TRIZIVIR - abacavir sulfate, lamivudine, and zidovudine tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ABACAVIR SULFATE (UNII: J220T4J9Q2) (ABACAVIR - UNII:WR2TIP26VS), LAMIVUDINE (UNII: 2T8Q726O95) (LAMIVUDINE - UNII:2T8Q726O95), ZIDOVUDINE (UNII: 4B9XT59T7S) (ZIDOVUDINE - UNII:4B9XT59T7S)
Available from:
State of Florida DOH Central Pharmacy
INN (International Name):
ABACAVIR SULFATE
Composition:
ABACAVIR 300 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of HIV-1 infection. Additional important information on the use of TRIZIVIR for treatment of HIV-1 infection: TRIZIVIR Tablets are contraindicated in patients with: TRIZIVIR: 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. 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 (incre
Product summary:
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 supplied by State of Florida DOH Central Pharmacy as follows: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).
Authorization status:
New Drug Application
Authorization number:
53808-0990-1

TRIZIVIR - abacavir sulfate, lamivudine, and zidovudine tablet, film coated

State of Florida DOH Central Pharmacy

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MEDICATION GUIDE

TRIZIVIR® (TRY-zih-veer)

(abacavir sulfate, lamivudine, and zidovudine

Tablets

Read this Medication Guide before you start taking TRIZIVIR and each time you get a refill. There may

be new information. This information does not take the place of talking to your healthcare provider about

your medical condition or your treatment. Be sure to carry your TRIZIVIR Warning Card with you at all

times.

What is the most important information I should know about TRIZIVIR?

1.Serious allergic reaction (hypersensitivity reaction). TRIZIVIR contains abacavir (also contained in

ZIAGEN® and EPZICOM®). Patients taking TRIZIVIR may have a serious allergic reaction

(hypersensitivity reaction) that can cause death. Your risk of this allergic reaction is much higher if you

have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if

you have this gene variation.

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

Fever

Group

Rash

Group

Nausea,

vomiting,

diarrhea,

abdominal

(stomach

area) pain

Group

Generally

ill feeling,

extreme

tiredness,

or achiness

Group

Shortness

of breath,

cough,

sore throat

A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card

with you at all times.

If you stop TRIZIVIR because of an allergic reaction, never take TRIZIVIR(abacavir sulfate, lamivudine,

and zidovudine)or any other abacavir-containing medicine (ZIAGEN and EPZICOM) again. If you take

TRIZIVIR or any other abacavir-containing medicine again after you have had an allergic reaction, within

hours you may get life-threatening symptoms that may include very low blood pressure or death. 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 life-threatening reaction, even if you never had an allergic reaction to it before.

If your healthcare provider tells you that you can take TRIZIVIR again, start taking it when you are

around medical help or people who can call a healthcare provider if you need one.

2. Blood problems. 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 patients

with advanced human immunodeficiency virus (HIV) disease or AIDS. Your doctor should be checking

your blood cell counts regularly while you are taking TRIZIVIR. This is especially important if you have

advanced HIV or AIDS. This is to make sure that any blood cell problems are found quickly.

3. Lactic Acidosis (buildup of acid in the blood). Some human immunodeficiency virus (HIV) medicines,

including TRIZIVIR, can cause a rare but serious condition called lactic acidosis. Lactic acidosis is a

serious medical emergency that can cause death and must be treated in the hospital.

Call your healthcare provider right away if you get any of the following signs or symptoms of lactic

acidosis:

you feel very weak or tired

you have unusual (not normal) muscle pain

you have trouble breathing

you have stomach pain with nausea and vomiting

you feel cold, especially in your arms and legs

you feel dizzy or light-headed

you have a fast or irregular heartbeat

4. Serious liver problems. Some people who have taken medicines like TRIZIVIR have developed serious

liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the liver

(steatosis). Hepatomegaly with steatosis is a serious medical emergency that can cause death.

Call your healthcare provider right away if you get any of the following signs or symptoms of liver

problems:

your skin or the white part of your eyes turns yellow (jaundice)

your urine turns dark

your bowel movements (stools) turn light in color

you don’t feel like eating food for several days or longer

you feel sick to your stomach (nausea)

you have lower stomach area (abdominal) pain

You may be more likely to get lactic acidosis or serious liver problems if you are female, very

overweight, or have been taking nucleoside analogue medicines for a long time.

5. Use with interferon and ribavirin-based regimens. Worsening of liver disease (sometimes resulting in

death) has occurred in patients infected with both HIV and hepatitis C virus who are taking anti-HIV

medicines and are also being treated for hepatitis C with interferon with or without ribavirin. If you are

taking TRIZIVIR as well as interferon with or without ribavirin and you experience side effects, be sure

to tell your healthcare provider.

6. If you have HIV and hepatitis B virus infection, your hepatitis B virus infection may get worse if you

stop taking TRIZIVIR.

Take TRIZIVIR exactly as prescribed.

Do not run out of TRIZIVIR.

Do not stop TRIZIVIR without talking to your healthcare provider.

Your healthcare provider should monitor your health and do regular blood tests to check your liver if you

stop taking TRIZIVIR.

7. Muscle weakness (myopathy). RETROVIR, one of the medicines in TRIZIVIR, can cause muscle

weakness. This can be a serious problem.

What is TRIZIVIR?

TRIZIVIR is a prescription medicine used to treat HIV infection. TRIZIVIR contains 3 medicines:

abacavir (ZIAGEN), lamivudine or 3TC (EPIVIR®), and zidovudine, AZT, or ZDV (RETROVIR). All 3

of these medicines are called nucleoside analogue reverse transcriptase inhibitors (NRTIs). When used

together, they help lower the amount of HIV in your blood.

TRIZIVIR does not cure HIV infection or AIDS.

It is not known if TRIZIVIR will help you live longer or have fewer of the medical problems that

people get with HIV or AIDS.

It is very important that you see your healthcare provider regularly while you are taking TRIZIVIR.

Who should not take TRIZIVIR?

Do not take TRIZIVIR if you:

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 certain liver problems.

are an adolescent who weighs less than 90 pounds.

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 HLA-B*5701.

have hepatitis B virus infection or have other liver problems.

have kidney problems.

have low blood cell counts (bone marrow problem). Ask your doctor 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.

are pregnant or plan to become pregnant. It is not known if TRIZIVIR will harm your unborn baby.

Talk to your healthcare provider if you are pregnant or plan to become pregnant.

Pregnancy Registry. If you take TRIZIVIR while you are pregnant, talk to your healthcare provider about

how you can take part in the Pregnancy Registry for TRIZIVIR. The purpose of the pregnancy registry is

to collect information about the health of you and your baby.

are breastfeeding or plan to breastfeed. Do not breastfeed. Lamivudine and zidovudine are excreted

in human breast milk. We do not know if abacavir can be passed to your baby in your breast milk

and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because

HIV-1 can be passed to the baby in the breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription

medicines, vitamins, and herbal supplements.

Especially tell your healthcare provider if you take:

alcohol

medicines used to treat hepatitis viruses such as interferon or ribavirin

methadone

BACTRIM ®, SEPTRA ® (trimethoprim [TMP/sulfamethoxazole SMX])

CYTOVENE ®, DHPG (ganciclovir)

interferon-alfa

ADRIAMYCIN ® (doxorubicin)

COPEGUS ®, REBETOL ®, VIRAZOLE ® (ribavirin)

any bone marrow suppressive medicines or cytotoxic medicines. Ask your doctor if you are not

sure.

ATRIPLA ® (efavirenz/emtricitabine/tenofovir disoproxil fumarate)

COMBIVIR ® (lamivudine and zidovudine)

COMPLERA ® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate)

EMTRIVA ® (emtricitabine)

EPIVIR or EPIVIR-HBV ® (lamivudine)

EPZICOM (abacavir sulfate and lamivudine)

RETROVIR (zidovudine)

TRUVADA ® (emtricitabine/tenofovir disoproxil fumarate)

ZERIT ® (stavudine)

ZIAGEN (abacavir sulfate)

Ask your healthcare provider if you are not sure if you take one of the medicines listed above.

