DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS TRIZIVIR tablets contain 300mg of abacavir as abacavir sulfate, 150mg of lamivudine, and 300mg 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. Tablets: 300mg abacavir, 150mg lamivudine, and 300mg zidovudine. (3)

BOXED WARNING SECTION.


WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIZIVIR (abacavir, lamivudine, and zidovudine). Patients who carry the HLAB*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLAB*5701 allele [see Warnings and Precautions (5.1)]. TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLAB*5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLAB*5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLAB*5701 allele assessment. Discontinue TRIZIVIR immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)]. Following a hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavircontaining product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1)]. Hematologic Toxicity Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV1) disease [see Warnings and Precautions (5.2)]. Myopathy Prolonged use of zidovudine has been associated with symptomatic myopathy [see Warnings and Precautions (5.3)]. 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. Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.4)]. Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV1 and have discontinued lamivudine, a component of TRIZIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIZIVIR and are co-infected with HIV1 and HBV. If appropriate, initiation of antihepatitis B therapy may be warranted [see Warnings and Precautions (5.5)]. WARNING: HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. (5.1) Hypersensitivity to abacavir is a multi-organ clinical syndrome. (5.1) Patients who carry the HLA-B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir. (5.1) TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. (4) Discontinue TRIZIVIR as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue TRIZIVIR if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1) Following a hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavir-containing product. (5.1) Hematologic Toxicity Hematologic toxicity, including neutropenia and anemia, has been associated with the use of zidovudine, a component of TRIZIVIR. (5.2) Myopathy Symptomatic myopathy associated with prolonged use of zidovudine. (5.3) 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. (5.4) Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIZIVIR. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.5)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINICIPAL DISPLAY PANEL NDC 49702-217-18 TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine) 300 mg 150 mg 300 mg TABLETS Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine. See prescribing information for dosage information. Store at 25oC (77oF); excursions permitted to 15o to 30oC (59o to 86oF) (see USP Controlled Room Temperature). Rx only Notice to Authorized Dispenser: Each time TRIZIVIR is dispensed, give the patient a Medication Guide and Warning Card from the carton. 60 Tablets 2017 the ViiV Healthcare group of companies 10000000146020 Rev. 4/17

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)]. Hematologic toxicity, including neutropenia and anemia [see Boxed Warning, Warnings and Precautions (5.2)]. Symptomatic myopathy [see Boxed Warning, Warnings and Precautions (5.3)]. Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.4)]. Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.5)]. Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings and Precautions (5.6)]. Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see Warnings and Precautions (5.6)]. Immune reconstitution syndrome [see Warnings and Precautions (5.7)]. Fat redistribution [see Warnings and Precautions (5.8)]. Myocardial infarction [see Warnings and Precautions (5.9)]. The most commonly reported adverse reactions (incidence at least 10%) in clinical trials were nausea, headache, malaise and fatigue, and nausea and vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Serious and Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR [see Boxed Warning, Warnings and Precautions (5.1)]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized). Additional Adverse Reactions with Use of TRIZIVIR Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300mg twice daily, lamivudine 150mg twice daily, and zidovudine 300mg twice daily compared with indinavir 800mg 3times daily, lamivudine 150mg twice daily, and zidovudine 300mg twice daily from CNA3005 are listed in Table1. Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48Weeks 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 4 x ULN) 18 (7%) 18 (7%) ALT (>5.0 x ULN) 16 (6%) 16 (6%) Neutropenia (750mg/dL) 5 (2%) 3 (1%) Hyperamylasemia (>2.0 x ULN) 5 (2%) 1 (13.9 mmol/L) 2 (<1%) 2 (<1%) Anemia (Hgb 6.9 g/dL) 0 (0%) 3 (1%) ULN=Upper limit of normal. n=Number of patients assessed. Other Adverse Events In addition to adverse reactions in Tables 1 and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from 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 StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see Adverse Reactions (6.1)]. Abacavir, Lamivudine, and/or Zidovudine Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.8)]. Cardiovascular: Cardiomyopathy. Digestive: Stomatitis. Endocrine and Metabolic: Gynecomastia. Gastrointestinal: Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation. General: Vasculitis, weakness. Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia. Hepatic: Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.4)], elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B [see Warnings and Precautions (5.5)]. Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Arthralgia, myalgia, muscle weakness, rhabdomyolysis. Nervous: Dizziness, paresthesia, peripheral neuropathy, seizures. Psychiatric: Insomnia and other sleep disorders. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV1) infection. Limitations of Use: Limited data exist on the use of TRIZIVIR alone in patients with higher baseline viral load levels (greater than 100,000copies per mL) [see Clinical Studies (14)]. TRIZIVIR, a combination of abacavir, lamivudine, and zidovudine, each nucleoside analogue HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV1 infection. (1)

