Abacavir; lamivudine, 3TC (Epzicom) is a combination of two nucleoside analog reverse transcriptase inhibitors (NRTIs) used for the treatment of human immunodeficiency virus (HIV) infection. Double NRTI therapy is not considered highly active antiretroviral therapy (HAART); thus, it must be used in combination with other antiretroviral agents. Epzicom received FDA-approval in August 2004; it was approved in pediatric patients weighing 25 kg or more in September 2015.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Screen for HLA-B*5701 before initiating treatment to reduce the risk of hypersensitivity reaction. HLA-B*5701-positive patients MUST not receive abacavir.
Route-Specific Administration
Oral Administration
-Administer with or without food.
-Administer as a whole tablet; assess pediatric patients for the ability to swallow tablets prior to administration.
This section discusses adverse reactions reported with the combination product Epzicom. Refer to the individual monographs for abacavir or lamivudine for specific information concerning adverse events related to the individual agents.
Neurologic adverse events that have been reported with treatment with abacavir; lamivudine during clinical trials include abnormal dreams (4-5%), anxiety (3-5%), depression (7%), dizziness (6%), fatigue (6-8%), headache including migraine (6-7%), insomnia (7-9%), malaise (6-8%), and vertigo (6%). Paresthesias, peripheral neuropathy, and seizures have been reported with post-marketing use. Due to the voluntary nature of post-market reports, neither a frequency nor a definitive causal relationship can be established.
Gastrointestinal adverse events experienced by abacavir; lamivudine-treated patients during clinical trials included abdominal pain (4-5%), diarrhea (5-6%, severe 2-5%), gastritis (4-5%), and nausea (5-6%). Stomatitis has been reported with post-marketing use. Due to the voluntary nature of post-market reports, neither a frequency nor a definitive causal relationship can be established.
Rash (unspecified) was reported by 5% of patient receiving treatment with abacavir; lamivudine during clinical trials. Other dermatologic adverse events reported with post-marketing use include alopecia, erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and urticaria. Due to the voluntary nature of post-market reports, neither a frequency nor a definitive causal relationship can be established.
Laboratory abnormalities reported by recipients of abacavir and lamivudine during clinical trials included elevated hepatic enzymes, creatine phosphokinase (CPK), gamma-glutamyl transpeptidase (GGT), and lipase, elevated amylase, elevated bilirubin, hyperglycemia, hypertriglyceridemia, anemia, leukopenia, neutropenia, and thrombocytopenia. Post-marketing cases of muscle weakness and rhabdomyolysis potentially associated with elevated CPK and cases of aplastic anemia and lymphadenopathy have been reported following treatment with abacavir; lamivudine. Due to the voluntary nature of post-market reports, neither a frequency nor a definitive causal relationship can be established.
Fever or pyrexia was reported in 3-5% of patients receiving treatment with abacavir; lamivudine during clinical trials. Fever may also be a sign of developing abacavir-hypersensitivity.
