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Abacavir + 3TC Fixed Dose Combination (One Pill Once Daily):
  antiviral efficacy, safety, tolerability, PK, pregnancy/fertility, hypersensitivity, HBV, resistance/cross-resistance, dosing (methadone, alcohol, hepatitis, renal impairment)
Reported by Jules Levin
Two Fixed Dose Combinations (FDC) were recently approved in August 2004 by the FDA (Food and Drug administration). These FDCs consist of abacavir (Ziagen) and Epivir (3TC) in one pill taken once daily and the second FDC is tenofovir (Viread) and FTC (Emtricitabine) also administered as one pill once daily. Tenofovir was originally developed and approved by the FDA as a once daily medication and so was FTC. 3TC was originally approved to be administered twice daily, but was FDA approved to be administered once daily. Along with the recent FDA approval of the two FDCs abacavir once daily was approved. This report provides a summary of results from studies (CNA30021, CNA30024) used to secure approval for once daily administration of abacavir. CNA30021 compared abacavir once daily along with 3TC & EFV once daily to abacavir twice daily along with 3TC once daily & EFV once daily. This study found ABC once daily non-inferior to ABC twice daily. As well, safety of once vs twice daily abacavir was reported in poster B5868 at IAC Bangkok 2004 and is reported below. This report also contains key excerpts from the FDA approved Ziagen Product Insert.
EPZICOM is available as tablets. Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
Effect of Food on Absorption of EPZICOM:
EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability study resulted in no change in AUC last, AUC∞ and 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 to 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.
Therapy-Naive Adults: CNA30021

was an international, multicenter, double-blind, controlled study in which 770 HIV-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Study participants had a mean age of 37 years, were: male (81%), Caucasian (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells/mm3 (range 21 to 918 cells/mm3) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies/mL (range: 2.60 to 6.99 log10 copies/mL).
Ziagen 600mg QD Ziagen 300mg BID
n=384 n=386
Responder* 64% (71%) 65% (72%)
Viroligic Failure+ 11% (5%) 11% (5%)
Disct due to AE 13% 11%
Disct-other reasons^ 11% 13%

*Patients achieved and maintained confirmed HIV-1 RNA <50 copies/mL (<400 copies/mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).
+Includes viral rebound, failure to achieve confirmed <50 copies/mL (<400 copies/mL) by Week 48, and insufficient viral load response.
^Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other.
After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells/mm3 in the group receiving ZIAGEN 600 mg once daily and 200 cells/mm3 in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to study medications.
At the Pharmacology Workshop (Rome, April 2004), Trevor Hawkins (Southwest Care Center, Santa Fe, NM) reported results of a study examining the pharmacokinetics of abacavir and tenofovir. As part of his findings he reported that in patients discontinuing TDF or ABC, TFV-DP intracellular concentrations were quantifiable in 8/8 patients for >=72 hrs while CBV-TP (ABC) levels fell and remained below the LLOQ in 1/7, 3/7, and 5/7 patients by 48, 60, and 72 hours post-dose. Estimates of IC decay rates suggest IC half-lives of TFV-DP >=60 hrs and CBV-TP of 12-19 hrs.
15 patients (n=14 <400 c/mlHIV-1 RNA) on stable TDF+ABC+3rd NRTI (3TC n=13, d4T n=2) discontinued either TDF or ABC, replacing it with a new third agent (14/15 a NNRTI or PI). Multiple PBMC samples were collected in CPT tubes following the last dose of TDF or ABC at baseline and on days 1, 2, 3, 14, and 28. IC levels of TFV-DP and CBV-TP were measured directly in about 1 x 106 PBMCs using LC/MS/MS with a lower limit of quanitification (LLOQ) of 15 fmol on-column. Changes in IC levels of TFV-DP and CBV-TP upon ABC or TDF discontinuation were assessed to provide evidence of an IC DI. Levels of the withdrawn drug were also measured to estimate IC decay rates.
Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, >=5% Frequency) in Therapy-Naive Adults (CNA30021) Through 48 Weeks of Treatment
Ziagen 600mg QD Ziagen 300mg
n=384 n=386
Drug hypersensitivity*+ 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%
Diarrhea** 5% 6%
Rash 5% 5%
Pyrexia (fever) 5% 5%
Abd pain/gastritis 4% 5%
Abnormal dreams 4% 5%
Anxiety 3% 5%

