EPZICOM
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EPZICOM, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection.
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INDICATIONS AND USAGE
EPZICOM, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection.
DOSAGE AND ADMINISTRATION
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2.1 Screening for HLA-B*5701 Allele prior to Starting EPZICOM
Screen for the HLA‑B*5701 allele prior to initiating therapy with EPZICOM [see BOXED WARNING, Warnings and Precautions (5.1)].
2.2 Recommended Dosage for Adult Patients
The recommended dosage of EPZICOM for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food.
2.3 Recommended Dosage for 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.
2.4 Not Recommended Due to Lack of Dosage Adjustment
Because EPZICOM is a fixed‑dose tablet and cannot be dose adjusted, EPZICOM is not recommended for:
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- patients with creatinine clearance less than 30 mL per minute [see Use in Specific Populations (8.6)].
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- patients with mild hepatic impairment. EPZICOM is contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7)].
Use of EPIVIR (lamivudine) oral solution or tablets and ZIAGEN (abacavir) oral solution may be considered.
DOSAGE FORMS AND STRENGTHS
EPZICOM tablets are composed of abacavir sulfate equivalent to 600 mg of abacavir and 300 mg of lamivudine. These tablets have a unique modified capsule shape, are coated in an orange film, and feature the imprint "GS FC2" on one side, while the other side remains unmarked.
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
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5.1 Hypersensitivity Reactions
Abacavir, a key ingredient in EPZICOM, has been linked to severe and occasionally lethal hypersensitivity reactions. These reactions, involving multiple organ failure and anaphylaxis, usually manifest within the initial six weeks of starting abacavir therapy, typically around nine days, though they can occur at any point during the treatment period [refer to Adverse Reactions (6.1) for details]. The risk of these reactions is heightened in individuals with the HLA‑B5701 allele, but hypersensitivity can also develop in those without this allele. In 9 clinical studies involving 2,670 patients using abacavir-containing products without HLA‑B5701 allele screening, about 206 (8%) experienced hypersensitivity to abacavir. When subjects with the HLA‑B*5701 allele were excluded, the rate of suspected hypersensitivity reactions in these trials was around 1%. Therefore, in patients undergoing abacavir treatment, clinical judgment regarding hypersensitivity reactions must guide medical decisions.
Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:
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- All patients should be screened for the HLA‑B*5701 allele prior to initiating therapy with EPZICOM or reinitiation of therapy with EPZICOM, unless patients have a previously documented HLA‑B*5701 allele assessment.
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- EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA‑B*5701-positive patients.
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- Before starting EPZICOM, review medical history for prior exposure to any abacavir-containing product. NEVER restart EPZICOM or any other abacavir‑containing product following a hypersensitivity reaction to abacavir, regardless of HLA‑B*5701 status.
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- To reduce the risk of a life‑threatening hypersensitivity reaction, regardless of HLA‑B*5701 status, discontinue EPZICOM immediately if a hypersensitivity reaction is suspected, 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).
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- If a hypersensitivity reaction cannot be ruled out, do not restart EPZICOM or any other abacavir‑containing products because more severe symptoms, which may include life‑threatening hypotension and death, can occur within hours.
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- If a hypersensitivity reaction is ruled out, patients may restart EPZICOM. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of EPZICOM or any other abacavir-containing product is recommended only if medical care can be readily accessed.
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- A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.
5.2 Patients with Hepatitis B Virus Co-infection
After stopping lamivudine treatment, there have been instances of hepatitis symptoms and lab findings worsening. For more details, consult the complete prescribing instructions for EPIVIR (lamivudine). It is crucial to closely monitor patients through both clinical assessments and lab tests for several months post-treatment.
Regarding the resistance of Hepatitis B Virus to Lamivudine, the safety and effectiveness of lamivudine for treating chronic hepatitis B in patients infected with both HIV‑1 and hepatitis B virus (HBV) are not confirmed. In HIV‑1-infected individuals who were treated with lamivudine-inclusive antiretroviral therapies while also having hepatitis B virus, there have been reports of the emergence of HBV strains resistant to lamivudine. For more information, refer to the complete prescribing instructions for EPIVIR (lamivudine).
5.3 Lactic Acidosis and Severe Hepatomegaly with Steatosis
The use of nucleoside analogues, such as abacavir and lamivudine, which are components of EPZICOM, has been linked to cases of lactic acidosis and severe hepatomegaly with steatosis, some of which have been fatal. Most of these cases have occurred in women. Being female and overweight are potential risk factors for developing lactic acidosis and severe hepatomegaly with steatosis in patients receiving antiretroviral nucleoside analogue therapy. For comprehensive prescribing details, refer to ZIAGEN (abacavir) and EPIVIR (lamivudine). If a patient on EPZICOM shows clinical or laboratory signs indicative of lactic acidosis or significant hepatotoxicity, including hepatomegaly and steatosis even without significant transaminase elevations, treatment should be discontinued.
