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Epzicom

Generic Name: abacavir sulfate and lamivudine
Dosage Form: tablet, film coated

WARNING: RISK OF HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, AND EXACERBATIONS OF HEPATITIS B

Hypersensitivity Reactions

Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate, a component of Epzicom® (abacavir sulfate and lamivudine) tablets.

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.

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.

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 (5.1)].

Lactic Acidosis and Severe Hepatomegaly

actic 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 and Precautions (5.2)].

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 and Precautions (5.3)].

Indications and Usage for Epzicom

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 [see Warnings and Precautions (5.1), Adverse Reactions (6)].
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.

Epzicom 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.
Epzicom can be taken with or without food.

Adult Patients

The recommended oral dose of Epzicom for adults is one tablet daily, in combination with other antiretroviral agents.

Pediatric Patients

The recommended oral dose of Epzicom for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents [see Clinical Studies (14.2)]. Before prescribing Epzicom tablets, pediatric patients should be assessed for the ability to swallow tablets.

Dosage Adjustment

Because it is a fixed-dose combination, Epzicom should not be prescribed for:

patients requiring dosage adjustment such as those with creatinine clearance less than 50 mL per min,
patients with hepatic impairment.

Use of EPIVIR® (lamivudine) oral solution or tablets and ZIAGEN® (abacavir sulfate) oral solution may be considered.

Dosage Forms and Strengths

Epzicom tablets contain 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are modified capsule-shaped, orange, film-coated, and debossed with “GS FC2” on one side with no markings on the reverse side.

Contraindications

Epzicom tablets are contraindicated in patients with:

previously demonstrated hypersensitivity to abacavir or to any other component of the product. NEVER restart Epzicom or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status [see Warnings and Precautions (5.1), Adverse Reactions (6)].
hepatic impairment [see Use in Specific Populations (8.7)].

Warnings and Precautions

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 subjects (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 subjects reported symptoms from 2 or more of the 5 groups listed above.

Figure 1. Hypersensitivity-related Symptoms Reported with Greater than or Equal to 10% Frequency in Clinical Trials (n = 206 Subjects)

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 trial, 4 subjects (11%) receiving ZIAGEN 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 subjects receiving ZIAGEN 300 mg twice daily.

Physical findings associated with hypersensitivity to abacavir in some subjects 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 subjects 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: Trials 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 trial, 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 trial, 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 of 847) to 3.4% (27 of 803). Based on this trial, 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.

Lactic Acidosis and 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).

Patients with HIV-1 and Hepatitis B Virus Co-infection

Posttreatment Exacerbations of Hepatitis

In clinical trials in non-HIV-1-infected subjects 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.

Emergence of Lamivudine-resistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. In non–HIV-1-infected subjects treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see full prescribing information for EPIVIR-HBV® [lamivudine] tablets and oral solution for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

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 subjects [see Clinical Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected subjects 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., Child-Pugh greater than 6) (see the complete prescribing information for interferon and ribavirin).

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Epzicom. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Myocardial Infarction

In a published prospective, observational, epidemiological trial 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).1 In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI 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, smoking).

Use with Other Abacavir-, Lamivudine-, and/or Emtricitabine-containing Products

Epzicom contains fixed doses of 2 nucleoside analogues, abacavir and lamivudine. Do not administer concomitantly with other abacavir-containing and/or lamivudine-containing products. In addition, do not administer Epzicom in combination with products containing emtricitabine.

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Serious and sometimes fatal hypersensitivity reaction. In one trial, once-daily dosing of abacavir was associated with more severe hypersensitivity reactions [see Boxed Warning, Warnings and Precautions (5.1)].
Lactic acidosis and severe hepatomegaly [see Boxed Warning, Warnings and Precautions (5.2)].
Acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.3)].
Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.4)].
Immune reconstitution syndrome [see Warnings and Precautions (5.5)].
Fat redistribution [see Warnings and Precautions (5.6)].
Myocardial infarction [see Warnings and Precautions (5.7)].

Clinical Trials Experience in Adult Subjects

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 clinical practice.

Therapy-naive Adults

Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 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 1.

Table 1. Treatment-emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-naive Adults (CNA30021) through 48 Weeks of Treatment

Adverse Event

ZIAGEN 600 mg q.d.

plus EPIVIR plus Efavirenz

(n = 384)

ZIAGEN 300 mg b.i.d.

plus EPIVIR plus Efavirenz

(n = 386)

Drug hypersensitivitya,b

9%

7%

Insomnia

7%

9%

Depression/Depressed mood

7%

7%

Headache/Migraine

7%

6%

Fatigue/Malaise

6%

8%

Dizziness/Vertigo

6%

6%

Nausea

5%

6%

Diarrheaa

5%

6%

Rash

5%

5%

Pyrexia

5%

3%

Abdominal pain/gastritis

4%

5%

Abnormal dreams

4%

5%

Anxiety

3%

5%

aSubjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event.

bCNA30024 was a multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.