Serious hypersensitivity reactions or anaphylaxis, including fatal reactions, have occurred in patients receiving abacavir containing regimens. In clinical trials, the incidence of hypersensitivity reactions to abacavir was 8% when HLA-B*5701 screening was not performed; the incidence was 1% when HLA-B*5701-positive patients were excluded. 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 toxic epidermal necrolysis; 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. Signs and symptoms of hypersensitivity include fatigue, fever, chills, skin rash (unspecified), pruritus, gastrointestinal symptoms such as abdominal pain, diarrhea, nausea or vomiting, and respiratory symptoms including pharyngitis, dyspnea, or cough. Respiratory symptoms occur in approximately 20% of patients with abacavir hypersensitivity reactions. Wheezing occur infrequently during abacavir hypersensitivity reactions. Other signs and symptoms include malaise, lethargy, myolysis, edema, chest x-ray abnormalities, and paresthesias. Physical findings include lymphadenopathy, mucous membrane lesions (conjunctivitis and oral ulceration), and rash. The rash, if present, usually appears as a maculopapular rash or urticarial rash (urticaria) but may be variable in appearance. There have been reports of erythema multiforme. Laboratory findings include elevated hepatic enzymes, increased creatine phosphokinase, increased creatinine, and lymphopenia. Deaths have been reported in patients receiving abacavir who were initially diagnosed with an acute respiratory disease (pneumonia, bronchitis, or flu-like illness) who were later recognized to have had a hypersensitivity reaction to abacavir that included respiratory symptoms. A delay in diagnosis of abacavir hypersensitivity can result in abacavir being continued or reintroduced, leading to more severe hypersensitivity reactions including, life-threatening hypotension, anaphylactoid reactions, hepatic failure, renal failure (unspecified), acute respiratory distress syndrome (ARDS), respiratory arrest, and death. Symptoms usually appear within the first 6 weeks of treatment, although these reactions may occur at any time during therapy. Hypersensitivity reactions have been reported upon reintroduction of abacavir therapy that has been discontinued for other medical reasons. In a minority of these patients, hypersensitivity occurred days or weeks after reintroduction of abacavir treatment. Symptoms worsen with continued therapy but often resolve upon discontinuation of the drug. Patients developing signs or symptoms of hypersensitivity should discontinue use of abacavir as soon as a hypersensitivity reaction is suspected. In patients presenting with symptoms of acute respiratory disease and other symptoms associated with hypersensitivity to abacavir, a hypersensitivity reaction should be suspected even if alternative respiratory diagnoses (i.e., pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. If the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction, abacavir should be permanently discontinued. Patients should never be restarted on any abacavir containing product following a hypersensitivity reaction because more severe symptoms will recur within hours of administration and may include life-threatening hypotension and death. To facilitate reporting of hypersensitivity reactions and collection of information on each case, health care professionals should report all hypersensitivity reactions to the Abacavir Hypersensitivity Registry at Glaxo Wellcome by calling (800) 270-0425 or the FDA MedWatch program at (800) FDA-1088.
Lactic acidosis and severe hepatotoxicity (i.e., fatal cases of hepatomegaly with steatosis) have been reported with the use of nucleoside reverse transcriptase inhibitors. Many of these cases have occurred in women; additional risk factors included obesity and prolonged nucleoside exposure. Abacavir; lamivudine, 3TC should be discontinued if a patient develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, including hepatomegaly and steatosis even in the absence of marked elevated transaminases. Pancreatitis and splenomegaly have also been reported during treatment with abacavir or lamivudine. The incidence of these adverse events is unknown.
Lipodystrophy syndrome consisting of redistribution and accumulation of body fat has been reported during postmarketing use of abacavir and lamivudine. The mechanism by which nucleoside analogues may cause body fat changes is not known. It has been suggested that nucleoside analogs may damage the mitochondria of adipocytes. An increased incidence of body fat changes is noted in those patients receiving long-term nucleoside therapy and in female patients.
There have been postmarketing reports of severe acute hepatitis B exacerbation in patients with HBV and HIV coinfection following the discontinuation of lamivudine therapy; close monitoring of clinical signs and symptoms, including laboratory monitoring, are recommended for several months following discontinuation. Typically, HBV exacerbation is associated with a return of HBV DNA and increases in ALT concentrations. Usually this exacerbation is self-limited; however, some fatalities have been reported. The casual relationship of discontinuation of lamivudine to the recurrence of HBV infection is not known. There is insufficient evidence to determine whether re-initiation of therapy alters the course of posttreatment exacerbations of hepatitis.