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Before initiating TRIZIVIR, screen for the HLAB*5701 allele because TRIZIVIR contains abacavir. (2.1) Adults and pediatric patients weighing at least 40kg: 1 tablet twice daily. (2.2) Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended in patients requiring dosage adjustment or patients with hepatic impairment. (2.3, 4) 2.1 Screening for HLA-B*5701 Allele prior to Starting TRIZIVIR Screen for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR [see Boxed Warning, Warnings and Precautions (5.1)]. 2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg The recommended dosage of TRIZIVIR is one tablet taken orally twice daily with or without food. 2.3 Not Recommended Due to Lack of Dosage Adjustment Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended for: pediatric patients who weigh less than 40 kg [see Use in Specific Populations (8.4)]. patients with creatinine clearance less than 50mL per minute [see Use in Specific Populations (8.6)]. patients with mild hepatic impairment. TRIZIVIR is contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING TRIZIVIR is available as tablets. Each tablet contains 300mg of abacavir as abacavir sulfate, 150mg of lamivudine, and 300mg of zidovudine. The tablets are bluegreen capsule-shaped, filmcoated, 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 25C (77F); excursions permitted to 15 to 30C (59 to 86F) (see USP Controlled Room Temperature).

DESCRIPTION SECTION.


11 DESCRIPTION TRIZIVIR tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN), lamivudine (also known as EPIVIR or 3TC), and zidovudine (also known as RETROVIR, azidothymidine, or ZDV) with inhibitory activity against HIV-1. TRIZIVIR tablets are for oral administration. Each film-coated tablet contains the active ingredients 300mg of abacavir as abacavir sulfate, 150mg of lamivudine, and 300mg of zidovudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY green 03B11434) that is made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide. Abacavir Sulfate: The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white solid and soluble in water. Dosages are expressed in terms of abacavir. Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2,3-dideoxy, 3-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine is a white to off-white crystalline solid and is soluble in water. Zidovudine: The chemical name of zidovudine is 3-azido-3-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24 g per mol. It has the following structural formula: Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25C.

OVERDOSAGE SECTION.


10 OVERDOSAGE There is no known specific treatment for overdose with TRIZIVIR. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Abacavir: It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis. Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. Zidovudine: Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3-azido-3-deoxy-5-O--D-glucopyranuronosylthymidine (GZDV), is enhanced.

SPL MEDGUIDE SECTION.


