Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
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:Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, lamivudine, and other antiretrovirals [see Warnings 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.
- To facilitate reporting of hypersensitivity reactions and collection of information on each case, an Abacavir Hypersensitivity Registry has been established. Physicians should register patients by calling 1-800-270-0425.
- 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.
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 <50 mL/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 studies (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 ≥10% Frequency in Clinical Studies (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 study, 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: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.
CNA106030 (PREDICT-1), a randomized, double-blind study, evaluated the clinical utility of prospective HLA-B*5701 screening on the incidence of abacavir hypersensitivity reaction in abacavir-naive HIV-1-infected adults (n = 1,650). In this study, use of pre-therapy screening for the HLA-B*5701 allele and exclusion of subjects with this allele reduced the incidence of clinically suspected abacavir hypersensitivity reactions from 7.8% (66/847) to 3.4% (27/803). Based on this study, it is estimated that 61% of patients with the HLA-B*5701 allele will develop a clinically suspected hypersensitivity reaction during the course of abacavir treatment compared with 4% of patients who do not have the HLA-B*5701 allele.
Screening for carriage of the HLA-B*5701 allele is recommended prior to initiating treatment with abacavir. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. For HLA-B*5701-positive patients, initiating or reinitiating treatment with an abacavir-containing regimen is not recommended and should be considered only with close medical supervision and under exceptional circumstances where potential benefit outweighs the risk.
Skin patch testing is used as a research tool and should not be used to aid in the clinical diagnosis of abacavir hypersensitivity.
In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision-making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue abacavir and not rechallenge with abacavir if a hypersensitivity reaction cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.
Abacavir Hypersensitivity Reaction Registry: An Abacavir Hypersensitivity Registry has been established to facilitate reporting of hypersensitivity reactions and collection of information on each case. Physicians should register patients by calling 1-800-270-0425.
Lactic Acidosis 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 studies 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 >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 system responds 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 study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of myocardial infarction (MI).1 In a sponsor-conducted pooled analysis of clinical studies, 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 studies are inconclusive.
As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking).
Use With Other Abacavir-, Lamivudine-, and/or Emtricitabine-Containing Products
Epzicom contains fixed doses of 2 nucleoside analogues, abacavir and lamivudine, and should not be administered concomitantly with other abacavir-containing and/or lamivudine-containing products (ZIAGEN, EPIVIR, COMBIVIR® [lamivudine and zidovudine] Tablets, or TRIZIVIR® [abacavir sulfate, lamivudine, and zidovudine] Tablets); or emtricitabine-containing products, including ATRIPLA® (efavirenz, emtricitabine, and tenofovir disoproxil fumarate) Tablets, EMTRIVA® (emtricitabine) Capsules and Oral Solution, TRUVADA® (emtricitabine and tenofovir disoproxil fumarate) Tablets, or COMPLERA™ (rilpivirine/emtricitabine/tenofovir).
The complete prescribing information for all agents being considered for use with Epzicom should be consulted before combination therapy with Epzicom is initiated.
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 study, 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
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies 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 a ≥5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily are listed in Table 1.
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. | ||
bStudy CNA30024 was a multi-center, double-blind, controlled study 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 study, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 patients in the abacavir group and 3% of 325 patients in the zidovudine group. | ||
Laboratory Abnormalities: Laboratory abnormalities observed in clinical studies of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical studies of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.
The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in Study CNA30021.
Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.
Postmarketing Experience
In addition to adverse reactions reported from clinical studies, the following reactions have been identified during postmarketing use of abacavir, lamivudine, and/or Epzicom. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to 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 studies 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 study 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
Epzicom: Pregnancy Category C. There are no adequate and well-controlled studies of Epzicom in pregnant women. Reproduction studies with abacavir and lamivudine have been performed in animals (see Abacavir and Lamivudine sections below). Epzicom should be used during pregnancy only if the potential benefits outweigh the risks.
Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC.
Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to Epzicom or other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
Abacavir: Abacavir is secreted into the milk of lactating rats.
Lamivudine: Lamivudine is excreted in human breast milk and into the milk of lactating rats.
Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Epzicom.
Pediatric Use
Safety and effectiveness of Epzicom in pediatric patients have not been established. Epzicom is not recommended for use in patients aged <18 years because it cannot be dose adjusted.
Geriatric Use
Clinical studies 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 (2.2), 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 <50 mL/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
Abacavir: There is no known antidote for abacavir. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.
Lamivudine: One case of an adult ingesting 6 grams of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. It is not known whether lamivudine can be removed by peritoneal dialysis or hemodialysis.
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/mL in distilled water at 25°C.
In vivo, abacavir sulfate dissociates to its free base, abacavir. All dosages for abacavir sulfate are expressed in terms of abacavir.
Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3 daltons. It has the following structural formula:
Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.
Epzicom - Clinical Pharmacology
Mechanism of Action
Epzicom is an antiviral agent [see Clinical Pharmacology (12.4)].
Pharmacokinetics
Pharmacokinetics in Adults:Epzicom: In a single-dose, 3-way crossover bioavailability study of 1 Epzicom Tablet versus 2 ZIAGEN Tablets (2 x 300 mg) and 2 EPIVIR Tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (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/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hr/mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide.
Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy volunteers, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hr/mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).
The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared with the EPIVIR 150-mg tablet twice daily for 7 days were assessed in a crossover study in 60 healthy volunteers. EPIVIR 300 mg once daily resulted in lamivudine exposures that were similar to EPIVIR 150 mg twice daily with respect to plasma 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,ssand 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. The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.
In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes.
The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.
| aData presented as mean ± standard deviation except where noted. | ||||
| bApproximate range. | ||||
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/hr/kg) | 0.80 ± 0.24 | n = 6 | 0.33 ± 0.06 | n = 20 |
Renal clearance (L/hr/kg) | .007 ± .008 | n = 6 | 0.22 ± 0.06 | n = 20 |
Elimination half-life (hr) | 1.45 ± 0.32 | n = 20 | 5 to 7b | |
Effect of Food on Absorption of Epzicom: Epzicom may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability study resulted in no change in 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 studies 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 <50 mL/min [see Dosage and Administration (2.2)].
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).
Abacavir and Lamivudine: No data are available on the pharmacokinetics of abacavir or lamivudine during pregnancy.
Nursing Mothers:See Use in Specific Populations (8.3).
Abacavir: No data are available on the pharmacokinetics of abacavir in nursing mothers.
Lamivudine: Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.
Pediatric Patients:Epzicom: The pharmacokinetics of Epzicom in pediatric subjects are under investigation. There are insufficient data at this time to recommend a dose.
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 study in healthy male (n = 12) and female (n = 12) subjects showed no gender differences in lamivudine AUC∞ normalized for body weight.
Race:Abacavir: There are no significant differences between blacks and Caucasians in abacavir pharmacokinetics.
Lamivudine: There are no significant racial differences in lamivudine pharmacokinetics.
Drug Interactions: The drug interactions described are based on studies conducted with the individual nucleoside analogues. In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways.
Abacavir:Lamivudine and Zidovudine: Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction study evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.
Methadone: In a study 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 (7.4)].
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 q 12 hr).
Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no
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