Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with TRIZIVIR. 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&reg; (abacavir), EPIVIR&reg; (lamivudine), and RETROVIR&reg; (zidovudine). Treatment with TRIZIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Patients With Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Emergence of Lamivudine-resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV&ndash;1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine). Use With Interferon-And Ribavirin-Based Regimens Patients receiving interferon alfa with or without ribavirin and TRIZIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Discontinuation of TRIZIVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin). Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and TRIZIVIR is not advised. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIZIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barr&eacute; syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &ldquo;cushingoid appearance&rdquo; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). Therapy-Experienced Patients In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients [see Microbiology]. Related Products That Are Not Recommended TRIZIVIR is a fixed-dose combination of 3 nucleoside analogue reverse transcriptase inhibitors (abacavir, lamivudine, and zidovudine). Concomitant administration of TRIZIVIR with other products containing abacavir, lamivudine, or zidovudine is not recommended. In addition, do not administer TRIZIVIR in combination with products containing emtricitabine. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reaction Inform patients that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIZIVIR, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIZIVIR. The complete text of the Medication Guide is reprinted at the end of this document. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIZIVIR. that a hypersensitivity reaction can worsen and lead to hospitalization or death if TRIZIVIR is not immediately discontinued. to not restart TRIZIVIR or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death. that a hypersensitivity reaction is usually reversible if it is detected promptly and TRIZIVIR is stopped right away. that if they have interrupted TRIZIVIR for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir. to not restart TRIZIVIR or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others. Related Products that are Not Recommended Inform patients that they should not take TRIZIVIR with ATRIPLA&reg;, COMBIVIR, COMPLERA&reg;, DUTREBIS&trade;, EMTRIVA&reg;, EPIVIR, EPIVIR-HBV&reg;, EPZICOM&reg; , RETROVIR, STRIBILD&reg;, TRIUMEQ&reg;, TRUVADA&reg;, or ZIAGEN. Neutropenia and Anemia Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV-1 disease [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Myopathy Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see WARNINGS AND PRECAUTIONS]. Lactic Acidosis/Hepatomegaly Inform patients that some HIV medicines, including TRIZIVIR, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see WARNINGS AND PRECAUTIONS]. Patients with Hepatitis B or C 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]. 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]. Immune Reconstitution Syndrome In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Information about HIV-1 Infection TRIZIVIR is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Advise patients to remain under the care of a physician when using TRIZIVIR. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others. Advise patients not to re-use or share needles or other injection equipment. Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Instruct patients to read the Medication Guide before starting TRIZIVIR and to reread it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. Zidovudine: Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on day 91 and then to 300 mg per kg per day on day 279. In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose. In rats, 2 late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species. At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately 3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg per kg per day dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine. Mutagenicity Abacavir: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation. Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver. Zidovudine: Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose. Impairment of Fertility Abacavir or Lamivudine: Abacavir or lamivudine did not affect male or female fertility in rats at a dose associated with exposures approximately 8 or 130 times, respectively, higher than the exposures in humans at the doses of 600 mg and 300 mg (respectively). Zidovudine: Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of TRIZIVIR in pregnant women. Reproduction studies with abacavir, lamivudine, and zidovudine have been performed in animals (see Abacavir, Lamivudine, and Zidovudine sections below). TRIZIVIR should be used during pregnancy only if the potential benefits outweigh the risks. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Abacavir Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC. Lamivudine Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Zidovudine Reproduction studies with orally administered zidovudine in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an additional teratology study in rats, a dose of 3,000 mg per kg per day (very near the oral median lethal dose in rats of approximately 3,700 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less. Two rodent carcinogenicity studies were conducted [see Nonclinical Toxicology]. Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed. Pediatric Use TRIZIVIR is not recommended in children who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations [see DOSAGE AND ADMINISTRATION]. Therapy-Experienced Pediatric Trial A randomized, double-blind trial, CNA3006, compared ZIAGEN plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had a limited response to abacavir. Geriatric Use Clinical trials of abacavir, lamivudine, and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIZIVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY]. Patients With Impaired Renal Function TRIZIVIR is not recommended for patients with creatinine clearance less than 50 mL per min because TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of TRIZIVIR is required for patients with renal impairment then the individual components should be used [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]. Patients With Impaired Hepatic Function TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIZIVIR, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see CLINICAL PHARMACOLOGY]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, TRIZIVIR is contraindicated in these patients [see CONTRAINDICATIONS]. Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

