Professional Information — Epzicom

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.

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.

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.

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.

Contraindications

EPZICOM Tablets are contraindicated in patients with previously demonstrated hypersensitivity to abacavir or to any other component of the product (see WARNINGS). NEVER restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status (see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS).

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

Adverse Reactions

Abacavir:

Hypersensitivity Reaction:

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

In one study, once-daily dosing of ZIAGEN was associated with more severe hypersensitivity reactions (see WARNINGS and PRECAUTIONS: Information for Patients).

Therapy-Naive Adults:

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a ≥5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily are listed in Table 4.

Laboratory Abnormalities:

Laboratory abnormalities observed in clinical studies of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical studies of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.

The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in Study CNA30021.

Other Adverse Events:

In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.

Observed During Clinical Practice:

The following reactions have been identified during post-approval use of abacavir and lamivudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to abacavir and/or lamivudine.

Abacavir:

Cardiovascular: Myocardial infarction.

Skin: Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.

There have also been reports of erythema multiforme with abacavir use.

Abacavir and Lamivudine:

Body as a Whole: Redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution).

Digestive: Stomatitis.

Endocrine and Metabolic: Hyperglycemia.

General: Weakness.

Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbation of hepatitis B (see WARNINGS).

Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria.

Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis.

Nervous: Paresthesia, peripheral neuropathy, seizures.

Respiratory: Abnormal breath sounds/wheezing.

Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome.

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.

Clinical Pharmacology

Pharmacokinetics in Adults:

EPZICOM:

In a single-dose, 3-way crossover bioavailability study of 1 EPZICOM Tablet versus 2 ZIAGEN Tablets (2 x 300 mg) and 2 EPIVIR Tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), 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 each component.

Abacavir:

Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 patients, C_max was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC_∞ was 11.95 ± 2.51 mcg•hr/mL. Binding of abacavir to human plasma proteins is approximately 50% and 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. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy volunteers, steady-state C_max (C_max,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24-hour steady-state AUC (AUC_24,ss) was 8.87 ± 1.83 mcg•hr/mL. 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).

The steady-state pharmacokinetic properties of the EPIVIR 300-mg Tablet once daily for 7 days compared with the EPIVIR 150-mg Tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC_24,ss; however, C_max,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC_24,ss and C_max24,ss; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.

In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes.

The pharmacokinetic properties of abacavir and lamivudine in fasting patients are summarized in Table 1.

Effect of Food on Absorption of EPZICOM:

EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability study resulted in no change in AUC_last, AUC_∞, and C_max for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC∞), but the rate of absorption (C_max) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous studies of the effect of food on abacavir and lamivudine tablets administered separately.

Special Populations:

Impaired Renal Function:

EPZICOM: Because lamivudine requires dose adjustment in the presence of renal insufficiency, EPZICOM is not recommended for use in patients with creatinine clearance <50 mL/min (see PRECAUTIONS).

Impaired Hepatic Function:

EPZICOM: Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment. Because EPZICOM is a fixed-dose combination and cannot be dose adjusted, EPZICOM is contraindicated for patients with hepatic impairment.

Pregnancy:

See PRECAUTIONS: Pregnancy.

Abacavir and Lamivudine: No data are available on the pharmacokinetics of abacavir or lamivudine during pregnancy.

Nursing Mothers:

See PRECAUTIONS: Nursing Mothers.

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.

Pediatric Patients:

EPZICOM: The pharmacokinetics of EPZICOM in pediatric patients are under investigation. There are insufficient data at this time to recommend a dose (see PRECAUTIONS: Pediatric Use).

Geriatric Patients:

The pharmacokinetics of abacavir and lamivudine have not been studied in patients over 65 years of age.

Gender:

Abacavir: A population pharmacokinetic analysis in HIV-1-infected male (n = 304) and female (n = 67) patients showed no gender differences in abacavir AUC normalized for lean body weight.

Lamivudine: A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in 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.

Drug Interactions:

See PRECAUTIONS: Drug Interactions. The drug interactions described are based on studies conducted with the individual nucleoside analogues. In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.

Abacavir:

Fifteen HIV-1-infected patients were enrolled in a crossover-designed drug interaction study 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.

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:

No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr). Lamivudine pharmacokinetics are not significantly affected by abacavir.

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 patients (see WARNINGS).

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.

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 / Storage and Handling

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:

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).

Patient Counseling Information

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.