Laboratory Abnormalities

Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials 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 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.

Clinical Trials Experience in Pediatric Subjects

The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as Epzicom, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults [see Adverse Reactions (6.1)].

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of abacavir, lamivudine, and/or Epzicom. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to abacavir, lamivudine, and/or Epzicom.

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 Warnings and Precautions (5.6)].

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: Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.2)], posttreatment exacerbation of hepatitis B [see Warnings and Precautions (5.3)].

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

No drug interaction trials have been conducted using Epzicom tablets [see Clinical Pharmacology (12.3)].

Ethanol

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 (12.3)].

Interferon- and Ribavirin-based Regimens

Lamivudine

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 subjects, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected subjects receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].

Methadone

Abacavir

The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3)]. 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.

Trimethoprim/Sulfamethoxazole (TMP/SMX)

Lamivudine

No change in dose of either drug is recommended [see Clinical Pharmacology (12.3)]. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Epzicom during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Risk Summary

Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for abacavir or lamivudine compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Abacavir produced fetal malformations and other embryonic and fetal toxicities in rats at 35 times the human exposure at the recommended clinical dose. Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures to the recommended clinical dose.The relevance of animal findings to human pregnancy registry data is not known.

Data

Human Data:Abacavir: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 900 exposed in the first trimester), there was no difference between abacavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of defects in the first trimester was 3.0% (95% CI: 2.0% to 4.4%).

Lamivudine: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%).

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily).

Animal Data: 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.

Lactation

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Because of the potential for HIV‑1 transmission mothers should be instructed not to breastfeed.

Pediatric Use

The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or Epzicom [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Studies (14.2)].

In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing.

Geriatric Use

Clinical trials of abacavir and lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 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 [see Dosage and Administration (2.3), Use in Specific Populations (8.6, 8.7)].

Patients with Impaired Renal Function

Epzicom is not recommended for patients with impaired renal function (creatinine clearance less than 50 mL per min) because Epzicom is a fixed-dose combination and the dosage of the individual components cannot be adjusted.

Patients with Impaired Hepatic Function

Epzicom is contraindicated for patients with hepatic impairment because Epzicom is a fixed-dose combination and the dosage of the individual components cannot be adjusted.

Overdosage

If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

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. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

Epzicom 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 per 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 per mL in water at 20°C.

Epzicom - Clinical Pharmacology

Mechanism of Action

Epzicom is an antiretroviral agent [see Microbiology (12.4)].

Pharmacokinetics

Pharmacokinetics in Adults

Epzicom: In a single-dose, 3-way crossover bioavailability trial 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 (Cmax), 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 subjects, Cmax was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC was 11.95 ± 2.51 mcg•hour per 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 subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour per 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 trial in 60 healthy subjects. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,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 AUC24,ss and Cmax24,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.

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

The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.

Table 2. Pharmacokinetic Parametersa for Abacavir and Lamivudine in Adults

Parameter

Abacavir

Lamivudine

Oral bioavailability (%)

86 ± 25

n = 6

86 ± 16

n = 12

Apparent volume of distribution (L/kg)

0.86 ± 0.15

n = 6

1.3 ± 0.4

n = 20

Systemic clearance (L/h/kg)

0.80 ± 0.24

n = 6

0.33 ± 0.06

n = 20

Renal clearance (L/h/kg)

0.007 ± 0.008

n = 6

0.22 ± 0.06

n = 20

Elimination half-life (h)

1.45 ± 0.32

n = 20

5 to 7b

aData presented as mean ± standard deviation except where noted.

bApproximate range.

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 trial resulted in no change in AUClast, AUC, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC), but the rate of absorption (Cmax) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately.

Special Populations

Renal Impairment: Epzicom: Because lamivudine requires dose adjustment in the presence of renal insufficiency, Epzicom is not recommended for use in patients with creatinine clearance less than 50 mL per min [see Dosage and Administration (2.3)].

Hepatic Impairment: Epzicom: Epzicom is contraindicated for patients with hepatic impairment because Epzicom 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).

Pediatric Patients: Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine following administration of Epzicom in pediatric subjects weighing 25 kg and above are limited. The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or Epzicom. Refer to the EPIVIR and ZIAGEN USPI for pharmacokinetic information on the individual products in pediatric patients [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Studies (14.2)].

