Trizivir Side Effects

TRIZIVIR contains 3 nucleoside analogues (abacavir sulfate, lamivudine, and zidovudine) and is intended only for patients whose regimen would otherwise include these 3 components.

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. 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: Information for Patients).

Hematologic Toxicity

Zidovudine has been associated with hematologic toxicity including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV) disease (see WARNINGS). Prolonged use of zidovudine has been associated with symptomatic myopathy.

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).

Exacerbations Of Hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) 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 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see WARNINGS).

Trizivir 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.

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 ( 1 S,cis)- 4-[2-amino-6-(cyclopropylamino)-9 H -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 (C14 H18 N6 O)2? H2 SO4 and a molecular weight of 670.76 daltons. It has the following structural formula:

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 C8 H11 N3 O3 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 C10 H13 N5 O4 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.

Trizivir Indications And Usage

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 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.
• Limited data exist on the use of TRIZIVIR alone in patients with higher baseline viral load levels (>100,000 copies/mL, see Description of Clinical Studies).

Description Of Clinical Studies

Trizivir

The following study was conducted with the individual components of TRIZIVIR (see CLINICAL PHARMACOLOGY for information about bioequivalence of TRIZIVIR).

CNA3005 was a multicenter, double-blind, controlled study in which 562 HIV-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 study 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. Study 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/mm3 , and median plasma HIV-1 RNA was 4.8 log10  copies/mL. Proportions of patients with plasma HIV-1 RNA <400 copies/mL (using Roche AMPLICOR HIV-1 MONITOR® Test) through 48 weeks of treatment are summarized in Table 3.

* 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 4.

In subjects with baseline viral load >100,000 copies/mL, percentages of patients 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/mm3 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.

Trizivir Contraindications

TRIZIVIR Tablets are contraindicated in patients with previously demonstrated hypersensitivity to abacavir or to any other component of the product (see WARNINGS).

Following a hypersensitivity reaction to abacavir, NEVER restart TRIZIVIR or any other abacavir-containing product. Fatal rechallenge reactions have been associated with readministration of abacavir to patients with a prior history of a hypersensitivity reaction to abacavir (see WARNINGS and PRECAUTIONS).

TRIZIVIR Tablets are contraindicated in patients with hepatic impairment (see CLINICAL PHARMACOLOGY).

Trizivir Side Effects

Hypersensitivity Reaction

Serious and sometimes fatal hypersensitivity reactions have been associated with TRIZIVIR and other abacavir-containing products. 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. 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 patients (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 hypersensitivitywere 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 patients reported symptoms from 2 or more of the 5 groups listed above.

A recent study with ZIAGEN used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the study, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 patients in the abacavir group and 3% of 325 patients in the zidovudine group.

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 patients 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 patients include elevated liver function tests, elevated creatine 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 hypersensitivity cannot be ruled out, DO NOT reintroduce abacavir. 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.

Abacavir Hypersensitivity Reaction Registry

To facilitate reporting of hypersensitivity reactions and collection of information on each case, an Abacavir Hypersensitivity Registry has been established. Physicians should register patients by calling 1-800-270-0425.

Lactic Acidosis/Severe 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).

Bone Marrow Suppression

Since TRIZIVIR contains zidovudine, TRIZIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count <1,000 cells/mm3 or hemoglobin <9.5 g/dL. Frequent blood counts are strongly recommended in patients with advanced HIV disease who are treated with TRIZIVIR. For HIV-infected individuals and patients with asymptomatic or early HIV disease, periodic blood counts are recommended.

Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with TRIZIVIR.

Posttreatment Exacerbations Of Hepatitis

In clinical trials in non-HIV-infected patients 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 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 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV 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 re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.

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, components of TRIZIVIR. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine or zidovudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV 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., Childs Pugh >6) (see the complete prescribing information for interferon and ribavirin).

Other

TRIZIVIR contains fixed doses of 3 nucleoside analogues: abacavir, lamivudine, and zidovudine and should not be administered concomitantly with abacavir, lamivudine, emtricitabine, or zidovudine. TRIZIVIR should also not be administered concomitantly with the fixed-dose combination drugs: lamivudine/zidovudine (COMBIVIR), abacavir and lamivudine (EPZICOM? ), or emtricitabine and tenofovir (TRUVADA® ).

Because TRIZIVIR is a fixed-dose tablet, it should not be prescribed for adolescents who weigh less than 40 kg or other patients requiring dosage adjustment.

The complete prescribing information for all agents being considered for use with TRIZIVIR should be consulted before combination therapy with TRIZIVIR is initiated.

Trizivir Precautions

Therapy-experienced Patients

Abacavir

In clinical trials, patients with prolonged prior NRTI exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients (see MICROBIOLOGY: Cross-Resistance).

