TRIZIVIR

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_max), 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.

Effect of Food on Absorption of TRIZIVIR: Administration with food in a single-dose bioavailability trial resulted in lower C_max, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine C_max 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.

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.

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_IIIB in lymphoblastic cell lines, a monocyte/macrophage tropic laboratory strain HIV-1_BaL in primary monocytes/macrophages, and clinical isolates in peripheral blood mononuclear cells. The concentration of drug necessary to effect viral replication by 50 percent (EC₅₀) ranged from 3.7 to 5.8 μM (1 μM = 0.28 mcg/mL) and 0.07 to 1.0 μM against HIV-1_IIIB and HIV-1_BaL, respectively, and was 0.26 ± 0.18 μM against 8 clinical isolates. The EC₅₀ 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. EC₅₀ 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 EC₅₀ 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 EC₅₀ 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 EC₅₀ and EC₉₀ 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 EC₅₀ 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 EC₅₀ 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 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/mm³, and median plasma HIV-1 RNA was 4.8 log₁₀ 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.

Treatment response by plasma HIV-1 RNA strata is shown in Table 6.

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/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.

15 REFERENCES

• 1.Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. Lancet. 2008;371 (9622):1417-1426.

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 packaged as follows:

Bottles of 60 Tablets (NDC 49702-217-18).

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:

• •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].
• •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.

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.

• • 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.
• • 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.

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

by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2013, ViiV Healthcare. All rights reserved.

TRZ: 7PI

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.

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

by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from

Shire Pharmaceuticals Group plc

Basingstoke, UK

©2013, ViiV Healthcare. All rights reserved.

May 2013

TRZ:7MG

Principal Display Panel

NDC 49702-217-18

TRIZIVIR^®

(abacavir sulfate, lamivudine, and zidovudine)

300 mg 150 mg 300 mg

TABLETS

R_x only

60 Tablets

Notice to Authorized Dispenser:

Each time TRIZIVIR is dispensed, give the patient a Medication Guide and Warning Card from the carton.

Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir, 150 mg of lamivudine, and 300 mg of zidovudine.

Store at 25^oC (77^oF); excursions permitted to 15^o to 30^oC (59^o to 86^oF) (see USP Controlled Room Temperature).

See prescribing information for dosage information.

Lamivudine is manufactured under agreement from  

Shire Pharmaceuticals Group plc

Basingstoke, UK

Manufactured for:

ViiV Healthcare

Research Triangle Park, NC 27709

by:

GlaxoSmithKline

Research Triangle Park, NC 27709

10000000082904 Rev. 9/10