TRIZIVIR may affect the way other medicines work, and other medicines may affect how TRIZIVIR

works.

Know the medicines you take. Keep a list of your medicines with you to show to your healthcare provider

and pharmacist when you get a new medicine.

How should I take TRIZIVIR?

Take TRIZIVIR exactly as your healthcare provider tells you to take it.

TRIZIVIR may be taken with or without food.

Do not skip doses.

Do not let your TRIZIVIR run out.

If you stop your anti-HIV medicines, even for a short time, the amount of virus in your blood may

increase and the virus may become harder to treat.If you take too much TRIZIVIR, call your healthcare

provider or poison control center 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 allergic reactions, lactic acidosis, and liver problems.

See “What is the most important information I should know about TRIZIVIR?”

Blood problems.

Muscle weakness.

Changes in immune system (Immune Reconstitution Syndrome). 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 if you start having new or worse symptoms of infection after you start taking

TRIZIVIR.

Changes in body fat (fat redistribution). Changes in body fat (lipoatrophy or lipodystrophy) can

happen in some people taking antiretroviral medicines including TRIZIVIR.

These changes may include:

more fat in or around your trunk, upper back and neck (buffalo hump), breast or chest

loss of fat in your legs, arms, or face

Heart attack (myocardial infarction). Some HIV medicines including TRIZIVIR may increase your

risk of heart attack.

The most common side effects of TRIZIVIR include:

nausea

headache

weakness or tiredness

vomiting

diarrhea

fever and/or chills

depression

muscle and joint pain

skin rashes

ear, nose, throat infections

cold symptoms

nervousness

Tell 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 1-800-

FDA-1088.

How should I store TRIZIVIR?

Store TRIZIVIR at 59°F to 86°F (15°C to 30°C).

Keep TRIZIVIR and all medicines out of the reach of children.

General information for safe and effective use of TRIZIVIR.

Avoid doing things that can spread HIV-1 infection to others.

Do not share needles or other injection equipment.

Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor

blades.

Do not have any kind of sex without protection. Always practice safe sex by using a latex or

polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or

blood.

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.

This Medication Guide summarizes the most important information about TRIZIVIR. If you would like

more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist

for the information about TRIZIVIR that is written for healthcare professionals.

For more information go to www.TRIZIVIR.com or call 1-877-844-8872.

What are the ingredients in TRIZIVIR?

Active ingredients: abacavir sulfate, lamivudine, and zidovudine

Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and

OPADRY® green 03B11434, a film coating made of FD&C Blue No. 2, hypromellose, polyethylene

glycol, titanium dioxide, and yellow iron oxide.

This Medication Guide has been approved by the US Food and Drug Administration.

COMBIVIR, EPIVIR, EPZICOM, RETROVIR, TRIZIVIR, and ZIAGEN are registered trademarks of

ViiV Healthcare.

The brands listed are trademarks of their respective owners and are not trademarks of ViiV Healthcare.

The makers of these brands are not affiliated with and do not endorse ViiV Healthcare or its products.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2013, ViiV Healthcare. All rights reserved.

This Product was Repackaged By:

State of Florida DOH Central Pharmacy

104-2 Hamilton Park Drive

Tallahassee, FL 32304

United States

Revised: 4/2014

Document Id: a6299f1c-1ddb-4da4-a38d-2cb34eca0c02

Set id: 3354e50f-4dc5-413f-b5ae-87353ab8913d

Version: 2

Effective Time: 20140424

State of Florida DOH Central Pharmacy

TRIZIVIR - abacavir sulfate, lamivudine, and zidovudine tablet, film coated

State of Florida DOH Central Pharmacy

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TRIZIVIR safely and effectively. See full

prescribing information for TRIZIVIR.

TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine) Tablets, for oral use

Initial U.S. Approval: 2000

WARNING: RISK OF HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY,

LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, EXACERBATIONS OF HEPATITIS B

See full prescribing information for complete boxed warning.

INDICATIONS AND USAGE

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 HIV-1 infection. (1) (1)

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

Tablets contain 300 mg abacavir, 150 mg of lamivudine, and 300 mg of zidovudine. (3) (3)

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Serious and sometimes fatal hypersensitivity reactions have been associated 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 high risk for experiencing a hypersensitivity

reaction to abacavir. (5.1)

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. (5.1)

Following a hypersensitivity reaction to abacavir, NEVER restart TRIZIVIR or any other abacavir-

containing product. (5.1)

Hematologic toxicity, including neutropenia and anemia, has been associated with the use of

zidovudine, a component of TRIZIVIR. (5.2)

Symptomatic myopathy associated with prolonged use of zidovudine. (5.3)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported

with the use of nucleoside analogues. (5.4)

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)

A medication guide and warning card should be dispensed with each new prescription and refill. (2)

Adults and Adolescents: 1 tablet twice daily. (2.1)

Not recommended in adolescents who weigh less than 40 kg. (2.1)

Do not prescribe for patients requiring dosage adjustment or patients with hepatic impairment. (2.2)

Previously demonstrated hypersensitivity to abacavir or any other component of the product. (4, 5.1, 6)

Hepatic impairment. (4)

See boxed warning for information about the following: hypersensitivity reactions, hematologic toxicity, myopathy,

lactic acidosis and severe hepatomegaly, and severe acute exacerbations of hepatitis B. (5.1, 5.2, 5.3, 5.4, 5.5)

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)

ADVERSE REACTIONS

The most commonly reported adverse reactions (incidence ≥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.

DRUG INTERACTIONS

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 4/2014

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISK OF HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY,

MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, EXACERBATIONS

OF HEPATITIS B

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adults and Adolescent Patients

2.2 Dosage Adjustment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5.1 Hypersensitivity Reaction

5.2 Hematologic Toxicity/Bone Marrow Suppression

5.3 Myopathy

5.4 Lactic Acidosis/Hepatomegaly With Steatosis

5.5 Patients With HIV-1 and Hepatitis B Virus Co-infection

5.6 Use With Interferon- and Ribavirin-Based Regimens

5.7 Immune Reconstitution Syndrome

5.8 Fat Redistribution

5.9 Myocardial Infarction

5.10 Therapy Experienced Patients

5.11 Use With Other Abacavir-, Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing

Products

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Antiretroviral Agents

7.2 Doxorubicin

7.3 Ethanol

7.4 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

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 (5.7) and redistribution/accumulation of body fat (5.8) have been reported in

patients treated with combination antiretroviral therapy.

TRIZIVIR should not be administered with other products containing abacavir, lamivudine, or zidovudine; or with

emtricitabine. (5.11)

Concomitant use with the following drugs should be avoided: stavudine (7.1), doxorubicin (7.2).

Ethanol: Decreases the elimination of abacavir. (7.3)

Bone marrow suppressive/cytotoxic agents: May increase the hematologic toxicity of zidovudine. (7.4)

Methadone: An increased methadone dose may be required in a small number of patients. (7.6)

7.5 Interferon- and Ribavirin-Based Regimens

7.6 Methadone

7.7 Trimethoprim/Sulfamethoxazole (TMP/SMX)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients With Impaired Renal Function

8.7 Patients With Impaired Hepatic Function

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: RISK OF HYPERSENSITIVITY REACTIONS, HEMATOLOGIC

TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY,

EXACERBATIONS OF HEPATITIS B

Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have

been associated with abacavir sulfate, a component of TRIZIVIR. Hypersensitivity to

abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2

or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea,

vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise,

fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis).

Discontinue TRIZIVIR as soon as a hypersensitivity reaction is suspected.

