Ziagen (Abacavir Sulfate) - Indications and Dosage

INDICATIONS AND USAGE

ZIAGEN Tablets and Oral Solution, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection.

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

• ZIAGEN is one of multiple products containing abacavir. Before starting ZIAGEN, 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.
• In one controlled study (CNA30021), more patients taking ZIAGEN 600 mg once daily had severe hypersensitivity reactions than patients taking ZIAGEN 300 mg twice daily.

See WARNINGS, ADVERSE REACTIONS, and Description of Clinical Studies.

Description of Clinical Studies

Therapy-Naive Adults

CNA30024 was a multicenter, double-blind, controlled study in which 649 HIV-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily) or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Study participants were: male (81%), Caucasian (51%), black (21%), and Hispanic (26%). The median age was 35 years, the median pretreatment CD4+ cell count was 264 cells/mm³, and median plasma HIV-1 RNA was 4.79 log₁₀ copies/mL. The outcomes of randomized treatment are provided in Table 1.

Table 1. Outcomes of Randomized Treatment Through Week 48 (CNA30024)

Outcome	ZIAGEN plus Lamivudine plus Efavirenz (n = 324)	Zidovudine plus Lamivudine plus Efavirenz (n = 325)
Responder*	69% (73%)	69% (71%)
Virologic failures†	6%	4%
Discontinued due to adverse reactions	14%	16%
Discontinued due to other reasons‡	10%	11%

* Patients achieved and maintained confirmed HIV-1 RNA ≤50 copies/mL (<400 copies/mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR^® standard test 1.0 PCR).

^†Includes viral rebound, insufficient viral response according to the investigator, and failure to achieve confirmed ≤50 copies/mL by Week 48.

^‡Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.

After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells/mm³ in the group receiving ZIAGEN and 155 cells/mm³ in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving ZIAGEN (5 CDC classification C events and 3 deaths) and 5 subjects (2%) on the zidovudine arm (3 CDC classification C events and 2 deaths) experienced clinical disease progression.

CNA3005 was a multicenter, double-blind, controlled 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 baseline CD4+ cell count was 360 cells/mm³, and median baseline 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 2.

Table 2. Outcomes of Randomized Treatment Through Week 48 (CNA3005)

Outcome	ZIAGEN plus Lamivudine/Zidovudine (n = 262)	Indinavir plus Lamivudine/Zidovudine (n = 265)
Responder*	49%	50%
Virologic failure†	31%	28%
Discontinued due to adverse reactions	10%	12%
Discontinued due to other reasons‡	11%	10%

* 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 3.

Table 3. Proportions of Responders Through Week 48 By Screening Plasma HIV-1 RNA Levels (CNA3005)

Screening HIV-1 RNA	ZIAGEN plus Lamivudine/Zidovudine (n = 262)		Indinavir plus Lamivudine/Zidovudine (n = 265)
(copies/mL)	<400 copies/mL	n	<400 copies/mL	n
≥10,000 - ≤100,000	50%	166	48%	165
>100,000	48%	96	52%	100

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.

CNA30021 was an international, multicenter, double-blind, controlled study in which 770 HIV-infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Study participants had a mean age of 37 years, were: male (81%), Caucasian (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells/mm³ (range 21 to 918 cells/mm³) and the median baseline plasma HIV-1 RNA was 4.89 log₁₀ copies/mL (range: 2.60 to 6.99 log₁₀ copies/mL).

The outcomes of randomized treatment are provided in Table 4.

Table 4. Outcomes of Randomized Treatment Through Week 48 (CNA30021)

Outcome	ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384)	ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386)
Responder*	64% (71%)	65% (72%)
Virologic failure†	11% (5%)	11% (5%)
Discontinued due to adverse reactions	13%	11%
Discontinued due to other reasons‡	11%	13%

^* Patients achieved and maintained confirmed HIV-1 RNA <50 copies/mL (<400 copies/mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).

^†Includes viral rebound, failure to achieve confirmed <50 copies/mL (<400 copies/mL) by Week 48, and insufficient viral load response.

^‡Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other.

After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm³ in the group receiving abacavir 600 mg once daily and 200 cells/mm³ in the group receiving abacavir 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to study medications.

DOSAGE AND ADMINISTRATION

A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. To facilitatereporting 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.

ZIAGEN may be taken with or without food.

Adults

The recommended oral dose of ZIAGEN for adults is 600 mg daily, administered as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.

Adolescents and Pediatric Patients

The recommended oral dose of ZIAGEN for adolescents and pediatric patients 3 months to up to 16 years of age is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents.

Dose Adjustment in Hepatic Impairment

The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child-Pugh score 5 to 6) is 200 mg twice daily. To enable dose reduction, ZIAGEN Oral Solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment, therefore ZIAGEN is contraindicated in these patients.

HOW SUPPLIED

ZIAGEN is available as tablets and oral solution.

ZIAGEN Tablets

Each tablet contains abacavir sulfate equivalent to 300 mg abacavir. The tablets are yellow, biconvex, capsule-shaped, film-coated, and imprinted with “GX 623” on one side with no marking on the reverse side. They are packaged as follows:

Bottles of 60 tablets (NDC 0173-0661-01).

Unit dose blister packs of 60 tablets (NDC 0173-0661-00). Each pack contains 6 blister cards of 10 tablets each.

Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP).

ZIAGEN Oral Solution

It is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows:

Bottles of 240 mL (NDC 0173-0664-00) with child-resistant closure. This product does not require reconstitution.

Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP). DO NOT FREEZE. May be refrigerated.