Serious allergic reactions (hypersensitivity reaction) If you get a symptom from 2 or more of the following groups while taking TRIZIVIR, call your healthcare provider right away to find out if you should stop taking TRIZIVIR. Symptom Group 1Fever Group 2Rash Group 3Nausea, vomiting, diarrhea, abdominal (stomach area) pain Group 4Generally ill feeling, extreme tiredness, or achiness Group 5Shortness of breath, cough, sore throat Carry this Warning Card with you at all times. If you stop TRIZIVIR because of an allergic reaction, never take TRIZIVIR (abacavir, lamivudine and zidovudine) or any other abacavircontaining medicine (EPZICOM TRIUMEQ, or ZIAGEN) again within hourslifethreatening symptomsvery low blood pressure death. If your healthcare provider tells you that you can take TRIZIVIR again, start taking it when you are around medical help or people who can call a healthcare provider if you need one. Blood problems. Muscle pain or weakness (myopathy) Build-up of acid in your blood (lactic acidosis). Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: feel very weak or tiredfeel cold, especially in your arms and legsunusual (not normal) muscle painfeel dizzy or light-headedtrouble breathinghave a fast or irregular heartbeatstomach pain with nausea and vomiting Serious liver problems Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:your skin or the white part of your eyesloss of appetite for several days or longerturns yellow (jaundice)nauseadark or tea-colored urinepain, aching, or tenderness on the right sidelight-colored stools (bowel movements)of your stomach area You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time. Worsening of hepatitis B virus in people who have HIV-1 infection. Resistant Hepatitis B Virus (HBV). Use with interferon and ribavirinbased regimens. Pregnancy Registry. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with TRIZIVIR. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with TRIZIVIR. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TRIZIVIR with other medicines. The most common side effects of TRIZIVIR include: nauseaweakness or tirednessheadachevomitingTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of TRIZIVIR. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800FDA1088. Keep TRIZIVIR and all medicines out of the reach of children. Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc, Basingstoke, UKEPIVIR, EPZICOM, RETROVIR, TRIUMEQ, TRIZIVIR, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies.The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.2017 the ViiV Healthcare group of companies. All rights reserved.TRZ:10MG MEDICATION GUIDE TRIZIVIR (TRY-zih-veer) (abacavir, lamivudine, and zidovudine) tablets What is the most important information I should know about TRIZIVIR? TRIZIVIR can cause serious side effects, including: that can cause death have happened with TRIZIVIR and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLAB*5701. Your healthcare provider can determine with a blood test if you have this gene variation. A list of these symptoms is on the Warning Card your pharmacist gives you. , . If you have an allergic reaction, dispose of any unused TRIZIVIR. Ask your pharmacist how to properly dispose of medicines. If you take TRIZIVIR or any other abacavircontaining medicine again after you have had an allergic reaction, you may get that may include or If you stop TRIZIVIR for any other reason, even for a few days, and you are not allergic to TRIZIVIR, talk with your healthcare provider before taking it again. Taking TRIZIVIR again can cause a serious allergic or lifethreatening reaction, even if you never had an allergic reaction to it before. Zidovudine (RETROVIR), one of the medicines in TRIZIVIR, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). These blood cell problems are especially likely to happen in people with advanced human immunodeficiency virus type 1 (HIV-1) disease or AIDS. Your healthcare provider should check your blood cell counts regularly during treatment with TRIZIVIR. can happen during treatment with TRIZIVIR. Zidovudine (RETROVIR), one of the medicines in TRIZIVIR, can cause muscle pain or weakness when used for a long time. Lactic acidosis can happen in some people who take TRIZIVIR. Lactic acidosis is a serious medical emergency that can cause death. can happen in people who take TRIZIVIR. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). If you have HIV-1 and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking TRIZIVIR. A flare-up is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease is serious and may lead to death. Do not run out of TRIZIVIR. Refill your prescription or talk to your healthcare provider before your TRIZIVIR is all gone. Do not stop TRIZIVIR without first talking to your healthcare provider. If you stop taking TRIZIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with TRIZIVIR and become harder to treat (resistant). Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who are taking antiretroviral medicines, and are also being treated for hepatitis C with interferon with or without ribavirin. If you are taking TRIZIVIR and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms. What is TRIZIVIR? TRIZIVIR is a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used alone or with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). TRIZIVIR contains 3 prescription medicines, abacavir (ZIAGEN), lamivudine (EPIVIR) and zidovudine (RETROVIR). TRIZIVIR should not be used in children weighing less than 88 pounds (40kg). Who should not take TRIZIVIR? Do not take TRIZIVIR if you: have a certain type of gene variation called the HLAB*5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIZIVIR. are allergic to abacavir or any of the ingredients in TRIZIVIR. See the end of this Medication Guide for a complete list of ingredients in TRIZIVIR. have liver problems. What should I tell my healthcare provider before taking TRIZIVIR? Before you take TRIZIVIR, tell your healthcare provider if you: have been tested and know whether or not you have a particular gene variation called HLAB*5701. have or have had liver problems, including hepatitis B or C virus infection. have kidney problems. have low blood cell counts (bone marrow problem). Ask your healthcare provider if you are not sure. have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes. drink alcohol or take medicines that contain alcohol. are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take TRIZIVIR. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. How should I take TRIZIVIR? Take TRIZIVIR exactly as your healthcare provider tells you to take it. If you miss a dose of TRIZIVIR, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take. Stay under the care of a healthcare provider during treatment with TRIZIVIR. TRIZIVIR may be taken with or without food. Tell your healthcare provider if you or your child has trouble swallowing TRIZIVIR tablets. Do not run out of TRZIVIR. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy. If you take too much TRIZIVIR, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of TRIZIVIR? TRIZIVIR can cause serious side effects including: See What is the most important information I should know about TRIZIVIR? Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIZIVIR. Changes in body fat can happen in people who take HIV1 medicines. These changes may include an increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. Heart attack (myocardial infarction). Some HIV-1 medicines including TRIZIVIR may increase your risk of heart attack. How should I store TRIZIVIR? Store TRIZIVIR at 59F to 86F (15C to 30C). General information for safe and effective use of TRIZIVIR. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRIZIVIR for a condition for which it was not prescribed. Do not give TRIZIVIR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for the information about TRIZIVIR that is written for health professionals. For more information go to www.TRIZIVIR.com or call 1-877-844-8872. What are the ingredients in TRIZIVIR? Active ingredients:abacavir, lamivudine, and zidovudine Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate Tablet film coating contains: OPADRY green 03B11434 made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide. Manufactured for:by: ViiV HealthcareGlaxoSmithKline Research Triangle Park, NC 27709Research Triangle Park, NC 27709 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2017