Patients who carry the HLA-B*5701 allele are at high risk for experiencing a

hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for

the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk

of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir

in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. HLA-

B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir;

however, this occurs significantly less frequently than in HLA-B*5701-positive patients.

Regardless of HLA-B*5701 status, permanently discontinue TRIZIVIR if hypersensitivity

cannot be ruled out, even when other diagnoses are possible.

Following a hypersensitivity reaction to abacavir, NEVER restart TRIZIVIR or any other

abacavir-containing product because more severe symptoms can occur within hours and

may include life-threatening hypotension and death.

Reintroduction of TRIZIVIR or any other abacavir-containing product, even in patients

who have no identified history or unrecognized symptoms of hypersensitivity to abacavir

therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur

within hours [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 (HIV-1) 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: Lactic acidosis and severe hepatomegaly with

steatosis, including fatal cases, have been reported with the use of nucleoside analogues

alone or in combination, including abacavir, lamivudine, zidovudine, and other

antiretrovirals [see Warnings and Precautions (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 HIV-1 and have

discontinued lamivudine, which is one component of TRIZIVIR. Hepatic function should be

monitored closely with both clinical and laboratory follow-up for at least several months in

patients who discontinue TRIZIVIR and are co-infected with HIV-1 and HBV. If

appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and

Precautions (5.5)].

1 INDICATIONS AND USAGE

TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of HIV-1

infection.

infection.

Additional important information on the use of TRIZIVIR for treatment of HIV-1 infection:

2 DOSAGE AND ADMINISTRATION

2.1 Adults and Adolescent Patients

The recommended oral dose of TRIZIVIR is one tablet twice daily.

TRIZIVIR is not recommended in adolescents who weigh less than 40 kg because it is a fixed-dose

tablet and cannot be dose adjusted.

2.2 Dosage Adjustment

Because it is a fixed-dose combination, TRIZIVIR should not be prescribed for:

3 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 “GX LL1” on

one side with no markings on the reverse side.

4 CONTRAINDICATIONS

TRIZIVIR Tablets are contraindicated in patients with:

5.1 Hypersensitivity Reaction

Serious and sometimes fatal hypersensitivity reactions have been associated with TRIZIVIR and other

abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for

experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening

TRIZIVIR is one of multiple products containing abacavir. Before starting TRIZIVIR, review

medical history for prior exposure to any abacavir-containing product in order to avoid

reintroduction in a patient with a history of hypersensitivity to abacavir [see Warnings and

Precautions (5.1), Adverse Reactions (6)].

TRIZIVIR is a fixed-dose combination of 3 nucleoside analogues: abacavir, lamivudine, and

zidovudine and is intended only for patients whose regimen would otherwise include these

3 components.

Limited data exist on the use of TRIZIVIR alone in patients with higher baseline viral load levels

(>100,000 copies/mL) [see Clinical Studies (14)].

A Medication Guide and Warning Card that provide information about recognition of

hypersensitivity reactions should be dispensed with each new prescription and refill.

TRIZIVIR can be taken with or without food.

patients requiring dosage adjustment such as those with creatinine clearance <50 mL/min.

patients with hepatic impairment.

previously demonstrated hypersensitivity to abacavir or any other component of the product.

NEVER restart TRIZIVIR or any other abacavir-containing product following a hypersensitivity

reaction to abacavir, regardless of HLA-B*5701 status [see Warnings and Precautions (5.1),

Adverse Reactions (6)].

hepatic impairment [see Use in Specific Populations (8.7)].

for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a

hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of

unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive

patients, treatment with an abacavir-containing regimen is not recommended and should be considered

only with close medical supervision and under exceptional circumstances when the potential benefit

outweighs the risk.

HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this

occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701

status, permanently discontinue TRIZIVIR if hypersensitivity cannot be ruled out, even when other

diagnoses are possible.

Important information on signs and symptoms of hypersensitivity, as well as clinical management, is

presented below.

Signs and Symptoms of Hypersensitivity: Hypersensitivity to abacavir is a multi-organ clinical

syndrome usually characterized by a sign or symptom in 2 or more of the following groups.

Group 1: Fever

Group 2: Rash

Group 3: Gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain)

Group 4: Constitutional (including generalized malaise, fatigue, or achiness)

Group 5: Respiratory (including dyspnea, cough, or pharyngitis)

Hypersensitivity to abacavir following the presentation of a single sign or symptom has been reported

infrequently.

Hypersensitivity to abacavir was reported in approximately 8% of 2,670 subjects (n = 206) in 9 clinical

trials (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset

and symptoms of suspected hypersensitivity were collected on a detailed data collection module. The

frequencies of symptoms are shown in Figure 1. Symptoms usually appeared within the first 6 weeks of

treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset

was 9 days; 89% appeared within the first 6 weeks; 95% of subjects reported symptoms from 2 or more

of the 5 groups listed above.

A trial with ZIAGEN (abacavir sulfate) 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.

Figure 1. Hypersensitivity-Related Symptoms Reported With ≥10% Frequency in Clinical Trials

(n = 206 Subjects)

Other less common signs and symptoms of hypersensitivity include lethargy, myolysis, edema, abnormal

chest x-ray findings (predominantly infiltrates, which can be localized), and paresthesia. Anaphylaxis,

liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, and

death have occurred in association with hypersensitivity reactions.

Physical findings associated with hypersensitivity to abacavir in some subjects include

lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash

usually appears maculopapular or urticarial, but may be variable in appearance. There have been reports

of erythema multiforme. Hypersensitivity reactions have occurred without rash.

Laboratory abnormalities associated with hypersensitivity to abacavir in some subjects include elevated

liver function tests, elevated creatinine phosphokinase, elevated creatinine, and lymphopenia.

Clinical Management of Hypersensitivity: Discontinue TRIZIVIR as soon as a hypersensitivity reaction

is suspected. To minimize the risk of a life-threatening hypersensitivity reaction, permanently

discontinue TRIZIVIR if hypersensitivity cannot be ruled out, 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).

Following a hypersensitivity reaction to abacavir, NEVER restart TRIZIVIR or any other abacavir-

containing product because more severe symptoms can occur within hours and may include life-

threatening hypotension and death.

When therapy with TRIZIVIR has been discontinued for reasons other than symptoms of a

hypersensitivity reaction, and if reinitiation of abacavir is under consideration, carefully evaluate the

reason for discontinuation to ensure that the patient did not have symptoms of a hypersensitivity reaction.

If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to

reinitiation of TRIZIVIR.

If hypersensitivity cannot be ruled out, DO NOT reintroduce TRIZIVIR or any other abacavir-

containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently

discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out

on clinical grounds, due to the potential for a severe or even fatal reaction.

If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with

continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a

hypersensitivity reaction can occur with reintroduction of abacavir and that abacavir reintroduction

needs to be undertaken only if medical care can be readily accessed by the patient or others.

Risk Factor:HLA-B*5701 Allele: Trials have shown that carriage of the HLA-B*5701 allele is

associated with a significantly increased risk of a hypersensitivity reaction to abacavir.

CNA106030 (PREDICT-1), a randomized, double-blind trial, evaluated the clinical utility of

prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-

naive HIV-1-infected adults (n = 1,650). In this trial, use of pre-therapy screening for the HLA-B*5701

allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir

hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this trial, it is estimated that

61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity

reaction during the course of abacavir treatment compared with 4% of patients who do not have the

HLA-B*5701 allele.

Screening for carriage of the HLA-B*5701 allele is recommended prior to initiating treatment with

abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-

B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or

reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered

only with close medical supervision and under exceptional circumstances where potential benefit

outweighs the risk.

Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of

abacavir hypersensitivity.

In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the

basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to

permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot

be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

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

1,000 cells/mm or hemoglobin less than 9.5 g/dL.

Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are

treated with TRIZIVIR. 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/Hepatomegaly With Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with

the use of nucleoside analogues alone or in combination, including abacavir, lamivudine, zidovudine,

and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged

nucleoside exposure may be risk factors. Particular caution should be exercised when administering

TRIZIVIR 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 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 HIV-1 and Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected subjects treated with

lamivudine for chronic HBV, clinical and laboratory evidence of exacerbations of hepatitis have

occurred after discontinuation of lamivudine. These exacerbations have been detected primarily by

serum ALT elevations in addition to re-emergence of hepatitis B viral DNA (HBV DNA). Although

most events appear to have been self-limited, fatalities have been reported in some cases. Similar events

have been reported from post-marketing experience after changes from lamivudine-containing HIV-1

treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and

HBV. The causal relationship to discontinuation of lamivudine treatment is unknown. Patients should be

closely monitored with both clinical and laboratory follow-up for at least several months after stopping

treatment. There is insufficient evidence to determine whether reinitiation of lamivudine alters the

course of posttreatment exacerbations of hepatitis.

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. In non-HIV-

infected subjects treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant

HBV has been detected and has been associated with diminished treatment response (see full

prescribing information for EPIVIR-HBV [lamivudine] for additional information). Emergence of

hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-

infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of

concurrent infection with hepatitis B virus.

5.6 Use With Interferon- and Ribavirin-Based Regimens

In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside

analogues such as lamivudine and zidovudine. Although no evidence of a pharmacokinetic or

pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin

was coadministered with lamivudine or zidovudine in HIV-1/HCV co-infected subjects [see Clinical

Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected

subjects receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without

ribavirin. Patients receiving interferon alfa with or without ribavirin and TRIZIVIR should be closely

monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and

anemia. 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 the

complete prescribing information for interferon and ribavirin).

Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and

zidovudine. Coadministration of ribavirin and TRIZIVIR 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-Barré syndrome) have also

been reported to occur in the setting of immune reconstitution; however, the time to onset is more

variable, and can occur many months after initiation of treatment.

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 in patients on combination antiretroviral therapy, the use of abacavir within the

previous 6 months was correlated with an increased risk of myocardial infarction (MI).

In a sponsor-

conducted pooled analysis of clinical trials, no excess risk of myocardial infarction was observed in

abacavir-treated subjects as compared with control subjects. In totality, the available data from the

observational cohort and from clinical 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

Clinical Pharmacology (12.4)].

5.11 Use With Other Abacavir-, Lamivudine-, Zidovudine-, and/or Emtricitabine-Containing

Products

TRIZIVIR is a fixed-dose combination of abacavir, lamivudine, and zidovudine and is intended only for

patients whose regimen would otherwise include these 3 components. TRIZIVIR should not be

administered concomitantly with other abacavir-, lamivudine-, or zidovudine-containing products

including ZIAGEN (abacavir sulfate) Tablets and Oral Solution, EPIVIR (lamivudine) Tablets and Oral

Solution, EPIVIR-HBV (lamivudine) Tablets and Oral Solution, RETROVIR (zidovudine) Tablets,

Capsules, Syrup, and IV Infusion, COMBIVIR (lamivudine and zidovudine) Tablets, EPZICOM

(abacavir sulfate and lamivudine) Tablets; or emtricitabine containing products, including ATRIPLA

(efavirenz/emtricitabine/tenofovir disoproxil fumarate) Tablets, EMTRIVA (emtricitabine) Capsules

and Oral Solution, TRUVADA (emtricitabine/tenofovir disoproxil fumarate) Tablets, or

COMPLERA (emtricitabine/rilpirivine/tenofovir disoproxil fumarate) Tablets.

The complete prescribing information for all agents being considered for use with TRIZIVIR should be

consulted before combination therapy with TRIZIVIR is initiated.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail 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)].

Acute 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)].

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.

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a

frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine

150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily,

lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in

Table 1.

Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity

(Grades 2-4, ≥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

Headache

Malaise and fatigue

Nausea and vomiting

Hypersensitivity reaction

Diarrhea

Fever and/or chills

Depressive disorders

Musculoskeletal pain

Skin rashes

Ear/nose/throat infections

Viral respiratory infections

Anxiety

Renal signs/symptoms

<1%

Pain (non-site-specific)

<1%

Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression

compared to none in the indinavir arm. The background rates of pre-existing depression were similar in

the 2 treatment arms.

Laboratory Abnormalities: Laboratory abnormalities in CNA3005 are listed in Table 2.

Table 2. Treatment-Emergent Laboratory Abnormalities (Grades 3/4) in CNA3005

Grade 3/4 Laboratory Abnormalities

Number of Subjects by Treatment Group

ZIAGEN plus

Lamivudine/Zidovudine

Indinavir plus

Lamivudine/Zidovudine

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)].

(n = 262)

(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 ≤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

In addition to adverse reactions reported from clinical trials, the following reactions have been

identified during postmarketing use of abacavir, lamivudine, and/or zidovudine. Because they are

reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These

reactions have been chosen for inclusion due to a combination of their seriousness, frequency of

reporting, or potential causal connection to abacavir, lamivudine and/or zidovudine.

Abacavir:

Cardiovascular: 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.

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, hyperglycemia.

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 exacerbation of hepatitis B [see Warnings and Precautions (5.5)].

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Arthralgia, myalgia, muscle weakness, CPK elevation, 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.

7 DRUG INTERACTIONS

7.1 Antiretroviral Agents

Zidovudine:Stavudine: Concomitant use of zidovudine with stavudine should be avoided since an

antagonistic relationship has been demonstrated in vitro.

Nucleoside Analogues Affecting DNA Replication: Some nucleoside analogues affecting DNA

replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1;

concomitant use of such drugs should be avoided.

7.2 Doxorubicin

Zidovudine: Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic

relationship has been demonstrated in vitro.

7.3 Ethanol

Abacavir: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the

elimination of abacavir causing an increase in overall exposure [see Clinical Pharmacology (12.3)].

7.4 Hematologic/Bone Marrow Suppressive/Cytotoxic Agents

Zidovudine: Coadministration of ganciclovir, interferon alfa, ribavirin, and other bone marrow

suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.

7.5 Interferon- and Ribavirin-Based Regimens

Lamivudine: Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of

HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in

HIV-1/HCV co-infected subjects, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-

infected subjects receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or

without ribavirin [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].

7.6 Methadone

Abacavir: The addition of methadone has no clinically significant effect on the pharmacokinetic

properties of abacavir. 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 (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.

7.7 Trimethoprim/Sulfamethoxazole (TMP/SMX)

Lamivudine: No change in dose of either drug is recommended [see Clinical Pharmacology (12.3)].

There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of

TMP/SMX such as those used to treat PCP.

8 USE IN SPECIFIC POPULATIONS

No drug interaction trials have been conducted using TRIZIVIR Tablets [see Clinical

Pharmacology (12.3)].

8.1 Pregnancy

TRIZIVIR: 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.

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/kg/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/kg/day and rabbits given 500 mg/kg/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/kg/day (very near the oral median lethal

dose in rats of approximately 3,700 mg/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/kg/day or less. Two rodent carcinogenicity studies were conducted [see Nonclinical

Toxicology (13.1)].

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to

TRIZIVIR or other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established.

Physicians are encouraged to register patients by calling 1-800-258-4263.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed

their infants to avoid risking postnatal transmission of HIV infection.

Abacavir, Lamivudine, and Zidovudine: Lamivudine and zidovudine are excreted in human breast milk;

abacavir and lamivudine are secreted into the milk of lactating rats.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in

nursing infants, mothers should be instructed not to breastfeed if they are receiving TRIZIVIR.

8.4 Pediatric Use

TRIZIVIR is not intended for use in pediatric patients and is not recommended in adolescents who

weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient

populations.

Therapy-Experienced Pediatric 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 studies 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, dose

selection for an elderly patient should be cautious, reflecting the greater frequency of decreased

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and

Administration (2.3), Use in Specific Populations (8.6)].