*Patients receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared to patients who received ZIAGEN 300 mg twice daily. Five percent (5%) of patients receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared to 2% of patients receiving ZIAGEN 300 mg twice daily.Two percent (2%) of patients receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the patients receiving ZIAGEN 300 mg twice daily had this event.
+Study CNA30024 was a multicenter, double-blind, controlled study in which
649 HIV-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.
At the IAC Bangkok 2004, GSK reported poster B5868 "Long-Term (>48 Week) Safety Profile of Abacavir (ABC) Once Daily (QD) or Twice Daily (BID), in Combination with Lamivudine (3TC) QD or BID and Efavirenz (EFV QD". The study authors concluded: In CNA30021 (ZODIAC) & CNA30024 ABC (BID or QD) + 3TC (BID or QD) was found to be highly effective in combination with EFV. The long-term tolerability of ABC is no different if a daily dose of 600mg is administered either once or twice daily.
Long term safety data of ABC (600mg QD) + 3TC (300mg QD) in combination with EFV is available from two studies. The purpose of this analysis was to examine the safety profile of the ABC+3TC backbone after 48 weeks of treatment in these studies.
--CNA30021 (ZODIAC) was a Phase III, 1:1 randomized, double-blind, multi-center, international study (n=770). A regimen comprising ABC QD + 3TC QD + EFV QD was compared to ABC BID + 3TC QD + EFV QD over 48 weeks in ART-naïve HIV+ adults.
--CNA30024 was a randomized, double-blind, multi-center, international study (n=649). ABC (BID) was compared to AZT (BID), both in combination with 3TC (BID) and EFV (QD) in ART-naïve HIV+ adults.
In CNA30024, 70% of subjects in the ABC group compared to 69% of subjects in the AZT group achieved <50 copies/ml. The study confirmed non-inferiority of ABC to AZT.
ABC bid+3TC bid ABC bid+3TC QD ABC+3TC QD
+EFV, n=248 +EFV n=297 +EFV n=293
Drug-related AEs 65% 70% 73%
all grades
--SAEs 8% 7% 6%
Treatment-limiting AEs <1% 3% 2%
Grade 2/3/4 AEs 62% 62% 65%

Drug-related AEs 6% 5% 8%
all grades
--SAEs 3% 2% 2%
treatment-limiting AEs <1% 1% 1%
Grade 2/3/4 AEs 32% 32% 27%


Any event 6% 8% 5%
Neurology <1% 2% 1%
Metabolic & endocrine 3% 2% 0
GI 1% 3% 2%
Psychiatric 1% 1% 1%
Skin 0 1% 1%
Reproduction 0 0 <1%
Hepatobiliary & pancreas <1% <1% <1%