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon alfa with or without ribavirin. Discontinue TRIZIVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.6) Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and zidovudine is not advised. (5.6) Immune reconstitution syndrome and redistribution/accumulation of body fat have been reported in patients treated with combination antiretroviral therapy. (5.7, 5.8) 5.1 Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6weeks of treatment with abacavir (median time to onset was 9days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1)]. Patients who carry the HLAB*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLAB*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 HLAB*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLAB*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 HLAB*5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLAB*5701 allele assessment. TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLAB*5701-positive patients. Before starting TRIZIVIR, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIZIVIR or any other abacavircontaining product following a hypersensitivity reaction to abacavir, regardless of HLAB*5701 status. To reduce the risk of a lifethreatening hypersensitivity reaction, regardless of HLAB*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 abacavircontaining products because more severe symptoms, which may include lifethreatening 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. 5.2 Hematologic Toxicity/Bone Marrow Suppression Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. TRIZIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000cells per mm3 or hemoglobin less than 9.5 grams per dL [see Adverse Reactions (6.1)]. Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with TRIZIVIR. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed. 5.3 Myopathy Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with TRIZIVIR. 5.4 Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), and RETROVIR (zidovudine). Treatment with TRIZIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.5 Patients with Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Emergence of Lamivudine-Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitisB 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 hepatitisB virus. See full prescribing information for EPIVIR (lamivudine). 5.6 Use with Interferon- and Ribavirin-Based Regimens Patients receiving interferon alfa with or without ribavirin and TRIZIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for EPIVIR (lamivudine) and RETROVIR (zidovudine). Discontinuation of TRIZIVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin). Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and TRIZIVIR is not advised. 5.7 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIZIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further 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. 5.8 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.9 Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking). 5.10 Therapy-Experienced Patients In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients [see Microbiology (12.4)].