8.6 Patients With Impaired Renal Function

TRIZIVIR is not recommended for patients with impaired renal function (i.e., creatinine clearance

<50 mL/min) because TRIZIVIR is a fixed-dose combination and the dosage of the individual

components cannot be adjusted.

8.7 Patients With Impaired Hepatic Function

TRIZIVIR is contraindicated for patients with hepatic impairment because TRIZIVIR is a fixed-dose

combination and the dosage of the individual components cannot be adjusted.

10 OVERDOSAGE

Abacavir: There is no known antidote for abacavir. It is not known whether abacavir can be removed by

peritoneal dialysis or hemodialysis.

Lamivudine: One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical

signs or symptoms noted and hematologic tests remained normal. It is not known whether lamivudine can

be removed by peritoneal dialysis or hemodialysis.

Zidovudine: Acute overdoses of zidovudine have been reported in pediatric patients and adults. These

involved exposures up to 50 grams. The only consistent findings were nausea and vomiting. Other

reported occurrences included headache, dizziness, drowsiness, lethargy, and confusion. Hematologic

changes were transient. All patients recovered. 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-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.

11 DESCRIPTION

TRIZIVIR: TRIZIVIR Tablets contain the following 3 synthetic nucleoside analogues: abacavir sulfate

(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

300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the

inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The

tablets are coated with a film (OPADRY green 03B11434) that is made of FD&C Blue No. 2,

hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.

Abacavir Sulfate: 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

H N O)

H SO and a molecular weight of 670.76 daltons. It has the following structural

formula:

2

Abacavir sulfate is a white to off-white solid with a solubility of approximately 77 mg/mL in distilled

water at 25°C.

In vivo, abacavir sulfate dissociates to its free base, abacavir. In this insert, all dosages for ZIAGEN

(abacavir sulfate) are expressed in terms of abacavir.

Lamivudine: 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 C H N O S and a molecular weight of 229.3 daltons. It has the following structural

formula:

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in

water at 20°C.

Zidovudine: The chemical name of zidovudine is 3′-azido-3′-deoxythymidine. It has a molecular

formula of C

H N O and a molecular weight of 267.24 daltons. It has the following structural

formula:

Zidovudine is a white to beige, crystalline solid with a solubility of 20.1 mg/mL in water at 25°C.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

TRIZIVIR is an antiviral agent [see Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Pharmacokinetics in Adults:TRIZIVIR: 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 (C

), 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.

Binding of abacavir to human plasma proteins is approximately 50%. Binding of abacavir to plasma

proteins 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 Parameters

for Abacavir, Lamivudine, and Zidovudine in Adults

a

Parameter

Abacavir

Lamivudine

Zidovudine

Oral bioavailability (%)

86 ± 25

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)

.007 ± .008

n = 6

0.22 ± 0.06

n = 20

0.34 ± 0.05 n = 9

Elimination half-life (h)

1.45 ± 0.32

n = 20

5 to 7

0.5 to 3

Data presented as mean ± standard deviation except where noted.

Approximate range.

Effect of Food on Absorption of TRIZIVIR: Administration with food in a single-dose bioavailability

trial resulted in lower C

, similar to results observed previously for the reference formulations. The

average [90% CI] decrease in abacavir, lamivudine, and zidovudine C

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 (2.1)].

Special Populations: Renal Impairment: TRIZIVIR: Because lamivudine and zidovudine require dose

adjustment in the presence of renal insufficiency, TRIZIVIR is not recommended for use in patients with

creatinine clearance <50 mL/min [see Use in Specific Populations (8.6)].

Hepatic Impairment: TRIZIVIR: TRIZIVIR is contraindicated for patients with impaired hepatic function

because TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be

adjusted. Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose

reduction is required in patients with mild hepatic impairment.

Pregnancy: See Use in Specific Populations (8.1).

Abacavir and Lamivudine: No data are available on the pharmacokinetics of abacavir or lamivudine

during pregnancy.

Zidovudine: Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last

trimester of pregnancy. As pregnancy progressed, there was no evidence of drug accumulation. The

pharmacokinetics of zidovudine were similar to that 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. In a

nonpregnant adult population, a potential for interaction has been identified [see Use in Specific

Populations (8.1)].

Nursing Mothers: See Use in Specific Populations (8.3).

Abacavir: No data are available on the pharmacokinetics of abacavir in nursing mothers.

Lamivudine: Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy

(300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine

twice daily) had measurable concentrations of lamivudine.

Zidovudine: After administration of a single dose of 200 mg zidovudine to 13 HIV 1-infected women,

the mean concentration of zidovudine was similar in human milk and serum [see Use in Specific

Populations (8.3)].

Pediatric Patients: TRIZIVIR is not intended for use in pediatric patients. TRIZIVIR is not recommended

in adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose adjusted

for this patient population.

Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied

in subjects over 65 years of age.

in subjects over 65 years of age.

Gender:

Abacavir: 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.

Lamivudine and Zidovudine: A pharmacokinetic trial in healthy male (n = 12) and female (n = 12) subjects

showed no gender differences in zidovudine exposure (AUC ) or lamivudine (AUC ) normalized for

body weight.

Race:

Abacavir: There are no significant differences between blacks and Caucasians in abacavir

pharmacokinetics.

Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.

Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined.

Drug Interactions: The drug interactions described below are based on trials conducted with the

individual nucleoside analogues.

Cytochrome P450: In humans, 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.

Lamivudine and 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 q 12 h).

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 (7.6)].

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 (5.6)].

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 AUC Note:

ROUTINE DOSE MODIFICATION OF ABACAVIR, LAMIVUDINE, AND ZIDOVUDINE IS

NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.

Drugs That May Alter Lamivudine Blood Concentrations

Coadministered Drug and

Dos e

Lamivudine Dose

n

Lamivudine

Concentrations

Concentration

of

Coadminis tered

Drug

AUC

Variability

a

Nelfinavir

750 mg q 8 h

x 7 to 10 days

single 150 mg

↑10%

95% CI:

1% to 20%

Trimethoprim 160 mg/

Sulfamethoxazole

800 mg daily

x 5 days

single 300 mg

↑43%

90% CI:

32% to 55%

Drugs That May Alter Zidovudine Blood Concentrations

Coadministered Drug and

Dos e

Zidovudine Dose

n

Zidovudine

Concentrations

Concentration

of

Coadminis tered

Drug

AUC

Variability

Atovaquone

750 mg q 12 h

with food

200 mg q 8 h

↑31%

Range

23% to 78%

Clarithromycin

500 mg twice daily

100 mg q 4 h x 7

days

↓12%

Range ↓34% to

↑14%

Not Reported

Fluconazole

400 mg daily

200 mg q 8 h

↑74%

95% CI:

54% to 98%

Not Reported

Methadone

30 to 90 mg daily

200 mg q 4 h

↑43%

Range

16% to 64%

Nelfinavir

750 mg q 8 h x 7 to

10 days

single 200 mg

↓35%

Range

28% to 41%

Probenecid

500 mg q 6 h x

2 days

2 mg/kg q 8 h x

3 days

↑106%

Range

100% to 170%

Not Assessed

Rifampin

600 mg daily x 14 days

200 mg q 8 h x 14

days

↓47%

90% CI: 41% to

Not Assessed

Ritonavir

300 mg q 6 h x

4 days

200 mg q 8 h x

4 days

↓25%

95% CI:

15% to 34%

Valproic acid

250 mg or 500 mg

q 8 h x 4 days

100 mg q 8 h x

4 days

↑80%

Range

64% to 130%

Not Assessed

Drugs That May Alter Abacavir Blood Concentrations

Coadministered Drug and

Dos e

Abacavir Dose

n

Abacavir Concentrations

Concentration

of

Coadminis tered

Drug

AUC

Variability

Ethanol

0.7 g/kg

single 600 mg

↑41%

90% CI:

35% to 48%

↑ = Increase; ↓ = Decrease; ↔ = no significant change; AUC = area under the concentration versus time

curve; CI = confidence interval.

