abacavir 600 MG / Lamivudine 300 MG Oral Tablet

Details

Generic Name: ABACAVIR SULFATE AND LAMIVUDINE

Brand Name: EPZICOM

Substance Name(s):
LAMIVUDINE
ABACAVIR SULFATE

WARNINGS

Hypersensitivity Reaction: Serious and sometimes fatal hypersensitivity reactions have been associated with EPZICOM 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 EPZICOM 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 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.

Figure 1: Hypersensitivity-Related Symptoms Reported with ≥10% Frequency in Clinical Trials (n = 206 Patients) 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 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 patients receiving ZIAGEN 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: Discontinue EPZICOM as soon as a hypersensitivity reaction is suspected.

To minimize the risk of a life-threatening hypersensitivity reaction, permanently discontinue EPZICOM 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 EPZICOM 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 EPZICOM has been discontinued for reasons other than symptoms of a hypersensitivity reaction, and if reinitiation of EPZICOM or any other abacavir-containing product is under consideration, carefully evaluate the reason for discontinuation of EPZICOM 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 EPZICOM.

If hypersensitivity cannot be ruled out, DO NOT reintroduce EPZICOM 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 EPZICOM or any other abacavir-containing product and that reintroduction of EPZICOM or introduction of any other abacavir-containing product needs to be undertaken only if medical care can be readily accessed by the patient or others.

Risk Factor: HLA-B*5701 Allele: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.

CNA106030 (PREDICT-1), a randomized, double-blind 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.

Abacavir Hypersensitivity Reaction Registry: An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions and collection of information on each case.

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 and lamivudine 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 EPZICOM 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 EPZICOM 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).

Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-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-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV.

The causal relationship to discontinuation of lamivudine treatment is unknown.

Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

There is insufficient evidence to determine whether 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, a component of EPZICOM.

Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions), 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.

Patients receiving interferon alfa with or without ribavirin and EPZICOM should be closely monitored for treatment-associated toxicities, especially hepatic decompensation.

Discontinuation of EPZICOM 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: EPZICOM contains fixed doses of 2 nucleoside analogues, abacavir and lamivudine, and should not be administered concomitantly with other abacavir-containing and/or lamivudine-containing products (ZIAGEN, EPIVIR, COMBIVIR®, or TRIZIVIR).

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

Figure 1: Hypersensitivity-Related Symptoms Reported with ≥10% Frequency in Clinical Trials (n = 206 Patients)

DRUG INTERACTIONS

Drug Interactions: EPZICOM: No clinically significant changes to pharmacokinetic parameters were observed for abacavir or lamivudine 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-1-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).

No change in dose of either drug is recommended.

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 EPZICOM in combination with zalcitabine is not recommended.

See CLINICAL PHARMACOLOGY for additional drug interactions.

OVERDOSAGE

Abacavir: There is no known antidote for abacavir.

It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Lamivudine: One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal.

It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.

DESCRIPTION

EPZICOM: EPZICOM Tablets contain the following 2 synthetic nucleoside analogues: abacavir sulfate (ZIAGEN®, also a component of TRIZIVIR®) and lamivudine (also known as EPIVIR® or 3TC) with inhibitory activity against HIV-1.

EPZICOM Tablets are for oral administration.

Each orange, film-coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

The tablets are coated with a film (OPADRY® orange YS-1-13065-A) that is made of FD&C Yellow No.

6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.

Abacavir Sulfate: The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1).

Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring.

It has a molecular formula of (C14H18N6O)2•H2SO4 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.

All dosages for 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 C8H11N3O3S 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.

abacavir sulfate structural formula lamivudine structural formula

CLINICAL STUDIES

Description of Clinical Studies: EPZICOM: There have been no clinical trials conducted with EPZICOM (see CLINICAL PHARMACOLOGY for information about bioequivalence of EPZICOM).

One EPZICOM Tablet given once daily is an alternative regimen to EPIVIR Tablets 300 mg once daily plus ZIAGEN Tablets 2 x 300 mg once daily as a component of antiretroviral therapy.

The following study was conducted with the individual components of EPZICOM.

Therapy-Naive Adults: CNA30021 was an international, multi-center, double-blind, controlled study in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 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 3.

Table 3.

Outcomes of Randomized Treatment Through Week 48 (CNA30021) * 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.

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% After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm3 in the group receiving ZIAGEN 600 mg once daily and 200 cells/mm3 in the group receiving ZIAGEN 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.

HOW SUPPLIED

EPZICOM is available as tablets.

Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine.

The tablets are orange, film-coated, modified capsule-shaped, and debossed with GS FC2 on one side with no markings on the reverse side.