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Methadone: An increased methadone dose may be required in a small number of patients. (7.1) Agents antagonistic with zidovudine: Concomitant use should be avoided (7.2). Hematologic/bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.2)) 7.1 Abacavir Methadone In a trial of 11HIV-1infected subjects receiving methadonemaintenance therapy with 600mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3)]. 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. 7.2 Zidovudine Agents Antagonistic with Zidovudine Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro: Stavudine Doxorubicin Nucleoside analogues, e.g., ribavirin Hematologic/Bone Marrow Suppressive/Cytotoxic Agents Coadministration with the following drugs may increase the hematologic toxicity of zidovudine: Ganciclovir Interferon alfa Ribavirin Other bone marrow suppressive or cytotoxic agents

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Abacavir: Abacavir was administered orally at 3dosage levels to separate groups of mice and rats in 2year carcinogenicity studies. Results showed an increase in the incidence of malignant and nonmalignant 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, nonmalignant 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 600mg. Lamivudine: Longterm carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10times (mice) and 58times (rats) the human exposures at the recommended dose of 300mg. Zidovudine: Zidovudine was administered orally at 3dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120mg per kg per day in mice and 80, 220, and 600mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40mg per kg per day after Day90 because of treatmentrelated anemia, whereas in rats only the high dose was reduced to 450mg per kg per day on Day91 and then to 300mg per kg per day on Day279. In mice, 7lateappearing (after 19months) vaginal neoplasms (5non-metastasizing squamous cell carcinomas, 1squamous cell papilloma, and 1squamous polyp) occurred in animals given the highest dose. One lateappearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose. In rats, 2lateappearing (after 20months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drugrelated 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 3times (mouse) and 24times (rat) the estimated human exposure at the recommended therapeutic dose of 100mg every 4hours. 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 20mg per kg per day or 40mg per kg per day from gestation Day10 through parturition and lactation with dosing continuing in offspring for 24months postnatally. At these doses, exposures were approximately 3times the estimated human exposure at the recommended doses. After 24months at the 40mg 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 25mg per day (approximately 1,000mg per kg nonpregnant body weight or approximately 450mg per kg of term body weight) to pregnant mice from Days12 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 invitro 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 invivo 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 invitro 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 invitro 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: 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. Lamivudine: Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42times(male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300mg. Zidovudine: Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates. 13.2 Animal Toxicology and/or Pharmacology Myocardial degeneration was found in mice and rats following administration of abacavir for 2years. The systemic exposures were equivalent to 7 to 24times the expected systemic exposure in humans at a dose of 600mg. The clinical relevance of this finding has not been determined.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Lactation: Women infected with HIV should be instructed not to breastfeed due to potential for HIV transmission. (8.2) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for abacavir, lamivudine, or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population [see Data]. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from 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 35times 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 9times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose [see Data]. Data Human Data: Abacavir: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) following second/third trimester exposure to abacavir-containing regimens. Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16women at 36weeks gestation using 150mg lamivudine twice daily with zidovudine, 10women at 38weeks gestation using 150mg lamivudine twice daily with zidovudine, and 10women at 38weeks gestation using lamivudine 300mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)fold greater compared with paired maternal serum concentration (n=8). Zidovudine: Based on prospective reports to the APR of over 13,000 exposures to zidovudine during pregnancy resulting in live births (including over 4,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.2%) following second/third trimester exposure to zidovudine-containing regimens. A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug. See full prescribing information for RETROVIR (zidovudine) and COMBIVIR (lamivudine and zidovudine). Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. Animal Data:Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on gestation Days 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 crownrump 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 500mg per kg per day. No developmental effects were observed in rats at 60mg 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 9times the human exposure at the recommended dose. Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit], respectively). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from gestation Day 6 through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine. Zidovudine: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose.An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on gestation Days 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600mg per kg per day. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV1 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 TRIZIVIR. 8.4 Pediatric Use TRIZIVIR is not recommended in children who weigh less than 40kg because it is a fixeddose tablet that cannot be adjusted for these patient populations [see Dosage and Administration (2.3)]. 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. 8.5 Geriatric Use Clinical trials of abacavir, lamivudine, and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIZIVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Patients with Impaired Renal Function TRIZIVIR is not recommended for patients with creatinine clearance less than 50mL per min because TRIZIVIR is a fixeddose 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 (2.3), Clinical Pharmacology (12.3)]. 8.7 Patients with Impaired Hepatic Function TRIZIVIR is a fixeddose 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 (12.3)]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, TRIZIVIR is contraindicated in these patients [see Contraindications (4)]. Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.