See Drug Interactions (7) for additional information on drug interactions.

Estimated 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 (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. The

lack of a 3′-OH group in the incorporated nucleotide analogue prevents the formation of the 5′ to 3′

phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is

terminated. CBV-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.

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. 3TC-TP is a weak inhibitor of cellular DNA polymerases α, β, and γ.

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. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and

has been reported to be incorporated into the DNA of cells in culture.

Antiviral Activity:Abacavir: The antiviral activity of abacavir against HIV-1 was evaluated against a T-

cell tropic laboratory strain HIV-1

in lymphoblastic cell lines, a monocyte/macrophage tropic

laboratory strain HIV-1

in primary monocytes/macrophages, and clinical isolates in peripheral blood

mononuclear cells. The concentration of drug necessary to effect viral replication by 50 percent (EC

ranged from 3.7 to 5.8 μM (1 μM = 0.28 mcg/mL) and 0.07 to 1.0 μM against HIV-1

and HIV-1

respectively, and was 0.26 ± 0.18 μM against 8 clinical isolates. The EC

values of abacavir against

different HIV-1 clades (A-G) ranged from 0.0015 to 1.05 μM, and against HIV-2 isolates, from 0.024

to 0.49 μM. Abacavir had synergistic activity in cell culture in combination with the NRTI zidovudine,

the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, and the protease inhibitor (PI)

amprenavir; and additive activity in combination with the NRTIs didanosine, emtricitabine, lamivudine,

stavudine, tenofovir, and zalcitabine. Ribavirin (50 μM) had no effect on the anti–HIV-1 activity of

abacavir in cell culture.

Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines

(including monocytes and fresh human peripheral blood lymphocytes) using standard susceptibility

assays. EC

values (50% effective concentrations) were in the range of 0.003 to 15 μM

(1 μM = 0.23 mcg/mL). HIV-1 from therapy-naive subjects with no amino acid substitutions associated

with resistance gave median EC

values of 0.429 µM (range: 0.200 to 2.007 µM) from Virco (n = 92

baseline samples from COLA40263) and 2.35 µM (1.37 to 3.68 µM) from Monogram Biosciences

(n = 135 baseline samples from ESS30009). The EC

values of lamivudine against different HIV-1

clades (A-G) ranged from 0.001 to 0.120 µM, and against HIV-2 isolates from 0.003 to 0.120 μM in

peripheral blood mononuclear cells. Ribavirin (50 μM) 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 EC

and EC

values for

zidovudine were 0.01 to 0.49 µM (1 μM = 0.27 mcg/mL) and 0.1 to 9 μM, respectively. HIV-1 from

therapy-naive subjects with no amino acid substitutions associated with resistance gave median EC

values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92 baseline samples from

COLA40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram Biosciences (n = 135 baseline

samples from ESS30009). The EC

values of zidovudine against different HIV-1 clades (A-G) ranged

from 0.00018 to 0.02 μM, and against HIV-2 isolates from 0.00049 to 0.004 μM. In cell culture drug

combination studies, zidovudine demonstrates synergistic activity with the NRTIs abacavir, didanosine,

lamivudine, and zalcitabine; the NNRTIs delavirdine and nevirapine; and the PIs indinavir, nelfinavir,

ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the

phosphorylation of zidovudine in cell culture.

Resistance: HIV-1 isolates with reduced sensitivity to abacavir, lamivudine, or zidovudine have been

selected in cell culture and were also obtained from subjects treated with abacavir, lamivudine, and

IIIB

IIIB

zidovudine, or the combination of lamivudine and zidovudine.

Abacavir: 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 in HIV-1 RT

contributed to abacavir resistance. In a trial of subjects receiving abacavir once or twice daily in

combination with lamivudine and efavirenz once daily, 39% (7/18) of the isolates from subjects who

experienced virologic failure in the abacavir once-daily arm had a >2.5-fold decrease in abacavir

susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5/17) of the

failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).

Lamivudine: Genotypic analysis of isolates selected in cell culture and recovered from lamivudine-

treated subjects showed that the resistance was due to a specific amino acid substitution in the HIV-1

RT at codon 184 changing the methionine to either valine or isoleucine (M184V/I).

Zidovudine: Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-

treated subjects showed mutations in the HIV-1 RT gene resulting in 6 amino acid substitutions (M41L,

D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher

levels of resistance were associated with greater number of mutations. In some subjects harboring

zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of

treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed

the emergence of substitutions conferring resistance to zidovudine.

Cross-Resistance: Cross-resistance has been observed among NRTIs.

Abacavir: Isolates containing abacavir resistance-associated amino acid substitutions, namely, K65R,

L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine,

tenofovir, and zalcitabine in cell culture and in subjects. The K65R substitution can confer resistance to

abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V

substitution can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V substitution

can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine. An increasing

number of thymidine analogue mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F,

K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.

Lamivudine: Cross-resistance to abacavir, didanosine, tenofovir, and zalcitabine has been observed in

some subjects harboring lamivudine-resistant HIV-1 isolates. In some subjects treated with zidovudine

plus didanosine or zalcitabine, isolates resistant to multiple drugs, including lamivudine, have emerged

(see under Zidovudine below). Cross-resistance between lamivudine and zidovudine has not been

reported.

Zidovudine: In a trial of 167 HIV-infected subjects, isolates (n = 2) with multi-drug resistance to

didanosine, lamivudine, stavudine, zalcitabine, and zidovudine were recovered from subjects treated for

≥1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-

associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L,

F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most

commonly associated with multi-drug resistance. The substitution at codon 151 in combination with

substitutions at 62, 75, 77, and 116 results in a virus with reduced susceptibility to didanosine,

lamivudine, stavudine, zalcitabine, and zidovudine. TAMs are selected by zidovudine and confer cross-

resistance to abacavir, didanosine, stavudine, tenofovir, and zalcitabine.

13 NONCLINICAL TOXICOLOGY

13.1 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. It is not known how predictive the

results of rodent carcinogenicity studies may be for humans.

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) those observed in humans

at the recommended therapeutic dose for HIV-1 infection.

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/kg/day in

mice and 80, 220, and 600 mg/kg/day in rats. The doses in mice were reduced to 20, 30, and

40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats only the high dose was

reduced to 450 mg/kg per day on day 91 and then to 300 mg/kg/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.

Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine

at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with

dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately

3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg/kg/day

dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or

lung or any other organ in either gender. These findings are consistent with results of the standard oral

carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum

tolerated doses of 12.5 mg/day or 25 mg/day (~1,000 mg/kg nonpregnant body weight or ~450 mg/kg of

term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the

number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving

the higher dose level of zidovudine.

It is not known how predictive the results of rodent carcinogenicity studies may be for humans.

Mutagenicity:

Abacavir: 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/TK+/- 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/TK+/- mouse lymphoma assay and clastogenic in a

cytogenetic assay using cultured human lymphocytes. Lamivudine was negative 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/TK+/- 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: Abacavir had no adverse effects on the mating performance or fertility of male and female

rats at a dose approximately 8 times the human exposure at the recommended dose based on body

surface area comparisons.

Lamivudine: In a study of reproductive performance, lamivudine, administered to male and female rats at

doses up to 130 times the usual adult dose based on body surface area considerations, revealed no

evidence of impaired fertility judged by conception rates and no effect on the survival, growth, and

development to weaning of the offspring.

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.

13.2 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.

The clinical relevance of this finding has not been determined.

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 562 HIV-1-infected, therapy-naive

adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR (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/mL and plasma HIV-1 RNA >100,000 copies/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/mm , and median plasma HIV-1 RNA was

4.8 log

copies/mL. Proportions of subjects with plasma HIV-1 RNA <400 copies/mL (using Roche

AMPLICOR HIV-1 MONITOR 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)

Responder

Virologic failure

Discontinued due to adverse reactions

Discontinued due to other reasons

Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL.