Geriatric Patients: The pharmacokinetics of abacavir and lamivudine 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: A pharmacokinetic trial 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 whites in abacavir pharmacokinetics.

Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions

The drug interactions described are based on trials 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: Lamivudine and Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction 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.

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 (7.3)].

Lamivudine: 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 every 12 h).

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 (5.4)].

The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.

Table 3. Effect of Coadministered Drugs on Abacavir and Lamivudine AUC

Note: ROUTINE DOSE MODIFICATION OF ABACAVIR AND LAMIVUDINE IS NOT WARRANTED WITH COADMINISTRATION OF THE FOLLOWING DRUGS.

Drugs that May Alter Abacavir Blood Concentrations

Coadministered

Drug and Dose

Abacavir Dose

n

Abacavir

Concentrations

Concentration of Coadministered Drug

AUC

Variability

     

Ethanol

0.7 g/kg

Single 600 mg

24

↑41%

90% CI:

35% to 48%

Drugs that May Alter Lamivudine Blood Concentrations

Coadministered

Drug and Dose

Lamivudine Dose

n

Lamivudine

Concentrations

Concentration of Coadministered Drug

AUC

Variability

     

Nelfinavir

750 mg every 8 h x 7 to 10 days

Single 150 mg

11

↑10%

95% CI:

1% to 20%

Trimethoprim 160 mg/

Sulfamethoxazole

800 mg daily x 5 days

Single 300 mg

14

↑43%

90% CI:

32% to 55%

↑ = Increase; ↔ = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval.

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.

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.

Antiviral Activity

Abacavir: The antiviral activity of abacavir against HIV‑1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV‑1IIIB and HIV‑1BaL, respectively, and was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV‑1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.024 to 0.49 microM.

Lamivudine: The antiviral activity of lamivudine against HIV‑1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.0003 to 0.120 microM in PBMCs.

The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non‑subtype B isolates and HIV‑2 isolates with equivalent antiviral activity as for subtype B isolates. Neither abacavir nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Ribavirin, used in the treatment of chronic HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2- to 6-fold in cell culture.

Resistance

HIV‑1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture and amino acid substitutions K65R, L74V, Y115F, and M184V/I emerged in HIV‑1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-fold to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.

Cross-resistance

Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the substitution K65R with or without the M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.

Nonclinical Toxicology

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.

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.

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 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 mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic 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.

Impairment of Fertility

Abacavir or lamivudine induced no adverse effects on the mating performance or fertility of male and female rats at doses producing systemic exposure levels approximately 8 or 130 times, respectively, higher than those in humans at the recommended dose based on body surface area comparisons.

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.

Clinical Studies

Adults

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 trial was conducted with the individual components of Epzicom.

Therapy-naive Adults

CNA30021 was an international, multi-center, double-blind, controlled trial 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. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm3 (range: 21 to 918 cells per mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.60 to 6.99 log10 copies per 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)

Respondera

64% (71%)

65% (72%)

Virologic failureb

11% (5%)

11% (5%)

Discontinued due to adverse reactions

13%

11%

Discontinued due to other reasonsc

11%

13%

aSubjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR® standard test version 1.0).

bIncludes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response.

cIncludes 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 per mm3 in the group receiving ZIAGEN 600 mg once daily and 200 cells per 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 trial medications.

Pediatric Subjects

ARROW (COL105677) was a 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. At baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared to 71% of subjects in the once-daily cohort.

Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Subjects randomized to receive once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as Epzicom.

The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 5. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.

Table 5. Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3)

Outcome

Abacavir plus Lamivudine
Twice-daily Dosing
(n = 333)

Abacavir plus Lamivudine
Once-daily Dosing
(n = 336)

HIV-1 RNA <80 copies/mLb

70%

67%

HIV-1 RNA ≥80 copies/mLc

28%

31%

No virologic data

Discontinued due to adverse event or death

1%

<1%

Discontinued study for other reasonsd

0%

<1%

Missing data during window but on study

1%

1%

aAnalyses were based on the last observed viral load data within the Week 96 window.

bRisk difference (95% CI) of response rate is -2.4% (-9% to 5%) at Week 96.

cIncludes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.

dOther includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).

REFERENCES

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

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:

Bottles of 30 tablets (NDC 49702-206-13).