CLINICAL PHARMACOLOGY Mechanism Of Action TRIZIVIR is an antiretroviral agent [see Microbiology]. Pharmacokinetics Pharmacokinetics in Adults In a single-dose, 3-way crossover bioavailability trial of 1 TRIZIVIR tablet versus 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) administered simultaneously in healthy subjects (n = 24), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of all 3 components. One TRIZIVIR tablet was bioequivalent to 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24). Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 &plusmn; 0.89 mcg per mL (mean &plusmn; SD) and AUC(0-12 h) was 6.02 &plusmn; 1.73 mcg&bull;hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide. Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). Zidovudine: Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3'-amino-3'deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC. In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes. The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3. Table 3: Pharmacokinetic Parametersa for Abacavir, Lamivudine, and Zidovudine in Adults Parameter Abacavir Lamivudine Zidovudine Oral bioavailability (%) 86 &plusmn; 25 n = 6 86 &plusmn; 16 n = 12 64 &plusmn; 10 n = 5 Apparent volume of distribution (L/kg) 0.86 &plusmn; 0.15 n = 6 1.3 &plusmn; 0.4 n = 20 1.6 &plusmn; 0.6 n = 8 Systemic clearance (L/h/kg) 0.80 &plusmn; 0.24 n = 6 0.33 &plusmn; 0.06 n = 20 1.6 &plusmn; 0.6 n = 6 Renal clearance (L/h/kg) 0.007 &plusmn; 0.008 n = 6 0.22 &plusmn; 0.06 n = 20 0.34 &plusmn; 0.05 n = 9 Elimination half-life (h) 1.45 &plusmn; 0.32 n = 20 5 to 7b 0.5 to 3b aData presented as mean &plusmn; standard deviation except where noted. bApproximate range. Effect of Food on Absorption of TRIZIVIR Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of TRIZIVIR with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) [see DOSAGE AND ADMINISTRATION]. Special Populations Renal Impairment: TRIZIVIR: The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components). Hepatic Impairment: TRIZIVIR: The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components). Pregnancy: Abacavir: No data are available on the pharmacokinetics of abacavir during pregnancy. Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Zidovudine: Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age. Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components. Race: Abacavir and Lamivudine: There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined. Drug Interactions The drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using TRIZIVIR. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine. Cytochrome P450 Enzymes: Abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Glucuronyl Transferase: Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir. 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. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects. Methadone: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see DRUG INTERACTIONS]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see WARNINGS AND PRECAUTIONS]. The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4. Table 4: Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUCa Coadministered Drug and Dose Drug and Dose n Concentrations of Abacavir, Lamivudine, or Zidovudine Concentration of Coadministered Drug AUC Variability Ethanol 0.7 g/kg Abacavir single 600 mg 24 &uarr;41% 90% CI: 35% to 48% &harr;b Nelfinavir 750 mg every 8 h x 7 to 10 days Lamivudine Single 150 mg 11 &uarr;10% 95% CI: 1% to 20% &harr; Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine Single 300 mg 14 &uarr;43% 90% CI: 32% to 55% &harr; Atovaquone 750 mg every 12 h with food Zidovudine 200 mg every 8 h 14 &uarr;31% Range: 23% to 78%c &harr; Clarithromycin 500 mg twice daily Zidovudine 100 mg every 4 h x 7 days 4 &darr;12% Range: &darr;34% to &uarr;14% Not Reported Fluconazole 400 mg daily Zidovudine 200 mg every 8 h 12 &uarr;74% 95% CI: 54% to 98% Not Reported Methadone 30 to 90 mg daily Zidovudine 200 mg every 4 h 9 &uarr;43% Range: 16% to 64%c &harr; Nelfinavir 750 mg every 8 h x 7 to 10 days Zidovudine single 200 mg 11 &darr;35% Range: 28% to 41% &harr; Probenecid 500 mg every 6 h x 2 days Zidovudine 2 mg/kg every 8 h x 3 days 3 &uarr;106% Range: 100% to 170%c Not Assessed Rifampin 600 mg daily x 14 days Zidovudine 200 mg every 8 h x 14 days 8 &darr;47% 90% CI: 41% to 53% Not Assessed Ritonavir 300 mg every 6 h x 4 days Zidovudine 200 mg every 8 h x 4 days 9 &darr;25% 95% CI: 15% to 34% &harr; Valproic acid 250 mg or 500 mg every 8 h x 4 days Zidovudine 100 mg every 8 h x 4 days 6 &uarr;80% Range: 64% to 130%c Not Assessed &uarr; = Increase; &darr; = Decrease; &harr; = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. aSee DRUG INTERACTIONS for additional information on drug interactions. bThe drug-drug interaction was only evaluated in males. cEstimated range of percent difference. Microbiology Mechanism of Action Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Zidovudine: Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 &plusmn; 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades AG and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells. Zidovudine: The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM = 0.27 mcg per mL) and 0.1 to 9 microM, respectively. HIV-1 from therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n = 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n = 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture. Neither abacavir, lamivudine, nor zidovudine were antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), RETROVIR (zidovudine). Resistance HIV-1 isolates with reduced susceptibility to abacavir, lamivudine, or zidovudine have been selected in cell culture and were also recovered from subjects treated with abacavir, lamivudine, and zidovudine, or the combinations of the individual components. Abacavir and Lamivudine: HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions, K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I 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 