Patients With Hiv and Hepatitis B Virus Co-infection

Lamivudine

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see EPIVIR-HBV® package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus

Patients With Impaired Renal Function

Trizivir

Since TRIZIVIR is a fixed-dose tablet and the dosage of the individual components cannot be altered, patients with creatinine clearance<50 mL/min should not receive TRIZIVIR.

Patients With Impaired Hepatic Function

Trizivir

TRIZIVIR is contraindicated in patients with hepatic impairment since it is a fixed-dose tablet and the dosage of the individual components cannot be altered.

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 system responds 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.

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.

Information For Patients

Abacavir

Hypersensitivity Reaction

Inform patients:

• that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIZIVIR, and 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 MEDICATION GUIDE).
• that if they develop symptoms consistent with a hypersensitivity reaction to discontinue treatment with TRIZIVIR and seek medical evaluation immediately.
• 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 COMBIVIR, EMTRIVA? , EPIVIR, EPIVIR-HBV, EPZICOM, RETROVIR, TRUVADA, or ZIAGEN.

Lamivudine

Patients co-infected with HIV 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.

Zidovudine

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 disease.

Trizivir

Inform patients that some HIV medicines, including TRIZIVIR can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).

TRIZIVIR is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using TRIZIVIR. Advise patients that the use of TRIZIVIR has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.

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.

TRIZIVIR Tablets are for oral ingestion only.

Patients should be advised of the importance of taking TRIZIVIR exactly as it is prescribed.

Drug Interactions

Trizivir

No clinically significant changes to pharmacokinetic parameters were observed for abacavir, lamivudine, or zidovudine when administered together.

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: Drug Interactions).

The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.

Lamivudine

Trimethoprim (TMP) 160 mg/sulfamethoxazole (SMX) 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of TMP/SMX on lamivudine pharmacokinetics has not been investigated (see CLINICAL PHARMACOLOGY).

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of TRIZIVIR in combination with zalcitabine is not recommended.

Zidovudine

Coadministration of ganciclovir, interferon-alfa, and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine. Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro. In addition, concomitant use of zidovudine with doxorubicin or ribavirin should be avoided because an antagonistic relationship has also been demonstrated in vitro.

See CLINICAL PHARMACOLOGY for additional drug interactions.

Carcinogenesis, Mutagenesis, and 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.

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 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.

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies of TRIZIVIR in pregnant women. Reproduction studies with abacavir, lamivudine, and zidovudine have been performed in animals (see Abacavir, Lamivudine, and Zidovudine sections below). TRIZIVIR should be used during pregnancy only if the potential benefits outweigh the risks.

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 and rabbits 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 up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the 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 Carcinogenesis, Mutagenesis, and Impairment of Fertility).

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.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-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 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving TRIZIVIR.

Pediatric Use

TRIZIVIR is not intended for use in pediatric patients. TRIZIVIR should not be administered to adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for this patient population.

Therapy-experienced Pediatric Patients

A randomized, double-blind study, CNA3006, compared ZIAGEN plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric patients, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Patients in this study had a limited response to abacavir.

Geriatric Use

Clinical studies of abacavir, lamivudine, and zidovudine did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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. TRIZIVIR is not recommended for patients with impaired renal function (i.e., creatinine clearance <50 mL/min; see PRECAUTIONS: Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).

Trizivir 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. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Zidovudine

Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 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, GZDV, is enhanced.

Trizivir Description Of Clinical Studies

Trizivir

The following study was conducted with the individual components of TRIZIVIR (see CLINICAL PHARMACOLOGY for information about bioequivalence of TRIZIVIR).

CNA3005 was a multicenter, double-blind, controlled study in which 562 HIV-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 study 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. Study 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/mm3 , and median plasma HIV-1 RNA was 4.8 log10  copies/mL. Proportions of patients with plasma HIV-1 RNA <400 copies/mL (using Roche AMPLICOR HIV-1 MONITOR® Test) through 48 weeks of treatment are summarized in Table 3.

* 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 4.

In subjects with baseline viral load >100,000 copies/mL, percentages of patients 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/mm3 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.

Trizivir Information For Patients

Abacavir

Hypersensitivity Reaction

Inform patients:

• that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIZIVIR, and 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 MEDICATION GUIDE).
• that if they develop symptoms consistent with a hypersensitivity reaction to discontinue treatment with TRIZIVIR and seek medical evaluation immediately.
• 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 COMBIVIR, EMTRIVA? , EPIVIR, EPIVIR-HBV, EPZICOM, RETROVIR, TRUVADA, or ZIAGEN.

Lamivudine

Patients co-infected with HIV 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.

Zidovudine

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 disease.

Trizivir

Inform patients that some HIV medicines, including TRIZIVIR can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).

TRIZIVIR is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using TRIZIVIR. Advise patients that the use of TRIZIVIR has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.

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.

TRIZIVIR Tablets are for oral ingestion only.

Patients should be advised of the importance of taking TRIZIVIR exactly as it is prescribed.