RECENT MAJOR CHANGES SECTION.


Warnings and Precautions, Related Products that are Not Recommended (5.11) Removed 02/2017

INFORMATION FOR PATIENTS SECTION.


17 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 (5.1), 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 abacavircontaining product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include lifethreatening hypotension and death. that if they have a hypersensitivity reaction, they should dispose of any unused TRIZIVIR to avoid restarting abacavir. 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 abacavircontaining product without medical consultation and only if medical care can be readily accessed by the patient or others. 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 HIV1 disease [see Boxed Warning, Warnings and Precautions (5.2)]. Myopathy Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV1 disease, have been associated with prolonged use of zidovudine [see Warnings and Precautions (5.3)]. 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 TRIZIVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.4)]. Patients with Hepatitis B or C Co-infection Advise patients co-infected with HIV1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see Warnings and Precautions (5.5)]. Inform patients with HIV1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV1/HCV co-infected patients receiving combination antiretroviral therapy for HIV1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.6)]. Drug Interactions Advise patients that other medications may interact with TRIZIVIR and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of TRIZIVIR [see Drug Interactions (7.2)]. 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 TRIZIVIR is started [see Warnings and Precautions (5.7)]. 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 (5.8)]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy [seeUse in Specific Populations (8.1)]. Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)]. Missed Dose Instruct patients that if they miss a dose of TRIZIVIR, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)]. Availability of Medication Guide Instruct patients to read the Medication Guide before starting TRIZIVIR and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens. COMBIVIR, EPIVIR, RETROVIR, TRIZIVIR, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies. Other brands are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products. Manufactured for: ViiV Healthcare Research Triangle Park, NC 27709 by: GlaxoSmithKline Research Triangle Park, NC 27709 Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc Basingstoke, UK 2017 the ViiV Healthcare group of companies. All rights reserved. TRZ:10PI

