Ziagen Information
Ziagen (Abacavir) Indications And Usage
Ziagen (Abacavir) Tablets and Oral Solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.
Additional important information on the use of Ziagen (Abacavir) for treatment of HIV-1 infection:
Ziagen (Abacavir) Dosage And Administration
The recommended oral dose of Ziagen (Abacavir) Oral Solution in HIV-1-infected pediatric patients aged 3 months and older is 8 mg/kg twice daily (up to a maximum of 300 mg twice daily) in combination with other antiretroviral agents.
Ziagen (Abacavir) is also available as a scored tablet for HIV-1-infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing Ziagen (Abacavir) Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow Ziagen (Abacavir) Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of Ziagen (Abacavir) Tablets for HIV-1-infected pediatric patients is presented in Table 1.
Ziagen (Abacavir) Dosage Forms And Strengths
Ziagen (Abacavir) Tablets, containing abacavir sulfate equivalent to 300 mg abacavir, are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides.
Ziagen (Abacavir) Oral Solution, each mL containing abacavir sulfate equivalent to 20 mg of abacavir, is a clear to opalescent, yellowish, strawberry-banana-flavored liquid.
Ziagen (Abacavir) Contraindications
Ziagen (Abacavir) is contraindicated in patients with previously demonstrated hypersensitivity to abacavir or any other component of the products. NEVER restart Ziagen (Abacavir) or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status .
Ziagen (Abacavir) is contraindicated in patients with moderate or severe hepatic impairment.
Ziagen (Abacavir) Warnings And Precautions
Serious and sometimes fatal hypersensitivity reactions have been associated with Ziagen (Abacavir) and other abacavir-containing products. Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances when the potential benefit outweighs the risk.
HLA-B*5701-negative patients may develop a hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue Ziagen (Abacavir) 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:
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 hypersensitivity were collected on a detailed data collection module. The frequencies of symptoms are shown in Figure 1. Symptoms usually appeared within the first 6 weeks of treatment with abacavir, although the reaction may occur at any time during therapy. Median time to onset was 9 days; 89% appeared within the first 6 weeks; 95% of patients reported symptoms from 2 or more of the 5 groups listed above.
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. In one study, 4 patients (11%) receiving Ziagen (Abacavir) 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 patients receiving Ziagen (Abacavir) 300 mg twice daily.
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:
Following a hypersensitivity reaction to abacavir, NEVER restart Ziagen (Abacavir) 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 Ziagen (Abacavir) has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of Ziagen (Abacavir) or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of Ziagen (Abacavir) to ensure that the patient did not have symptoms of a hypersensitivity reaction. If the patient is of unknown HLA-B*5701 status, screening for the allele is recommended prior to reinitiation of Ziagen (Abacavir) .
If hypersensitivity cannot be ruled out, DO NOT reintroduce Ziagen (Abacavir) or any other abacavir-containing product. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
If symptoms consistent with hypersensitivity are not identified, reintroduction can be undertaken with continued monitoring for symptoms of a hypersensitivity reaction. Make patients aware that a hypersensitivity reaction can occur with reintroduction of Ziagen (Abacavir) or any other abacavir-containing product and that reintroduction of Ziagen (Abacavir) or any other abacavir-containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.
CNA106030 (PREDICT-1), a randomized, double-blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.
Screening for carriage of the HLA -B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.
Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity.
In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
Abacavir Hypersensitivity Reaction Registry:
In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI). In a sponsor-conducted pooled analysis of clinical trials, no excess risk of myocardial infarction was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking).
Ziagen (Abacavir) Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with Ziagen (Abacavir) 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3.
Five patients receiving Ziagen (Abacavir) in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.
Ziagen (Abacavir) Once Daily Versus Ziagen (Abacavir) Twice Daily (CNA30021):
Laboratory Abnormalities:
Laboratory abnormalities in CNA3005 are listed in Table 5.
The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.
Laboratory Abnormalities:
Other Adverse Events:
In addition to adverse reactions reported from clinical trials, the following reactions have been identified during postmarketing use of Ziagen (Abacavir) . Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Ziagen (Abacavir) .
Body as a Whole:
Cardiovascular:
Hepatic:
Skin:
There have also been reports of erythema multiforme with abacavir use.
Ziagen (Abacavir) Use In Specific Populations
Pregnancy Category C. 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.
There are no adequate and well-controlled studies in pregnant women. Ziagen (Abacavir) should be used during pregnancy only if the potential benefits outweigh the risk.
Antiretroviral Pregnancy Registry:
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
Although it is not known if abacavir is excreted in human milk, abacavir is secreted into the milk of lactating rats. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Ziagen (Abacavir) .
Ziagen (Abacavir) Overdosage
There is no known antidote for Ziagen (Abacavir) . It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
Ziagen (Abacavir) Description
Ziagen (Abacavir) is the brand name for abacavir sulfate, a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-1. The chemical name of abacavir sulfate is 14-[2-amino-6-(cyclopropylamino)-9-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with , absolute configuration on the cyclopentene ring. It has a molecular formula of (CHNO)•HSO 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. It has an octanol/water (pH 7.1 to 7.3) partition coefficient (log ) of approximately 1.20 at 25°C.