Includes viral rebound and failure to achieve confirmed <400 copies/mL by Week 48.

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 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

<400 copies/mL

≥10,000 - ≤100,000

>100,000

In subjects with baseline viral load >100,000 copies/mL, percentages of subjects with HIV-1 RNA

levels <50 copies/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/mm was observed

in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir sulfate

(6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir

(2 CDC classification C events and 1 death) experienced clinical disease progression.

15 REFERENCES

16 HOW SUPPLIED/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 supplied by State of Florida DOH Central Pharmacy as follows:

NDC

Strength

Quantity/Form

Color

Source

Prod.

Code

53808-

0990-1

300 mg / 150 mg / 300

30 Tablets in a Blister

Pack

blue-green

49702-217

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled

Room Temperature).

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide)

Hypersensitivity Reaction: Inform patients:

Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. Lancet. 2008;371

(9622):1417-1426.

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 encourage 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].

Neutropenia and Anemia: Patients should be informed that the important toxicities associated with

zidovudine are neutropenia and/or anemia. They should be told of the extreme importance of having

their blood counts followed closely while on therapy, especially for patients with advanced HIV-1

disease [see Warnings and Precautions (5.2)].

Myopathy: Patients should be informed that myopathy and myositis with pathological changes, similar to

that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see Warnings

and Precautions (5.3)].

Lactic Acidosis/Hepatomegaly: 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 (5.4)].

HIV-1/ HBV Co-Infection: Patients co-infected with HIV-1 and HBV should be informed that

deterioration of liver disease has occurred in some cases when treatment with lamivudine was

discontinued. Patients should be advised to discuss any changes in regimen with their physician [see

Warnings and Precautions (5.5)].

HIV-1/HCV Co-Infection: Patients with HIV-1/HCV co-infection should be informed that hepatic

decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination

antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and

Precautions (5.6)].

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)].

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 should remain under the care of a physician when using TRIZIVIR.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

that if they develop symptoms consistent with a hypersensitivity reaction they should call their

doctor 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

that restarting abacavir needs to be undertaken only if medical care can be readily accessed by the

patient or others.

TRIZIVIR should not be coadministered with ATRIPLA, COMBIVIR, COMPLERA, EMTRIVA,

EPIVIR, EPIVIR-HBV, EPZICOM, RETROVIR (zidovudine), TRUVADA, or ZIAGEN.

Do not share needles or other injection equipment.

Do not share personal items that can have blood or body fluids on them, like toothbrushes

and razor blades.

Do not have any kind of sex without protection. Always practice safe sex by using a latex or

Patients should be informed to take all HIV medications exactly as prescribed.

COMBIVIR, EPIVIR, EPZICOM, RETROVIR, TRIZIVIR, and ZIAGEN are registered trademarks of

ViiV Healthcare.

Other brands are trademarks of their respective owners and are not trademarks of ViiV Healthcare. The

makers of these brands are not affiliated with and do not endorse ViiV Healthcare or its products.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2013, ViiV Healthcare. All rights reserved.

This Product was Repackaged By:

State of Florida DOH Central Pharmacy

104-2 Hamilton Park Drive

Tallahassee, FL 32304

United States

MEDICATION GUIDE

TRIZIVIR (TRY-zih-veer)

(abacavir sulfate, lamivudine, and zidovudine

Tablets

Read this Medication Guide before you start taking TRIZIVIR and each time you get a refill. There may

be new information. This information does not take the place of talking to your healthcare provider

about your medical condition or your treatment. Be sure to carry your TRIZIVIR Warning Card with

you at all times.

What is the most important information I should know about TRIZIVIR?

1.Serious allergic reaction (hypersensitivity reaction). TRIZIVIR contains abacavir (also contained in

ZIAGEN and EPZICOM ). Patients taking TRIZIVIR may have a serious allergic reaction

(hypersensitivity reaction) that can cause death. Your risk of this allergic reaction is much higher if you

have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if

you have this gene variation.

If you get a symptom from 2 or more of the following groups while taking TRIZIVIR, call your

polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or

blood.

Do not breastfeed. Lamivudine and zidovudine are excreted in human breast milk. It is not

known if abacavir can be passed to your baby in your breast milk and whether it could harm

your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed

to the baby in the breast milk.

®

healthcare provider right away to find out if you should stop taking TRIZIVIR.

Symptom(s )

Group 1

Fever

Group 2

Ras h

Group 3

Nausea, vomiting, diarrhea, abdominal (stomach area) pain

Group 4

Generally ill feeling, extreme tiredness, or achiness

Group 5

Shortness of breath, cough, sore throat

A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card

with you at all times.

If you stop TRIZIVIR because of an allergic reaction, never take TRIZIVIR(abacavir sulfate,

lamivudine, and zidovudine)or any other abacavir-containing medicine (ZIAGEN and EPZICOM)

again. If you take TRIZIVIR or any other abacavir-containing medicine again after you have had an

allergic reaction, within hours you may get life-threatening symptoms that may include very low

blood pressure or death. 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 life-threatening reaction, even if you never had an allergic

reaction to it before.

If your healthcare provider tells you that you can take TRIZIVIR again, start taking it when you

are around medical help or people who can call a healthcare provider if you need one.

2. Blood problems. 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

patients with advanced human immunodeficiency virus (HIV) disease or AIDS. Your doctor should be

checking your blood cell counts regularly while you are taking TRIZIVIR. This is especially important

if you have advanced HIV or AIDS. This is to make sure that any blood cell problems are found

quickly.

3. Lactic Acidosis (buildup of acid in the blood). Some human immunodeficiency virus (HIV)

medicines, including TRIZIVIR, can cause a rare but serious condition called lactic acidosis.

Lactic acidosis is a serious medical emergency that can cause death and must be treated in the

hos pital.

Call your healthcare provider right away if you get any of the following signs or symptoms of

lactic acidosis:

4. Serious liver problems. Some people who have taken medicines like TRIZIVIR have developed

serious liver problems called hepatotoxicity, with liver enlargement (hepatomegaly) and fat in the

liver (steatosis). Hepatomegaly with steatosis is a serious medical emergency that can cause

death.

Call your healthcare provider right away if you get any of the following signs or symptoms of liver

you feel very weak or tired

you have unusual (not normal) muscle pain

you have trouble breathing

you have stomach pain with nausea and vomiting

you feel cold, especially in your arms and legs

you feel dizzy or light-headed

you have a fast or irregular heartbeat

problems :

You may be more likely to get lactic acidosis or serious liver problems if you are female, very

overweight, or have been taking nucleoside analogue medicines for a long time.

5. Use with interferon and ribavirin-based regimens. Worsening of liver disease (sometimes

resulting in death) has occurred in patients infected with both HIV and hepatitis C virus who are taking

anti-HIV medicines and are also being treated for hepatitis C with interferon with or without ribavirin. If

you are taking TRIZIVIR as well as interferon with or without ribavirin and you experience side

effects, be sure to tell your healthcare provider.

6. If you have HIV and hepatitis B virus infection, your hepatitis B virus infection may get worse if

you stop taking TRIZIVIR.

Your healthcare provider should monitor your health and do regular blood tests to check your liver if

you stop taking TRIZIVIR.

7. Muscle weakness (myopathy). RETROVIR, one of the medicines in TRIZIVIR, can cause

muscle weakness. This can be a serious problem.

What is TRIZIVIR?

TRIZIVIR is a prescription medicine used to treat HIV infection. TRIZIVIR contains 3 medicines:

abacavir (ZIAGEN), lamivudine or 3TC (EPIVIR ), and zidovudine, AZT, or ZDV (RETROVIR). All 3

of these medicines are called nucleoside analogue reverse transcriptase inhibitors (NRTIs). When used

together, they help lower the amount of HIV in your blood.