Abacavir treatment was linked with the development of myocardial infarction (MI) in several prospective, observational, epidemiologic trials. In contrast to these observational trials, a sponsor-conducted, pooled analysis of clinical trials showed no excess risk of MI in abacavir-treated subjects as compared with control subjects. Furthermore, a meta-analysis of 26 randomized clinical trials conducted by the FDA failed to reveal an association between treatment with abacavir-containing regimens and development of MI (OR = 1.02; 95% CI 0.56 to 1.84). In light of the conflicting data, caution is advised when prescribing abacavir to patients with pre-existing coronary heart disease. Further, health care providers are encouraged to minimize a patient's modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) prior to prescribing.
Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., < 1-2 days) is necessary, in general it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine range from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
Abacavir has been associated with serious hypersensitivity reactions or anaphylaxis (some cases have been fatal); to reduce the risk, perform HLA-B*5701 testing on all patients before initiating treatment. Abacavir is contraindicated in any HLA-B*5701-positive patient; clearly record the positive status as an abacavir allergy in the patients' medical record. According to the manufacturer, the estimated incidence of hypersensitivity to abacavir was 8% when HLA-B*5701 screening was not performed; the incidence was 1% when HLA-B*5701-positive patients were excluded. Racial background may help identify those at higher risk for carrying the gene, as in the United States approximately 8% of Caucasian patients, 2.5% of Black patients, and 1% of Asian patients are carriers. Regardless of HLA-B*5701 status, immediately discontinue treatment in patients developing or with suspected signs or symptoms of abacavir hypersensitivity, including those presenting with 2 or more of the following: fever, rash, gastrointestinal (e.g., nausea, vomiting, diarrhea, abdominal pain), constitutional (generalized malaise, fatigue, achiness), or respiratory (dyspnea, cough, pharyngitis). Permanently discontinue abacavir if the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction. NEVER reinitiate an abacavir containing product in a patient who experiences a hypersensitivity reaction as more severe symptoms will recur within hours of administration and may include life-threatening hypotension and death. Severe or fatal hypersensitivity reactions may also occur within hours after abacavir reintroduction in patients who have no identified history of hypersensitivity, but who discontinued abacavir for reasons unrelated to symptoms of hypersensitivity (e.g., interruption in drug supply or discontinuation while treating other medical conditions). In some cases, symptoms consistent with hypersensitivity may have been present before abacavir was discontinued, but may have been attributed to other medical conditions (e.g., acute onset respiratory diseases, gastroenteritis, or reactions to other medications). In a minority of cases, hypersensitivity reactions occurred days to weeks after abacavir reintroduction. If abacavir has been discontinued for reasons other than symptoms of hypersensitivity and if reinitiation is being considered, re-evaluate the reason for discontinuation and ensure that the patient did not have any suspected symptoms of hypersensitivity. If hypersensitivity symptoms are suspected upon review, do not reinitiate abacavir. If symptoms consistent with hypersensitivity are not identified and the patient is HLA-B*5701-negative, undertake reintroduction with caution. If HLA-B*5701 status is unknown, screening should occur prior to restarting therapy. Health care professionals should report all hypersensitivity reactions to the FDA MedWatch program (800-FDA-1088).
Clinical studies of abacavir or lamivudine did not include sufficient numbers of patients aged 65 years or over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in response between geriatric and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Abacavir; Lamivudine, 3TC (Epzicom) should not be used in neonates, infants, or children weighing less than 25 kg. Use abacavir and lamivudine as the individual components in small pediatric patients to achieve appropriate dosing.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contain multiple mutations conferring antimicrobial resistance to other NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir, lamivudine, and other NRTIs should be considered when choosing new therapeutic regimens in previously treated patients.
Use abacavir; lamivudine, 3TC (Epzicom) cautiously in patients with peripheral neuropathy. Patients with peripheral neuropathy can experience exacerbations during lamivudine therapy.