Impaired Hepatic Function: EPZICOM:
Abacavir is contraindicated in patients with moderate to severe hepatic impairment and dose reduction is required in patients with mild hepatic impairment. Because EPZICOM is a fixed-dose combination and cannot be dose adjusted, EPZICOM is contraindicated for patients with hepatic impairment.
Dose Adjustment: Because it is a fixed-dose tablet, EPZICOM should not be prescribed for patients requiring dosage adjustment such as those with creatinine clearance <50 mL/min, those with hepatic impairment, or those experiencing dose-limiting adverse events. Use of EPIVIR Oral Solution and ZIAGEN Oral Solution may be considered.
In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.
Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.
EPZICOM Tablets are contraindicated in patients with previously demonstrated hypersensitivity to abacavir or to any other component of the product. Following a hypersensitivity reaction to abacavir, NEVER restart EPZICOM or any other abacavir-containing product. Fatal rechallenge reactions have been associated with readministration of abacavir to patients with a prior history of a hypersensitivity reaction to abacavir.
Hypersensitivity Reaction: Serious and sometimes fatal hypersensitivity reactions have been associated with EPZICOM and other abacavir-containing products. 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.
A hypersensitivity reaction is usually reversible if it is detected promptly and EPZICOM is stopped right away. In one study, more severe hypersensitivity reactions were seen when ZIAGEN was dosed 600 mg once daily.
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.
Impairment of Fertility:
Abacavir or lamivudine induced no adverse effects on the mating performance or fertility of male and female rats at doses producing systemic exposure levels approximately 8 or 130 times, respectively, higher than those in humans at the recommended dose based on body surface area comparisons.
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.
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.
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 that 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-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV 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 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving EPZICOM.
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. Although rash is the most common sign or symtom, rash does not always occur as part of hypersensitivity.
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 patients (n = 206) in 9 clinical trials (range: 2% to 9%) with enrollment from November 1999 to February 2002. Data on time to onset and symptoms of suspected hypersensitivity were collected on a detailed data collection module. 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 patients reported symptoms from 2 or more of the 5 groups listed above.
Hypersensitivity-Related Symptoms Reported with >=10% Frequency in Clinical Trials (n = 206 Patients)
Fever: 65%
Rash: 60%
Malaise: 60%
Nausea: 48%
Headache: 40%
Myalgia: 33%
Chills: 32%
Diarrhea: 31%
Vomiting: 30%
Abdominal pain: 27%
Dyspnea: 27%
Arhralgia: 26%
Cough: 22%
Fatigue: 18%
Tachycardia (rapid heart rate): 16%
Pharyngitiis: (inflammation of pharynx): 11%
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 patients (11%) receiving ZIAGEN 600 mg once daily experienced hypotension with a hypersensitivity reaction compared with 0 patients receiving ZIAGEN 300 mg twice daily.
Physical findings associated with hypersensitivity to abacavir in some patients 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 patients 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 hypersensitivity cannot be ruled out, DO NOT reintroduce EPZICOM or any other abacavir-containing product. 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.
Mechanism of action:
Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted intracellularly by cellular enzymes to the active metabolite, carbovir triphosphate, an analogue of deoxyguanosine-5•-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) in viral DNA synthesis both by competing with the natural substrate dGTP and by its incorporation into viral DNA resulting in chain termination. Lamivudine is a synthetic nucleoside analogue, which is phosphorylated intracellularly to its active metabolite, lamivudine triphosphate. The principal mode of action of lamivudine triphosphate is inhibition of RT via viral DNA chain termination after incorporation of the nucleoside analogue.
Exacerbations of Hepatitis B:
In clinical trials in non-HIV-infected patients treated with lamivudine for chronic HBV, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. (note from Jules Levin: This exacerbation of hepatitis has also been seen after discontinuation of tenofovir and I think can occur as part of HBV & discontinuation of medicsation). 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 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV 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. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Patients with HIV and Hepatitis B Virus Coinfection: Lamivudine:
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients dually infected with HIV and HBV. In non-HIV-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response (see EPIVIR-HBV package insert for additional information). Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.
Patients co-infected with HIV and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Patients should be advised to discuss any changes in regimen with their physician.
HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in vitro and have also been obtained from patients failing abacavir/lamivudine-containing regimens. Genotypic characterization of abacavir/lamivudine-resistant viruses selected in vitro identified amino acid substitutions M184V/I, K65R, L74V, and Y115F in HIV-1 RT.
Genetic analysis of isolates from patients failing an abacavir-containing regimen demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V in HIV-1 RT contributed to abacavir resistance. Genotypic analysis of isolates recovered from patients failing a lamivudine-containing regimen showed that the resistance was due to the M184V mutation in HIV-1 RT. In a study of therapy-naive adults receiving ZIAGEN 600 mg once daily (n = 384) or 300 mg twice daily (n = 386) in a background regimen of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), the incidence of virologic failure at 48 weeks was similar between the 2 groups (11% in both arms). Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the RT mutations that emerged during abacavir/lamivudine once-daily and twice-daily therapy were K65R, L74V, Y115F, and M184V/I. The abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed mutation in virologic failure isolates from patients receiving abacavir/lamivudine once daily (56,% 10/18) and twice daily (40,% 8/20).
Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a >2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range 0.7 to 13). Fifty-six percent (10/18) of the virologic failure isolates in the once-daily abacavir group compared to 41% (7/17) of the failure isolates in the twice-daily abacavir group had a >2.5-fold decrease in lamivudine susceptibility with median-fold changes of 81 (range 0.79 to >116) and 1.1 (range 0.68 to >116) in the once-daily and twice-daily abacavir arms, respectively.
Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors. Viruses containing abacavir and lamivudine resistance-associated mutations, namely, K65R, L74V, M184V, and Y115F, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine in vitro and in patients. The K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine; and the M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine.
The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the mutations K65R with or without the M184V/I mutation, viruses with L74V plus the M184V/I mutation, and viruses with thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.
Note from Jules Levin: Conversely, failure of tenofovir may result in the K65R mutation developing and this might in theory, because I don't think this sequencing of nukes has been studied in clinical trials, result in reduced susceptibility to abacavir.
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.
Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 patients, 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.
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.
The steady-state pharmacokinetic properties of the EPIVIR 300-mg tablet once daily for 7 days compared to 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 to the 150-mg twice-daily regimen. Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared to 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.
Active ingredients: abacavir sulfate and lamivudine
Inactive ingredients: Each film-coated Epzicom Tablet contains 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.
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