5.4 Immune Reconstitution Syndrome
Patients receiving combination antiretroviral therapy, including EPZICOM, have experienced immune reconstitution syndrome. In the early stages of this combined therapy, patients with improving immune function might develop an inflammatory reaction to dormant or remaining opportunistic infections, such as Mycobacterium avium, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis. This may require additional assessment and treatment.
Additionally, autoimmune disorders like Graves’ disease, polymyositis, and Guillain-Barré syndrome have been observed in the context of immune reconstitution. Unlike the inflammatory response to infections, these autoimmune conditions may arise at a more variable time, often several months after the start of treatment.
5.5 Myocardial Infarction
Several observational, epidemiological studies that are prospective in nature have suggested a link between the use of abacavir and an increased risk of myocardial infarction (MI). However, meta-analyses of randomized, controlled clinical trials have not found a heightened risk of MI in subjects treated with abacavir compared to those in the control group. Currently, there is no clearly defined biological mechanism that could account for this potential risk increase. When considering all available data from both observational studies and controlled clinical trials, there is a lack of consistency; thus, the evidence supporting a direct cause-and-effect relationship between abacavir usage and MI risk remains unclear.
As a precautionary measure, it is advisable to assess the existing risk of coronary heart disease when prescribing any antiretroviral therapies, including abacavir. Efforts should be made to reduce all modifiable risk factors, such as hypertension, high cholesterol, diabetes mellitus, and smoking.
ADVERSE REACTIONS
The following adverse reactions are discussed in other sections of the labeling:
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- Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, Warnings and Precautions (5.1)].
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- Exacerbations of hepatitis B [see BOXED WARNING, Warnings and Precautions (5.2)].
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- Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.3)].
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- Immune reconstitution syndrome [see Warnings and Precautions (5.4)].
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- Myocardial infarction [see Warnings and Precautions (5.5)].
6.1 Clinical Trials Experience in Adult Subjects
Due to the diverse conditions under which clinical trials are conducted, the frequency of adverse reactions seen in the trials of one drug cannot be reliably compared with those in the trials of another drug, nor do they necessarily mirror what might be seen in general clinical practice.
Serious and Occasionally Lethal Hypersensitivity Reactions Linked to Abacavir
In clinical trials, there have been serious and in some cases fatal hypersensitivity reactions to abacavir, an ingredient in EPZICOM [refer to BOXED WARNING and Warnings and Precautions (5.1)]. These reactions typically present with at least two of the following symptoms: (1) fever, (2) skin rash, (3) gastrointestinal issues (such as nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional symptoms (like general discomfort, fatigue, or body aches), and (5) respiratory symptoms (including shortness of breath, cough, or sore throat). Fever and/or rash are common features in almost all cases of abacavir hypersensitivity.
Other symptoms have included fatigue, headache, muscle pain, swelling, joint pain, and numbness or tingling. More severe reactions have involved anaphylaxis, liver and kidney failure, low blood pressure, severe respiratory distress syndrome, respiratory failure, muscle breakdown, and death. Physical signs noted in these reactions have encompassed swollen lymph nodes, lesions on mucous membranes (such as eye inflammation and mouth ulcers), and various types of rashes, including maculopapular or hives (though some patients experienced different rashes or no rash at all). Erythema multiforme was also reported. Laboratory findings in these cases have shown high liver enzyme levels, increased creatine phosphokinase, raised creatinine, and lymphopenia, with chest X-rays often showing infiltrates, which were mainly localized.
Additional Adverse Reactions with Use of EPZICOM
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.
| a Subjects 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. b CNA30024 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. |
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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% |
Laboratory Abnormalities: Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of creatine phosphokinase (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 gamma-glutamyl transferase (GGT).
6.2 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)].
6.3 Postmarketing Experience
The following adverse reactions have been identified during postmarketing use. 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.
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 [see Adverse Reactions (6.1)].
Abacavir and Lamivudine
Body as a Whole: Redistribution/accumulation of body fat.
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 (5.3)], posttreatment exacerbations of hepatitis B [see Warnings and Precautions (5.2)].
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
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7.1 Methadone
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.
7.2 Sorbitol
Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology (12.3)].
7.3 Riociguat
Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see Clinical Pharmacology (12.3)]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).
OVERDOSAGE
There is no known specific treatment for overdose with EPZICOM. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.
Abacavir: It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
Lamivudine: 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.
DESCRIPTION
EPZICOM tablets contain the following 2 synthetic nucleoside analogues: abacavir (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 g per mol.
Abacavir sulfate is a white to off‑white solid and is soluble in water.
In vivo, abacavir sulfate dissociates to its free base, abacavir. Dosages 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 g per mol.
The highlights above do not include all or the complete information needed to use EPZICOM safely and effectively. See full prescribing information for EPZICOM. Additional information at https://dailymed.nlm.nih.gov
EPZICOM (abacavir and lamivudine tablets), for oral use
Initial U.S. Approval: 2004