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

Advise the patient to read the 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 Epzicom, and instruct 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 Precautions (5.1), Medication Guide].
that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider 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.
that in one trial, more severe hypersensitivity reactions were seen when ZIAGEN was dosed 600 mg once daily.
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.
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.
Epzicom should not be coadministered with ATRIPLA®, COMBIVIR®, COMPLERA®, DUTREBIS, EMTRIVA®, EPIVIR, EPIVIR-HBV, STRIBILD®, TRIUMEQ®, TRIZIVIR, TRUVADA®, or ZIAGEN.

Lactic Acidosis/Hepatomegaly

Inform patients that some HIV medicines, including Epzicom, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.2)].

HIV-1/ HBV Co-infection

Inform patients co-infected with HIV-1 and HBV that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see Boxed Warning, Warnings and Precautions (5.3)].

HIV-1/HCV Co-infection

Inform patients with HIV-1/HCV co-infection 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 (5.4)].

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 (5.6)].

Information about HIV-1 Infection

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 must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Patients should be told that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician when using Epzicom.

Patients should be informed to take all HIV medications exactly as prescribed. If you miss a dose of Epzicom, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

Do not re-use or 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.
Continue to practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

COMBIVIR, EPIVIR, Epzicom, TRIUMEQ, TRIZIVIR, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies.

EPIVIR-HBV is a registered trademark of the GSK group of companies.

The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies 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

©2015 the ViiV Healthcare group of companies. All rights reserved.

EPZ:11PI

MEDICATION GUIDE

Epzicom® (ep' zih com)

(abacavir sulfate and lamivudine)

tablets

What is the most important information I should know about Epzicom?

Epzicom can cause serious side effects, including:

Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with Epzicom and other abacavir-containing products. 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 Epzicom, call your healthcare provider right away to find out if you should stop taking Epzicom.
 
                                                                                    Symptom

          Group 1                                     Fever

          Group 2                                     Rash

          Group 3                                     Nausea, vomiting, diarrhea, abdominal (stomach area) pain

          Group 4                                     Generally ill feeling, extreme tiredness, or achiness

          Group 5                                     Shortness of breath, cough, sore throat

 
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 Epzicom because of an allergic reaction, never take Epzicom (abacavir sulfate and lamivudine) or any other abacavir‑containing medicine (TRIUMEQ®, TRIZIVIR® or ZIAGEN®) again.
If you take Epzicom 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 pressureor death.
If you stop Epzicom for any other reason, even for a few days, and you are not allergic to Epzicom, talk with your healthcare provider before taking it again. Taking Epzicom 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 Epzicom again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.

Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take Epzicom. Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:

         •  feel very weak or tired                                            •  feel cold, especially in your arms and legs

         •  unusual (not normal) muscle pain                             •  feel dizzy or light-headed

         •  trouble breathing                                                     •  have a fast or irregular heartbeat

         •  stomach pain with nausea and vomiting   

Serious liver problems can happen in people who take Epzicom.In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). 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                  •  loss of appetite for several days or longer

             turns yellow (jaundice)                                           •  nausea

         •  dark or “tea-colored” urine                                    •  pain, aching, or tenderness on the right side

         •  light-colored stools (bowel movements)                     of your stomach area

You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time.

Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking Epzicom. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death
Do not run out of Epzicom. Refill your prescription or talk to your healthcare provider before your Epzicom is all gone.
Do not stop Epzicom without first talking to your healthcare provider.
If you stop taking Epzicom, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver.
Use with interferon and ribavirin‑based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who are taking antiretroviral medicines and are also being treated for hepatitis C with interferon with or without ribavirin. If you are taking Epzicom and interferon with or without ribavirin tell your healthcare provider if you have any new symptoms.

What is Epzicom?

Epzicom is a prescription HIV-1 (Human Immunodeficiency Virus-type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). Epzicom contains 2 prescription medicines, abacavir (ZIAGEN) and lamivudine (EPIVIR®).

Epzicom should not be used in children weighing less than 55 pounds (25 kg).

When used with other antiretroviral medicines to treat HIV-1 infection, Epzicom may help:

reduce the amount of HIV-1 in your blood. This is called “viral load”.
increase the number of CD4+ (T) cells in your blood, that help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

Epzicom does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV‑1 infection to others.

Do not share or re-use 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 safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood.

Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people.

Who should not take Epzicom?

Do not take Epzicom if you:

have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with Epzicom.
are allergic to abacavir or any of the ingredients in Epzicom. See the end of this Medication Guide for a complete list of ingredients in Epzicom.
have liver problems.

What should I tell my healthcare provider before taking Epzicom?