Who should not take TRIZIVIR?

Do not take TRIZIVIR if you:

What should I tell my healthcare provider before taking TRIZIVIR?

your skin or the white part of your eyes turns yellow (jaundice)

your urine turns dark

your bowel movements (stools) turn light in color

you don’t feel like eating food for several days or longer

you feel sick to your stomach (nausea)

you have lower stomach area (abdominal) pain

Take TRIZIVIR exactly as prescribed.

Do not run out of TRIZIVIR.

Do not stop TRIZIVIR without talking to your healthcare provider.

TRIZIVIR does not cure HIV infection or AIDS.

It is not known if TRIZIVIR will help you live longer or have fewer of the medical problems that

people get with HIV or AIDS.

It is very important that you see your healthcare provider regularly while you are taking

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 certain liver problems.

are an adolescent who weighs less than 90 pounds.

Before you take TRIZIVIR, tell your healthcare provider if you:

Pregnancy Registry. If you take TRIZIVIR while you are pregnant, talk to your healthcare provider

about how you can take part in the Pregnancy Registry for TRIZIVIR. The purpose of the pregnancy

registry is to collect information about the health of you and your baby.

Tell your healthcare provider about all the medicines you take, including prescription and

nonprescription medicines, vitamins, and herbal supplements.

Especially tell your healthcare provider if you take:

Ask your healthcare provider if you are not sure if you take one of the medicines listed above.

TRIZIVIR may affect the way other medicines work, and other medicines may affect how TRIZIVIR

have been tested and know whether or not you have a particular gene variation called HLA-

B*5701.

have hepatitis B virus infection or have other liver problems.

have kidney problems.

have low blood cell counts (bone marrow problem). Ask your doctor 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.

are pregnant or plan to become pregnant. It is not known if TRIZIVIR will harm your unborn

baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.

are breastfeeding or plan to breastfeed. Do not breastfeed. Lamivudine and zidovudine are

excreted in human breast milk. We do not know if abacavir can be passed to your baby in your

breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed

because HIV-1 can be passed to the baby in the breast milk.

alcohol

medicines used to treat hepatitis viruses such as interferon or ribavirin

methadone

BACTRIM , SEPTRA (trimethoprim [TMP/sulfamethoxazole SMX])

CYTOVENE , DHPG (ganciclovir)

interferon-alfa

ADRIAMYCIN (doxorubicin)

COPEGUS , REBETOL , VIRAZOLE (ribavirin)

any bone marrow suppressive medicines or cytotoxic medicines. Ask your doctor if you are not

sure.

ATRIPLA (efavirenz/emtricitabine/tenofovir disoproxil fumarate)

COMBIVIR (lamivudine and zidovudine)

COMPLERA (emtricitabine/rilpivirine/tenofovir disoproxil fumarate)

EMTRIVA (emtricitabine)

EPIVIR or EPIVIR-HBV (lamivudine)

EPZICOM (abacavir sulfate and lamivudine)

RETROVIR (zidovudine)

TRUVADA (emtricitabine/tenofovir disoproxil fumarate)

ZERIT (stavudine)

ZIAGEN (abacavir sulfate)

works.

Know the medicines you take. Keep a list of your medicines with you to show to your healthcare

provider and pharmacist when you get a new medicine.

How should I take TRIZIVIR?

If you stop your anti-HIV medicines, even for a short time, the amount of virus in your blood may

increase and the virus may become harder to treat.If you take too much TRIZIVIR, call your healthcare

provider or poison control center 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 allergic reactions, lactic acidosis, and liver

problems. See “What is the most important information I should know about TRIZIVIR?”

The most common side effects of TRIZIVIR include:

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Take TRIZIVIR exactly as your healthcare provider tells you to take it.

TRIZIVIR may be taken with or without food.

Do not skip doses.

Do not let your TRIZIVIR run out.

Blood problems.

Muscle weakness.

Changes in immune system (Immune Reconstitution Syndrome). 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 if you start having new or worse symptoms of infection after you start

taking TRIZIVIR.

Changes in body fat (fat redistribution). Changes in body fat (lipoatrophy or lipodystrophy) can

happen in some people taking antiretroviral medicines including TRIZIVIR.

These changes may include:

more fat in or around your trunk, upper back and neck (buffalo hump), breast or chest

loss of fat in your legs, arms, or face

Heart attack (myocardial infarction). Some HIV medicines including TRIZIVIR may increase

your risk of heart attack.

nausea

headache

weakness or tiredness

vomiting

diarrhea

fever and/or chills

depression

muscle and joint pain

skin rashes

ear, nose, throat infections

cold symptoms

nervousness

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 1-800-

FDA-1088.

How should I store TRIZIVIR?

General information for safe and effective use of TRIZIVIR.

Avoid doing things that can spread HIV-1 infection to others.

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.

This Medication Guide summarizes the most important information about TRIZIVIR. If you would like

more information, talk with your healthcare provider. You can ask your healthcare provider or

pharmacist for the information about TRIZIVIR that is written for healthcare professionals.

For more information go to www.TRIZIVIR.com or call 1-877-844-8872.

What are the ingredients in TRIZIVIR?

Active ingredients: abacavir sulfate, lamivudine, and zidovudine

Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and

OPADRY green 03B11434, a film coating made of FD&C Blue No. 2, hypromellose, polyethylene

glycol, titanium dioxide, and yellow iron oxide.

This Medication Guide has been approved by the US Food and Drug Administration.

COMBIVIR, EPIVIR, EPZICOM, RETROVIR, TRIZIVIR, and ZIAGEN are registered trademarks of

ViiV Healthcare.

The brands listed are trademarks of their respective owners and are not trademarks of ViiV Healthcare.

The makers of these brands are not affiliated with and do not endorse ViiV Healthcare or its products.

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Store TRIZIVIR at 59°F to 86°F (15°C to 30°C).

Keep TRIZIVIR and all medicines out of the reach of children.

Do not share needles or other injection equipment.

Do not share personal items that can have blood or body fluids on them, like toothbrushes

and razor blades.

Do not have any kind of sex without protection. Always practice safe sex by using a latex or

polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or

blood.

Basingstoke, UK

©2013, ViiV Healthcare. All rights reserved.

This Product was Repackaged By:

State of Florida DOH Central Pharmacy

104-2 Hamilton Park Drive

Tallahassee, FL 32304

United States

PACKAGE LABEL

Label Image for 53808-0990

300mg / 150mg / 300mg

TRIZIVIR

abacavir sulfate, lamivudine, and zidovudine tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:538 0 8 -0 9 9 0 (NDC:49 70 2-217)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ABACAVIR SULFATE (UNII: J220 T4J9 Q2) (ABACAVIR - UNII:WR2TIP26 VS)

ABACAVIR

30 0 mg

LAMIVUDINE (UNII: 2T8 Q726 O9 5) (LAMIVUDINE - UNII:2T8 Q726 O9 5)

LAMIVUDINE

150 mg

ZIDO VUDINE (UNII: 4B9 XT59 T7S) (ZIDOVUDINE - UNII:4B9 XT59 T7S)

ZIDOVUDINE

30 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

State of Florida DOH Central Pharmacy

PO LYETHYLENE GLYCO LS (UNII: 3WJQ0 SDW1A)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

Product Characteristics

Color

BLUE (blue-green)

S core

no sco re

S hap e

OVAL (capsule-shaped)

S iz e

21mm

Flavor

Imprint Code

GX;LL1

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:538 0 8 -0 9 9 0 -1

30 in 1 BLISTER PACK

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 2120 5

0 2/0 1/20 13

Labeler -

State of Florida DOH Central Pharmacy (829348114)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

State o f Flo rida DOH Central Pharmacy

8 29 348 114

re pa c k(538 0 8 -0 9 9 0 )

Revised: 4/2014

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