Ziagen (Abacavir) Tablets are for oral administration. Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir as active ingredient and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.
Ziagen (Abacavir) Oral Solution is for oral administration. Each milliliter (1 mL) of Ziagen (Abacavir) Oral Solution contains abacavir sulfate equivalent to 20 mg of abacavir (i.e., 20 mg/mL) as active ingredient and the following inactive ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water.
In vivo, abacavir sulfate dissociates to its free base, abacavir. All dosages for Ziagen (Abacavir) are expressed in terms of abacavir.
Ziagen (Abacavir) Clinical Pharmacology
Pharmacokinetics in Adults:
Absorption and Bioavailability:
Distribution:
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.
Metabolism:
Elimination:
14
In single-dose studies, the observed elimination half-life (t) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L/hr/kg (mean ± SD).
Effects of Food on Oral Absorption:
∞
Hepatic Impairment:
Geriatric Patients:
Gender:
Race:
Drug Interactions:
Lamivudine and/or Zidovudine:
Ethanol:
1/2
Methadone:
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.
Resistance:
Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a greater than 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).
Cross-Resistance:
Ziagen (Abacavir) Nonclinical Toxicology
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.
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 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.
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.
Ziagen (Abacavir) Clinical Studies
Therapy-Naive Adults:
3
10
After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells/mm in the group receiving Ziagen (Abacavir) and 155 cells/mm in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving Ziagen (Abacavir) (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-1-infected, therapy-naive adults were randomized to receive either Ziagen (Abacavir) (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 greater than 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/mm, and median baseline plasma HIV-1 RNA was 4.8 log copies/mL. Proportions of patients with plasma HIV-1 RNA less than 400 copies/mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8.
Treatment response by plasma HIV-1 RNA strata is shown in Table 9.
In subjects with baseline viral load greater than 100,000 copies/mL, percentages of patients with HIV-1 RNA levels less than 50 copies/mL were 31% in the group receiving abacavir vs. 45% in the group receiving indinavir.
Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells/mm was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir sulfate (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.
CNA30021 was an international, multicenter, double-blind, controlled study in which 770 HIV-1-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/mm (range 21 to 918 cells/mm) and the median baseline plasma HIV-1 RNA was 4.89 logcopies/mL (range: 2.60 to 6.99 logcopies/mL).
The outcomes of randomized treatment are provided in Table 10.
After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm in the group receiving abacavir 600 mg once daily and 200 cells/mm in the group receiving abacavir 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving Ziagen (Abacavir) 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving Ziagen (Abacavir) 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.
Therapy-Experienced Pediatric Patients:
2
2
3
3
10
10
10
Ziagen (Abacavir) How Supplied/storage And Handling
Ziagen (Abacavir) Tablets, containing abacavir sulfate equivalent to 300 mg abacavir are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides. 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.
Ziagen (Abacavir) Oral Solution 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.
Ziagen (Abacavir) Patient Counseling Information
See Medication Guide. (17.2)
Hypersensitivity Reaction:
Lactic Acidosis/Hepatomegaly:
Redistribution/Accumulation of Body Fat:
Information About HIV-1 Infection:
Ziagen (Abacavir) Medication Guide
Read the Medication Guide that comes with Ziagen (Abacavir) before you start taking it and each time you get a refill because there may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. Be sure to carry your Ziagen (Abacavir) Warning Card with you at all times.
A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you.
Ziagen (Abacavir) can have other serious side effects. Be sure to read the section below entitled "What are the possible side effects of Ziagen (Abacavir) ?"
Ziagen (Abacavir) is a prescription medicine used to treat HIV infection. Ziagen (Abacavir) is taken by mouth as a tablet or a strawberry-banana-flavored liquid. Ziagen (Abacavir) is a medicine called a nucleoside analogue reverse transcriptase inhibitor (NRTI). Ziagen (Abacavir) is always used with other anti-HIV medicines. When used in combination with these other medicines, Ziagen (Abacavir) helps lower the amount of HIV found in your blood. This helps to keep your immune system as healthy as possible so that it can help fight infection.
Different combinations of medicines are used to treat HIV infection. You and your doctor should discuss which combination of medicines is best for you.
Ziagen (Abacavir) has not been studied in children under 3 months of age or in adults over 65 years of age.
Some HIV medicines including Ziagen (Abacavir) may increase your risk of heart attack. If you have heart problems, smoke, or suffer from diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes, tell your doctor.
The most common side effects of Ziagen (Abacavir) include nausea, vomiting, tiredness, headache, diarrhea, trouble sleeping, fever and chills, and loss of appetite. Most of these side effects did not cause people to stop taking Ziagen (Abacavir) .
This list of side effects is not complete. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use Ziagen (Abacavir) for a condition for which it was not prescribed. Do not give Ziagen (Abacavir) 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 Ziagen (Abacavir) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for the information that is written for healthcare professionals or call 1-888-825-5249.
GlaxoSmithKlineResearch Triangle Park, NC 27709
©2009, GlaxoSmithKline. All rights reserved.
January 2009
ZGN:2MG
Ziagen (Abacavir)
Ziagen (Abacavir)