Abacavir; lamivudine, 3TC (Epzicom) should not be used in patients with hepatic disease and should be used with caution in those with known risk factors for liver disease (e.g., alcoholism). Abacavir should be avoided in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment. Because abacavir; lamivudine is a fixed-dose combination product and the abacavir dose cannot adjusted, the combination product should not be used in patients with hepatic impairment. Obesity and prolonged nucleoside exposure may also be risk factors for hepatotoxicity or lactic acidosis during nucleoside analog therapy. Fatalities have been reported with use of antiretroviral agents alone or in combination, including abacavir and lamivudine. A majority of these cases occurred in females; it is unknown if pregnant women are at increased risk for this syndrome. However, because being pregnant itself can mimic some of the early symptoms of the lactic acid or hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Treatment should be discontinued 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 increases in transaminases.
Perform HBV screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide with emtricitabine or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. It should also be noted that following discontinuation of lamivudine in patients with HBV and HIV infection, some patients experienced clinical or laboratory evidence of hepatitis B exacerbation, which has been fatal in some cases. This reaction may be more severe in patients with decompensated hepatic disease. Thus, patients with HBV and HIV should have transaminase concentrations monitored every 6 weeks for the first 3 months after stopping abacavir; lamivudine, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct hepatitis and HIV coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. HIV guidelines recommend the use of abacavir; lamivudine as a preferred 2-NRTI backbone in HLA-B*5701 negative women who are pregnant or trying to conceive. Available data from the Antiretroviral Pregnancy Registry, which includes more than 1,300 first trimester exposures to abacavir and more than 5,350 first trimester exposures to lamivudine, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When exposure occurred in the first trimester, the prevalence of defects was 3.2% (95% CI: 2.3 to 4.3) for abacavir and 3.1% (95% CI: 2.7 to 3.6) for lamivudine. Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to abacavir; lamivudine; information about the registry can be obtained at http://www.apregistry.com/ or by calling 1-800-258-4263.
The manufacturer recommends mothers be instructed to discontinue breast-feeding if they are receiving abacavir; lamivudine. The Centers for Disease Control and Prevention recommend all mothers with HIV within the United States avoid breast-feeding as a method of preventing postnatal transmission of HIV. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765). Both abacavir and lamivudine are excreted into human breast milk. In 1 study conducted in Botswana, the mean breast milk-to-plasma ratio of abacavir was 0.85 in the 15 women tested. Further, an analysis of 9 breast-feeding infants found detectable plasma drug concentrations in 1 infant. Lamivudine was found to be secreted in human breast milk during a study involving 20 breast-feeding women with HIV who were administered either 300 mg of lamivudine twice daily as a single agent (n = 10) or lamivudine 150 mg twice daily in combination with zidovudine (n = 10). The mean breast milk concentrations of lamivudine in the respective groups were similar at 1.22 mg/L (range less than 0.5 to 6.09 mg/L) and 0.9 mg/L (range less than 0.5 to 8.2 mg/L). Other antiretroviral mediations whose passage into human breast milk have been evaluated include nevirapine, zidovudine, and nelfinavir.
Lamivudine is excreted in the urine and requires dosage adjustment in patients with renal dysfunction (see Lamivudine Contraindications). Since abacavir; lamivudine, 3TC (Epzicom) is a fixed-dose, combination tablet, patients with renal failure or renal impairment with a creatinine clearance <= 50 ml/min should not receive abacavir; lamivudine, 3TC.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to abacavir; lamivudine therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Conflicting data have been published regarding the potential for increased risk of myocardial infarction (MI) in persons receiving treatment with abacavir-containing regimens. Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of MI. Patients in these studies who started abacavir for the first time had worse initial cardiovascular risk profiles than observed with the other nucleoside reverse transcriptase inhibitor (NRTI) agents; therefore, it can not be ruled out that some of these results could be the result of channeling bias. The authors of these studies speculate that the underlying mechanism for increased risk of CVD may be due to an increased propensity for subclinical atherosclerosis to manifest itself clinically as a consequence of the pro-inflammatory potential of abacavir; however, a biological mechanism to explain the potential increase in risk has not been definitely established. In contrast to the observational trials, a sponsor-conducted, pooled analysis of clinical trials showed no excess risk of MI in abacavir-treated subjects as compared with control subjects. Furthermore, a meta-analysis of 26 randomized clinical trials conducted by the FDA failed to reveal an association between treatment with abacavir-containing regimens and development of MI (OR = 1.02; 95% CI 0.56 to 1.84). As a precaution, the manufacturer of abacavir recommends considering the underlying risk of cardiac disease and taking action to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking) when prescribing antiretroviral therapies, including abacavir. The HIV guidelines recommend consideration be given to avoiding use of abacavir-containing regimens in patients with known high cardiovascular risk.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
HIV guidelines recommend screening for HLA-B*5701 before initiating an abacavir-containing regimen to reduce the risk of hypersensitivity reaction. HLA-B*5701-positive patients should not be prescribed abacavir.