Before you take Epzicom 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 or have had liver problems, including hepatitis B or C virus infection.
have kidney problems.
have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.
drink alcohol or take medicines that contain alcohol.
are pregnant or plan to become pregnant. Taking Epzicom during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
 
Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
are breastfeeding or plan to breastfeed. Do not breastfeed if you take Epzicom.
You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medicines interact with Epzicom. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with Epzicom. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take Epzicom with other medicines.

You should not take Epzicom if you also take:

abacavir (TRIUMEQ, TRIZIVIR or ZIAGEN)
lamivudine (COMBIVIR®, DUTREBIS, EPIVIR, EPIVIR-HBV®, TRIUMEQ, or TRIZIVIR)
emtricitabine (EMTRIVA®, ATRIPLA®, COMPLERA®, STRIBILD®, or TRUVADA®)

Tell your healthcare provider if you take:

any other medicine to treat HIV-1
medicines to treat hepatitis viruses such as interferon or ribavirin
methadone

How should I take Epzicom?

Take Epzicom exactly as your healthcare provider tells you.
Do not change your dose or stop taking Epzicom without talking with your healthcare provider. If you miss a dose of Epzicom, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.
Stay under the care of a healthcare provider while taking Epzicom.
Epzicom may be taken with or without food.
Tell your healthcare provider if your child has trouble swallowing Epzicom tablets.
Do not run out of Epzicom.The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy
If you take too much Epzicom, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of Epzicom?

Epzicom can cause serious side effects including:
See “What is the most important information I should know about Epzicom?”
Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. 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 right away if you start having new symptoms after you start taking Epzicom.
Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
Heart attack (myocardial infarction). Some HIV-1 medicines including Epzicom may increase your risk of heart attack.

The most common side effects of Epzicom include:

 
         •  trouble sleeping                                   •  nausea
 
         •  depression                                          •  diarrhea
 
         •  headache                                            •   rash
 
         •  tiredness                                             •   fever
 
         •  dizziness

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 Epzicom. 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 Epzicom?

Store Epzicom at 59°F to 86°F (15°C to 30°C).
 
Keep Epzicom and all medicines out of the reach of children.

General information for safe and effective use of Epzicom.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Epzicom for a condition for which it was not prescribed. Do not give Epzicom to other people, even if they have the same symptoms that you have. It may harm them.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information about Epzicom that is written for health professionals.

For more information go to www.Epzicom.com or call 1-877-844-8872.

What are the ingredients in Epzicom?

Active ingredients: abacavir sulfate and lamivudine

Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate.

Tablet film coating contains: OPADRY® orange YS-1-13065-A made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.

 
  Manufactured for:                                              by:
 
  ViiV Healthcare                                                 GlaxoSmithKline
 
  Research Triangle Park, NC 27709                   Research Triangle Park, NC 27709

Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc, Basingstoke, UK

COMBIVIR, EPIVIR, Epzicom, TRIUMEQ, TRIZIVIR, and ZIAGEN are registered trademarks of the ViiV Healthcare group of companies.

EPIVIR-HBV is a registered trademark of the GSK group of companies.

The other brands listed are trademarks of their respective owners and are not trademarks of the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.

©2015 the ViiV Healthcare group of companies. All rights reserved.

EPZ:10MG

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Revised: 09/2015

PRINCIPAL DISPLAY PANEL

NDC 49702-206-13

Epzicom®

(abacavir sulfate and lamivudine)

600 mg 300 mg

TABLETS

30 Tablets

Notice to Authorized Dispenser: Each time Epzicom is dispensed, give the patient a Medication Guide and Warning Card from the carton.

Rx only

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

Store at 25oC (77oF); excursions permitted to 15o to 30oC (59o to 86oF) (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

Made in England

10000000082970 Rev. 7/10

Epzicom 
abacavir sulfate and lamivudine tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:49702-206
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
ABACAVIR SULFATE (ABACAVIR) ABACAVIR 600 mg
LAMIVUDINE (LAMIVUDINE) LAMIVUDINE 300 mg
Inactive Ingredients
Ingredient Name Strength
MAGNESIUM STEARATE  
CELLULOSE, MICROCRYSTALLINE  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
FD&C YELLOW NO. 6  
HYPROMELLOSES  
POLYETHYLENE GLYCOL 400  
POLYSORBATE 80  
TITANIUM DIOXIDE  
Product Characteristics
Color ORANGE Score no score
Shape OVAL (capsule-shaped) Size 20mm
Flavor Imprint Code GS;FC2
Contains         
Packaging
# Item Code Package Description
1 NDC:49702-206-13 30 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021652 10/12/2010
Labeler - ViiV Healthcare Company (027295585)
Revised: 09/2015
 
ViiV Healthcare Company
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