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES The following trial was conducted with the individual components of TRIZIVIR [see Clinical Pharmacology (12.3)]. CNA3005 was a multicenter, double-blind, controlled trial in which 562HIV1-infected, therapynaive adults were randomized to receive either ZIAGEN (300mg twice daily) plus COMBIVIR (lamivudine 150mg/zidovudine 300mg twice daily), or indinavir (800mg 3times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV1 RNA 10,000 to 100,000copies per mL and plasma HIV1 RNA greater than 100,000copies per mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36years; the median pretreatment CD4+ cell count was 360cells per mm3, and median plasma HIV-1 RNA was 4.8 log10copies per mL. Proportions of subjects with plasma HIV1 RNA less than 400copies per mL (using Roche AMPLICOR HIV1 MONITOR Test) through 48weeks 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 400copies per mL. bIncludes viral rebound and failure to achieve confirmed less than 400copies 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 Table6. Table6. Proportions of Responders through Week 48 by Screening Plasma HIV1 RNA Levels (CNA3005) Screening HIV1 RNA (copies/mL) ZIAGEN plus Lamivudine/Zidovudine (n=262) Indinavir plus Lamivudine/Zidovudine (n=265) 100,000 48% 96 52% 100 In subjects with baseline viral load greater than 100,000copies per mL, percentages of subjects with HIV-1 RNA levels less than 50copies per mL were 31% in the group receiving abacavir vs. 45% in the group receiving indinavir. Through Week48, an overall mean increase in CD4+ cell count of about 150cells per mm3 was observed in both treatment arms. Through Week 48, 9subjects (3.4%) in the group receiving abacavir (6CDC classification C events and 3deaths) and 3subjects (1.5%) in the group receiving indinavir (2CDC classification C events and 1death) experienced clinical disease progression.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action TRIZIVIR is an antiretroviral agent [see Microbiology (12.4)]. 12.3 Pharmacokinetics Pharmacokinetics in Adults In a single-dose, 3-way crossover bioavailability trial of 1TRIZIVIR tablet versus 1ZIAGEN tablet (300mg), 1EPIVIR tablet (150mg), plus 1RETROVIR tablet (300mg) 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 3components. One TRIZIVIR tablet was bioequivalent to 1ZIAGEN tablet (300mg), 1EPIVIR tablet (150mg), plus 1RETROVIR tablet (300mg) following single-dose administration to fasting healthy subjects (n=24). Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 0.89 mcg per mL (mean SD) and AUC(0-12 h) was 6.02 1.73 mcghour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drugrelated 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 5carboxylic acid and glucuronyl transferase to form the 5glucuronide. 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 12hours). 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 3fold 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 onefifth 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 (%) 8625 n=6 86 16 n=12 64 10 n=5 Apparent volume of distribution (L/kg) 0.86 0.15 n=6 1.3 0.4 n=20 1.6 0.6 n=8 Systemic clearance (L/h/kg) 0.80 0.24 n=6 0.33 0.06 n=20 1.6 0.6 n=6 Renal clearance (L/h/kg) 0.007 0.008 n=6 0.220.06 n=20 0.34 0.05 n=9 Elimination half-life (h) 1.45 0.32 n=20 5 to 7b 0.5 to 3b a Data presented as mean standard deviation except where noted. b Approximate 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 (2.2)]. Specific 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: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery. Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2clinical 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 Phase1 trial of 8women 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 5pregnant women did not appear to alter zidovudine pharmacokinetics. Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65years 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, 15HIV1infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600mg), lamivudine (150mg), and zidovudine (300mg) 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 19healthy male subjects. Methadone: In a trial of 11HIV1infected subjects receiving methadonemaintenance therapy (40mg and 90mg daily), with 600mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions (7.1)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: Invitro 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 HIV1/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 multidrug regimen to HIV1/HCV coinfected subjects [see Warnings and Precautions (5.6)]. The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table4. 