NOTE: HIV guidelines recommend consideration be given to avoiding use of abacavir-containing regimens in patients at high risk for cardiovascular adverse events. Although a definitive correlation has not been established, recent (within 6 months) or current use of abacavir has been associated with an increased risk of myocardial infarction.
Initiation of therapy for HIV treatment:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy and prior to changing therapy for treatment failure.
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-Pediatric guidelines are also available.
Place in therapy for HIV treatment:
-For most HLA-B*5701 negative adults and adolescents (including pregnant women and women who are trying to conceive), abacavir; lamivudine is a preferred 2-NRTI backbone.
-Pediatric guidelines are also available.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage:
Adults: 1 tablet (abacavir 600 mg; lamivudine 300 mg) PO once daily.
Children and Adolescents weighing 25 kg or more: 1 tablet (abacavir 600 mg; lamivudine 300 mg) PO once daily.
Maximum Dosage Limits:
-Adults
Abacavir 600 mg/day; lamivudine 300 mg/day.
-Geriatric
Abacavir 600 mg/day; lamivudine 300 mg/day.
-Adolescents
Weight 25 kg or more: Abacavir 600 mg/day; lamivudine 300 mg/day.
Weight less than 25 kg: Safety and efficacy have not been established.
-Children
Weight 25 kg or more: Abacavir 600 mg/day; lamivudine 300 mg/day.
Weight less than 25 kg: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Abacavir; lamivudine, 3TC is contraindicated in patients with hepatic impairment. Abacavir is contraindicated in patients with moderate to severe hepatic impairment, and a dosage adjustment, which is required in patients with mild hepatic impairment, cannot be achieved with the fixed dose abacavir; lamivudine combination product.
Patients with Renal Impairment Dosing
CrCl <= 50 ml/min: Lamivudine requires dose adjustment in the presence of renal insufficiency, therefore, the fixed-dose combination of abacavir; lamivudine, 3TC is not recommended for patients with impaired renal function.
*non-FDA-approved indication
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing 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 analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir 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).
Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Amiloride: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Cabozantinib: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with abacavir is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and abacavir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Dofetilide: (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
Donepezil; Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Efavirenz; Emtricitabine; Tenofovir: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Empagliflozin; Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Empagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Emtricitabine: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir disoproxil fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Ertugliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Ethanol: (Major) Because abacavir is metabolized via alcohol dehydrogenase, ethanol decreases the elimination of abacavir causing an increase in overall exposure to abacavir. In a study involving HIV-infected men, coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC and a 26% increase in abacavir half-life. In males, abacavir had no effect on the pharmacokinetic properties of ethanol; this interaction has not been studied in females. Abacavir has no effect on the pharmacokinetic properties of ethanol (alcohol).