They are packaged as follows: NDC 54868-5600-0 Bottles of 30 Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).

GERIATRIC USE

Geriatric Use: Clinical studies of abacavir and lamivudine 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.

EPZICOM is not recommended for patients with impaired renal function or impaired hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

MECHANISM OF ACTION

Mechanism of Action: 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 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.

CBV-TP and 3TC-TP are weak inhibitors of cellular DNA polymerases α, β, and γ.

INDICATIONS AND USAGE

EPZICOM Tablets, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection.

Additional important information on the use of EPZICOM for treatment of HIV-1 infection: EPZICOM is one of multiple products containing abacavir.

Before starting EPZICOM, 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 compared with patients taking ZIAGEN 300 mg twice daily.

As part of a triple-drug regimen, EPZICOM Tablets are recommended for use with antiretroviral agents from different pharmacological classes and not with other nucleoside/nucleotide reverse transcriptase inhibitors.

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

Description of Clinical Studies: EPZICOM: There have been no clinical trials conducted with EPZICOM (see CLINICAL PHARMACOLOGY for information about bioequivalence of EPZICOM).

One EPZICOM Tablet given once daily is an alternative regimen to EPIVIR Tablets 300 mg once daily plus ZIAGEN Tablets 2 x 300 mg once daily as a component of antiretroviral therapy.

The following study was conducted with the individual components of EPZICOM.

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 3.

Table 3.

† 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.

Outcome ZIAGEN 600 mg q.d.

plus EPIVIR plus Efavirenz(n = 384) ZIAGEN 300 mg b.i.d.

None of the deaths were attributed to study medications.

PEDIATRIC USE

Pediatric Use: Safety and effectiveness of EPZICOM in pediatric patients have not been established.

PREGNANCY

Pregnancy: Pregnancy Category C.

There are no adequate and well-controlled studies of EPZICOM in pregnant women.

Reproduction studies with abacavir and lamivudine have been performed in animals (see Abacavir and Lamivudine sections below).

EPZICOM should be used during pregnancy only if the potential benefits outweigh the risks.

Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta.

Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC.

Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats.

In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC.

Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta.

Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose.

No evidence of teratogenicity due to lamivudine was observed.

Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to EPZICOM or other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established.

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

NUSRING MOTHERS

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Abacavir: Abacavir is secreted into the milk of lactating rats.

Lamivudine: Lamivudine is excreted in human breast milk and 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 EPZICOM.

BOXED WARNING

WARNINGS EPZICOM contains 2 nucleoside analogues (abacavir sulfate and lamivudine) and is intended only for patients whose regimen would otherwise include these 2 components.

Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate, a component of EPZICOM.

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 EPZICOM as soon as a hypersensitivity reaction is suspected.

Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir.

Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction.

Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir.

HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients.

Regardless of HLA-B*5701 status, permanently discontinue EPZICOM if hypersensitivity cannot be ruled out, even when other diagnoses are possible.

Reintroduction of EPZICOM 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).

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, 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-1) and have discontinued lamivudine, which is one component of EPZICOM.

Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPZICOM and are co-infected with HIV-1 and HBV.

If appropriate, initiation of anti-hepatitis B therapy may be warranted (see WARNINGS).

INFORMATION FOR PATIENTS

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 EPZICOM, and encourage the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about EPZICOM.

(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 they should call their doctor right away to determine if they should stop taking EPZICOM.

that a hypersensitivity reaction can worsen and lead to hospitalization or death if EPZICOM is not immediately discontinued.

to not restart EPZICOM 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 EPZICOM is stopped right away.

that if they have interrupted EPZICOM 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.

that in one study, more severe hypersensitivity reactions were seen when ZIAGEN was dosed 600 mg once daily.

to not restart EPZICOM 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.

Lamivudine: 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.

EPZICOM: Inform patients that some HIV-1 medicines, including EPZICOM, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).

EPZICOM 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 EPZICOM.

Advise patients that the use of EPZICOM has not been shown to reduce the risk of transmission of HIV-1 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.

EPZICOM Tablets are for oral ingestion only.

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

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 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.

The recommended oral dose of EPZICOM for adults is one tablet daily, in combination with other antiretroviral agents (see INDICATIONS AND USAGE: Description of Clinical Studies, PRECAUTIONS, MICROBIOLOGY, and CLINICAL PHARMACOLOGY).

EPZICOM can be taken with or without food.

Dose Adjustment: Because it is a fixed-dose tablet, EPZICOM should not be prescribed for patients requiring dosage adjustment such as those with creatinine clearance <50 mL/min, those with hepatic impairment, or those experiencing dose-limiting adverse events.

Use of EPIVIR Oral Solution and ZIAGEN Oral Solution may be considered.