I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility. Zidovudine: Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analog mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with a greater number of substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Cross-resistance Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with TAM substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility. TAMs are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir. Cross-resistance between lamivudine and zidovudine has not been reported. Animal Toxicology And/Or Pharmacology Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined. Clinical Studies The following trial was conducted with the individual components of TRIZIVIR [see CLINICAL PHARMACOLOGY]. CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR&reg; (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years,; the median pretreatment CD4+ cell count was 360 cells per mm&sup3;, and median plasma HIV-1 RNA was 4.8 log10 copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR&reg; Test) through 48 weeks of treatment are summarized in Table 5. Table 5: Outcomes of Randomized Treatment through Week 48 (CNA3005) Outcome ZIAGEN plus Lamivudine/ Zidovudine (n = 262) Indinavir plus Lamivudine/ Zidovudine (n = 265) Respondera 49% 50% Virologic failureb 31% 28% Discontinued due to adverse reactions 10% 12% Discontinued due to other reasonsc 11% 10% aSubjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL. bIncludes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48. cIncludes consent withdrawn, lost to follow-up, protocol violations, those with missing data, clinical progression, and other. Treatment response by plasma HIV-1 RNA strata is shown in Table 6. Table 6: Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005) Screening HIV-1 RNA (copies/mL) ZIAGEN plus Lamivudine/ Zidovudine (n = 262) Indinavir plus Lamivudine/ Zidovudine (n = 265) < 400 copies/mL n < 400 copies/mL n &ge; 10,000 - &le; 100,000 50% 166 48% 165 > 100,000 48% 96 52% 100 In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir vs. 45% in the group receiving indinavir. Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm&sup3; was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.

Find Lowest Prices on Brand Names: Trizivir Generic Name: abacavir, lamivudine, and zidovudine (Pronunciation: a BACK a veer, la MIV yoo deen, zye DOE vyoo deen) What is abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? What are the possible side effects of this medication (Trizivir)? What is the most important information I should know about abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? What should I discuss with my healthcare provider before taking this medication (Trizivir)? How should I take this medication (Trizivir)? What happens if I miss a dose (Trizivir)? What happens if I overdose (Trizivir)? What should I avoid while taking this medication (Trizivir)? What other drugs will affect this medication (Trizivir)? Where can I get more information? What is abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? Abacavir, lamivudine, and zidovudine are antiviral medications that prevent human immunodeficiency virus (HIV) cells from multiplying in your body.The combination of abacavir, lamivudine, and zidovudine is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). This medication is not a cure for HIV or AIDS.Abacavir, lamivudine, and zidovudine may also be used for purposes not listed in this medication guide. What are the possible side effects of this medication (Trizivir)? Stop using Trizivir and call your doctor at once if you have symptoms of an allergic reaction from two or more of these specific side effect groups:Group 1 - fever;Group 2 - rash;Group 3 - nausea, vomiting, diarrhea, stomach pain;Group 4 - general ill feeling, extreme tiredness, body aches;Group 5 - shortness of breath, cough, sore throat.Once you have had an allergic reaction to this medication, you must never use it again. If you stop taking Trizivir for any reason, talk to your doctor before you start taking it again.Trizivir may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Trizivir can cause other serious side effects that may not be signs of an allergic reaction. Call your doctor at once if you have:the first sign of any skin rash, no matter how mild;signs of a new infection such as flu symptoms, easy bruising or unusual bleeding, loss of appetite, mouth sores;severe pain in your upper stomach spreading to your back;pale skin, feeling light-headed, rapid heart rate, trouble concentrating;itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);increased sweating, tremors in your hands, anxiety, feeling irritable, sleep problems (insomnia);diarrhea, unexplained weight loss, menstrual changes, impotence, loss of interest in sex;swelling in your neck or throat (goiter);problems with walking, breathing, speech, swallowing, or eye movement;severe lower back pain, loss of bladder or bowel control; orchest pain or heavy feeling, pain spreading to the arm or shoulder.Less serious side effects may include:headache, joint pain, depression, nervousness;cold symptoms such as stuffy nose, sneezing, sinus pain;mild nausea or diarrhea; orchanges in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and trunk);This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is the most important information I should know about abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? Stop using this medication and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.Once you have had an allergic reaction to this medication, you must never use it again.Some people develop lactic acidosis while taking Trizivir. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.This medication can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have any of these symptoms while taking Trizivir: pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).If you have hepatitis B you may develop liver symptoms after you stop taking Trizivir, even months after stopping. Your doctor may want to check your liver function for several months after you stop using the medication. Visit your doctor regularly.Do not allow your medicine to run out completely before you get your prescription refilled. It is important that you not stop taking Trizivir once you have started. If you miss several doses, you may have a dangerous or even fatal allergic reaction once you start taking the medication again. If you stop taking Trizivir for any reason, talk to your doctor before you start taking it again.