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 600mg 24 41% 90% CI: 35% to 48% b Nelfinavir 750mgevery 8h x 7 to 10days Lamivudine single 150mg 11 10% 95% CI: 1% to 20% Trimethoprim 160mg/ Sulfamethoxazole 800mg daily x 5days Lamivudine single 300mg 14 43% 90% CI: 32% to 55% Atovaquone 750mg every 12h with food Zidovudine 200mg every 8h 14 31% Range: 23% to 78%c Clarithromycin 500mg twice daily Zidovudine 100mg every 4h x 7days 4 12% Range: 34% to 14% Not Reported Fluconazole 400mg daily Zidovudine 200mg every 8h 12 74% 95% CI: 54% to 98% Not Reported Methadone 30 to 90mg daily Zidovudine 200mg every 4h 9 43% Range: 16% to 64%c Nelfinavir 750mgevery 8h x 7 to 10days Zidovudine single 200mg 11 35% Range: 28% to 41% Probenecid 500 mg every 6h x 2days Zidovudine 2mg/kg every 8h x 3days 3 106% Range: 100% to 170%c Not Assessed Rifampin 600mg daily x 14days Zidovudine 200mg every 8h x 14days 8 47% 90% CI: 41% to 53% Not Assessed Ritonavir 300mg every 6h x 4 days Zidovudine 200 mg every 8h x 4days 9 25% 95% CI: 15% to 34% Valproic acid 250mg or 500mg every 8h x 4days Zidovudine 100 mg every 8h x 4days 6 80% Range: 64% to 130%c Not Assessed = Increase; = Decrease; =No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval. aSee Drug Interactions (7) for additional information on drug interactions. bThe drug-drug interaction was only evaluated in males. cEstimated range of percent difference. 12.4 Microbiology Mechanism of Action Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBVTP), an analogue of deoxyguanosine5triphosphate (dGTP). CBVTP inhibits the activity of HIV1 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 (3TCTP). The principal mode of action of 3TCTP 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 (ZDVTP). The principal mode of action of ZDVTP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Antiviral Activity Abacavir: The antiviral activity of abacavir against HIV1 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 (1microM=0.28mcg per mL) and 0.07 to 1.0 microM against HIV1IIIB and HIV1BaL, respectively, and the mean EC50 value was 0.260.18microM against 8clinical isolates. The median EC50 values of abacavir were 344nM (range: 14.8 to 676nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356nM (range: 35.7 to 396nM), 105nM (range: 28.1 to 168nM), 47.6 nM (range: 5.2 to 200nM), 51.4 nM (range: 7.1 to 177nM), and 282nM (range: 22.4 to 598nM) against HIV1 clades A-G and group O viruses (n=3 except n=2 for clade B), respectively. The EC50 values against HIV2 isolates (n=4), ranged from 0.024 to 0.49microM. Lamivudine: The antiviral activity of lamivudine against HIV1 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 15microM (1microM=0.23mcg per mL). The median EC50 values of lamivudine were 60nM (range: 20 to 70nM), 35nM (range: 30 to 40nM), 30nM (range: 20 to 90nM), 20nM (range: 3 to 40nM), 30nM (range: 1 to 60 nM), 30nM (range: 20 to 70nM), 30nM (range: 3 to 70nM), and 30nM (range: 20 to 90nM) against HIV1 clades A-G and group O viruses (n=3 except n=2 for clade B), respectively. The EC50 values against HIV2 isolates (n=4) ranged from 0.003 to 0.120microM in PBMCs. Ribavirin (50microM) used in the treatment of chronic HCV infection decreased the anti-HIV1 activity of lamivudine by 3.5 fold in MT4 cells. Zidovudine: The antiviral activity of zidovudine against HIV1 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 0.49microM (1microM=0.27mcg per mL) and 0.1 to 9microM, respectively. HIV1 from therapynaive subjects with no amino acid substitutions associated with resistance gave median EC50 values of 0.011microM (range: 0.005 to 0.110microM) from Virco (n=92 baseline samples) and 0.0017microM (range: 0.006 to 0.0340microM) from Monogram Biosciences (n=135 baseline samples). The EC50 values of zidovudine against different HIV1 clades (A-G) ranged from 0.00018 to 0.02microM, and against HIV2 isolates from 0.00049 to 0.004microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture. Neither abacavir, lamivudine, nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), RETROVIR (zidovudine). Resistance HIV1 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 zidovudinetreated subjects showed thymidine analogue mutation (TAM) substitutions in HIV1 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 zidovudineresistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12weeks of treatment with lamivudine and zidovudine. CrossResistance Crossresistance 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 crossresistance to abacavir, didanosine, stavudine, and tenofovir. Crossresistance between lamivudine and zidovudine has not been reported.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS TRIZIVIR is contraindicated in patients: who have the HLAB*5701 allele [see Warnings and Precautions (5.1)]. with prior hypersensitivity reaction to abacavir [see Warnings and Precautions (5.1)], lamivudine, or zidovudine. with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)]. Presence of HLA-B*5701 allele. (4) Prior hypersensitivity reaction to abacavir, lamivudine, or zidovudine (4) Moderate or severe hepatic impairment. (4, 8.7)