Food: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Interferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfa-2b; Ribavirin: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfacon-1: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Alfa-n3: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Beta-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferon Gamma-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Interferons: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Lopinavir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Pioglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Repaglinide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Rosiglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Saxagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Sitagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Methadone: (Moderate) In a study of 11 adult HIV-infected subjects receiving methadone maintenance therapy (40 to 90 mg/day) and abacavir 600 mg twice daily (twice the current recommended dose), methadone clearance increased by 22% (6% to 42%). While this interaction will not require dosage adjustment in the majority of patients, a small number of patients may require increased doses of methadone. In addition, a significant decrease in abacavir Cmax (34%) and increase in Tmax (67%) were noted, but no changes in overall abacavir clearance or half-life were reported. The clinical significance regarding abacavir therapy is not known.
Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Peginterferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Procainamide: (Moderate) Cationic drugs that are eliminated by renal tubular secretion such as procainamide may compete with lamivudine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of the response to lamivudine and/or procainamide is recommended to individualize dosage. In selected individuals, procainamide serum concentration monitoring may be appropriate.
Ribavirin: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Riociguat: (Moderate) Monitor for an increase in riociguat-related adverse effects like hypotension if concomitant use with abacavir is necessary. Consider a riociguat dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Concomitant use of riociguat and abacavir may increase riociguat exposure although the magnitude of increase is unknown. Riociguat is a CYP1A1 substrate; abacavir may inhibit CYP1A1.
Ritonavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Sorbitol: (Major) Avoid coadministration of lamivudine oral solution and sorbitol if possible due to sorbitol dose-dependent reduction in lamivudine exposure. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol. Consider more frequent monitoring of viral load when treating with lamivudine oral solution. In a drug interaction study in 16 healthy adult patients, coadministration of a single 300 mg dose of lamivudine oral solution with sorbitol 3.2 g, 10.2 g, or 13.4 g resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC24 and 28%, 52%, and 55% in the Cmax of lamivudine.
Tipranavir: (Moderate) Concurrent administration of tipranavir and ritonavir with abacavir results in decreased abacavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for abacavir dosage adjustments are available.
Trospium: (Moderate) Trospium is eliminated by active tubular secretion and has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion including lamivudine. In theory, coadministration of trospium with lamivudine may increase the serum concentrations of trospium or lamivudine due to competition for the drug elimination pathway.
Abacavir and lamivudine inhibit viral reverse transcriptase, and are both active against HIV-1.
-Abacavir: Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate, an analog of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. The lack of a 3'-hydroxyl group in the incorporated nucleoside analog prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is inhibited.
Abacavir hypersensitivity may be related to an induced autoimmunity process related to HLA-B*5701. Human Leukocyte Antigens (HLAs) help the body to distinguish "self" versus "foreign" proteins (peptides). A study determined that abacavir alters the quantity and quality of self-peptide loading into HLA-B*5701. These self-peptides are then presented for the first time and because the body has not previously recognized them, it mistakenly treats them as foreign, resulting in a polyclonal T-cell autoimmune response and multi-organ systemic toxicity. Once the drug is discontinued, reactive T-cells would be reduced and then differentiate into T memory cells. Re-exposure would again generate these peptides leading to a rapid expansion of T memory cells which could cause severe and potentially life-threatening reactions.
-Lamivudine: The in vitro activity of lamivudine has been assessed in a number of cell lines where lamivudine showed anti-HIV activity in all virus-cell infections tested. Intracellular phosphorylation of lamivudine produces the 5'-triphosphate metabolite (L-TP) in vitro. This active metabolite inhibits reverse transcriptase and viral DNA synthesis. L-TP also inhibits cellular DNA polymerase. Combination therapy targets different points in the life cycle of HIV, reducing the ability of HIV to mutate to drug-resistant strains.
The development of drug resistance is a problem in the treatment of HIV infection. The combination of abacavir and lamivudine has demonstrated decreased susceptibility to viruses with certain viral mutations, including M184, K65R, L74V, and Y115F. Abacavir has additive activity when used in combination with lamivudine. The combination of abacavir and lamivudine has also demonstrated additive to synergistic activity in vitro when combined with specific NRTIs, NNRTIs, PIs, or enfuvirtide.
The abacavir; lamivudine, 3TC; combination tablet (Epzicom) is given orally.
-Abacavir: Once in the systemic circulation, abacavir distributes into extravascular space. In humans, cytochrome P450 enzymes do not significantly metabolize abacavir. 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). The metabolites have no antiviral activity. Abacavir metabolites are primarily eliminated in the urine. Fecal elimination accounted for 16% of the dose. In single-dose studies, the observed elimination half-life ranges in patients with normal renal function from 0.91 to 2.17 hours.
-Lamivudine: Hepatic metabolism is a minor route of elimination for lamivudine. The only known metabolite of lamivudine in humans is the trans-sulfoxide metabolite, which accounts for less than 5% of a dose appearing in the urine. The mean elimination half-life with normal renal function after a single dose of lamivudine ranges 5 to 7 hours. Total clearance of lamivudine decreases as creatinine clearance decreases.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A1, CYP3A4
Data from in vitro studies show abacavir has the potential to inhibit CYP1A1 and the limited potential to inhibit CYP3A4. Other CYP isoenzymes (e.g., CYP2C9 and CYP2D6) are not inhibited or induced by abacavir. Similarly, abacavir at therapeutic drug exposures is not expected to affect the pharmacokinetics of substrates of the following drug transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.
-Route-Specific Pharmacokinetics
Oral Route
In a single-dose, 3-way crossover study in healthy volunteers, one Epzicom tablet was bioequivalent to two 300 mg abacavir tablets and two 150 mg lamivudine tablets. Administration of Epzicom with food did not alter the extent of abacavir or lamivudine absorption (AUC) as compared to fasted conditions.
-Lamivudine: Following oral administration, lamivudine is rapidly and extensively distributed. Most of an oral dose of lamivudine (71%) is excreted unchanged in the urine.
-Special Populations
Hepatic Impairment
Abacavir is eliminated via hepatic metabolism, and clearance is reduced in patients with moderate to severe hepatic dysfunction. Because abacavir; lamivudine, 3TC is only available in a fixed dose, it is not recommended in patients with hepatic dysfunction.
Renal Impairment
Lamivudine, 3TC is renally eliminated and clearance is reduced in patients with moderate to severe renal impairment. Because abacavir; lamivudine, 3TC is only available in a fixed dose, it is not recommended in patients with renal dysfunction.
Pediatrics
Pharmacokinetic data for abacavir and lamivudine after administration of Epzicom in pediatric patients are limited. In general, abacavir clearance is faster in children and slows down in adolescents and young adults to approximately the clearance noted in adults. Weight-corrected oral clearance of single-ingredient lamivudine was higher at age 2 and declined from 2 to 12 years, where values were then similar to adults. Studies in pediatric patients with clinically stable HIV have shown that once-daily dosing provides comparable exposure as twice-daily dosing for both abacavir and lamivudine.
Other
Pregnancy
-Abacavir: A population pharmacokinetic analysis of 266 samples from 36 pregnant and 114 non-pregnant females, found the pharmacokinetic parameters of abacavir to be unchanged during pregnancy. Similarly, 1 pharmacokinetic study found abacavir exposure in 25 pregnant women receiving 300 mg twice daily during the third trimester to be comparable to exposures observed in postpartum women and historical controls of non-pregnant women with HIV. Abacavir crosses the placenta via passive diffusion, with drug concentrations in neonatal plasma cord samples at birth being essentially equal to those in the maternal plasma at the time of delivery.
-Lamivudine: Although population pharmacokinetic modeling suggests the oral clearance of lamivudine is increased by 22% during pregnancy; limited data from 2 studies involving 36 pregnant women (16 at 36 weeks, 20 at 38 weeks gestation) found the pharmacokinetic parameters of lamivudine to be similar to those observed in non-pregnant and postpartum adults. No change in dose is indicated. In addition, placental transfer of lamivudine results in drug concentrations that are 2 times greater than maternal serum levels.