Epivir 150 MG Oral Tablet
Generic Name: LAMIVUDINE
Brand Name: EPIVIR
- Substance Name(s):
- LAMIVUDINE
DRUG INTERACTIONS
7 Lamivudine is predominantly eliminated in the urine by active organic cationic secretion.
The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim).
No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Zalcitabine is not recommended for use in combination with EPIVIR.
(7.2) 7.1 Interferon- and Ribavirin-Based Regimens Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3)].
7.2 Zalcitabine Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another.
Therefore, use of lamivudine in combination with zalcitabine is not recommended.
7.3 Trimethoprim/Sulfamethoxazole (TMP/SMX) No change in dose of either drug is recommended.
There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.
7.4 Drugs with No Observed Interactions With EPIVIR A drug interaction study showed no clinically significant interaction between EPIVIR and zidovudine.
OVERDOSAGE
10 There is no known antidote for EPIVIR.
One case of an adult ingesting 6 g of EPIVIR was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal.
Two cases of pediatric overdose were reported in Study ACTG300.
One case involved a single dose of 7 mg/kg of EPIVIR; the second case involved use of 5 mg/kg of EPIVIR twice daily for 30 days.
There were no clinical signs or symptoms noted in either case.
Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.
If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.
DESCRIPTION
11 EPIVIR (also known as 3TC) is a brand name for lamivudine, a synthetic nucleoside analogue with activity against HIV-1 and HBV.
The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one.
Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine.
Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine.
It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3.
It has the following structural formula: Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C.
EPIVIR Tablets are for oral administration.
Each scored 150-mg film-coated tablet contains 150 mg of lamivudine and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
Each 300-mg film-coated tablet contains 300 mg of lamivudine and the inactive ingredients black iron oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
EPIVIR Oral Solution is for oral administration.
One milliliter (1 mL) of EPIVIR Oral Solution contains 10 mg of lamivudine (10 mg/mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg).
lamivudine structural formula
CLINICAL STUDIES
14 The use of EPIVIR is based on the results of clinical studies in HIV-1-infected patients in combination regimens with other antiretroviral agents.
Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.
14.1 Adults Clinical Endpoint Study: NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled study comparing continued current therapy (zidovudine alone [62% of patients] or zidovudine with didanosine or zalcitabine [38% of patients]) to the addition of EPIVIR or EPIVIR plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1.
A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells/mm3 (median = 122 cells/mm3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive.
The median duration on study was 12 months.
Results are summarized in Table 8.
Table 8.
Number of Patients (%) With at Least One HIV-1 Disease Progression Event or Death Endpoint Current Therapy (n = 460) EPIVIR plus Current Therapy (n = 896) EPIVIR plus an NNRTIa plus Current Therapy (n = 460) HIV progression or death 90 (19.6%) 86 (9.6%) 41 (8.9%) Death 27 (5.9%) 23 (2.6%) 14 (3.0%) a An investigational non-nucleoside reverse transcriptase inhibitor not approved in the United States.
Surrogate Endpoint Studies: Dual Nucleoside Analogue Studies: Principal clinical trials in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine.
These studies demonstrated the antiviral effect of lamivudine in a 2-drug combination.
More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.
Dose Regimen Comparison Surrogate Endpoint Studies in Therapy-Naive Adults: EPV20001 was a multi-center, double-blind, controlled study in which patients were randomized 1:1 to receive EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily.
A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm3 (median = 362 cells/mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL.
Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9.
Figure 2.
Virologic Response Through Week 48, EPV20001ab(Intent-to-Treat) a Roche AMPLICOR HIV-1 MONITOR.
bResponders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit.
Table 9.
Outcomes of Randomized Treatment Through 48 Weeks (Intent-to-Treat) Outcome EPIVIR 300 mg Once Daily plus RETROVIR plus Efavirenz (n = 278) EPIVIR 150 mg Twice Daily plus RETROVIR plus Efavirenz (n = 276) Respondera 67% 65% Virologic failureb 8% 8% Discontinued due to clinical progression <1% 0% Discontinued due to adverse events 6% 12% Discontinued due to other reasonsc 18% 14% a Achieved confirmed plasma HIV-1 RNA <400 copies/mL and maintained through 48 weeks.
b Achieved suppression but rebounded by Week 48, discontinued due to virologic failure, insufficient viral response according to the investigator, or never suppressed through Week 48.
c Includes consent withdrawn, lost to followup, protocol violation, data outside the study-defined schedule, and randomized but never initiated treatment.
The proportions of patients with HIV-1 RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for patients receiving EPIVIR 300 mg once daily and 63% for patients receiving EPIVIR 150 mg twice daily.
Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in patients receiving EPIVIR 300 mg once daily and 146 cells/mm3 for patients receiving EPIVIR 150 mg twice daily.
A small, randomized, open-label pilot study, EPV40001, was conducted in Thailand.
A total of 159 treatment-naive adult patients (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm3, median plasma HIV-1 RNA 4.8 log10 copies/mL) were enrolled.
Two of the treatment arms in this study provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily.
In intent-to-treat analyses of 48-week data, the proportions of patients with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group.
14.2 Pediatric Patients Clinical Endpoint Study: ACTG300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR plus RETROVIR (zidovudine) with didanosine monotherapy.
A total of 471 symptomatic, HIV-1-infected therapy-naive (≤56 days of antiretroviral therapy) pediatric patients were enrolled in these 2 treatment arms.
The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian.
The mean baseline CD4+ cell count was 868 cells/mm3 (mean: 1,060 cells/mm3 and range: 0 to 4,650 cells/mm3 for patients ≤5 years of age; mean: 419 cells/mm3 and range: 0 to 1,555 cells/mm3 for patients >5 years of age) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL.
The median duration on study was 10.1 months for the patients receiving EPIVIR plus RETROVIR and 9.2 months for patients receiving didanosine monotherapy.
Results are summarized in Table 10.
Table 10.
Number of Patients (%) Reaching a Primary Clinical Endpoint (Disease Progression or Death) Endpoint EPIVIR plus RETROVIR (n = 236) Didanosine (n = 235) HIV disease progression or death (total) 15 (6.4%) 37 (15.7%) Physical growth failure 7 (3.0%) 6 (2.6%) Central nervous system deterioration 4 (1.7%) 12 (5.1%) CDC Clinical Category C 2 (0.8%) 8 (3.4%) Death 2 (0.8%) 11 (4.7%) Figure 2.
Virologic Response Through Week 48, EPV20001ab (Intent-to-Treat)
HOW SUPPLIED
16 /STORAGE AND HANDLING EPIVIR Scored Tablets, 150 mg White, diamond-shaped, scored, film-coated tablets debossed with “GX CJ7” on both sides.
EPIVIR Tablets, 300 mg Gray, modified diamond-shaped, film-coated tablets engraved with “GX EJ7” on one side and plain on the reverse side.
Recommended Storage: Store EPIVIR Tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
EPIVIR Oral Solution, 10 mg/mL A clear, colorless to pale yellow, strawberry-banana-flavored liquid, contains 10 mg of lamivudine in each 1 mL.
Recommended Storage: Store in tightly closed bottles at 25°C (77°F) [see USP Controlled Room Temperature].
This product is supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod.
Code 53808-0245-1 150 mg 30 Tablets in a Blister Pack WHITE 0173-0470 53808-0246-1 300 mg 30 Tablets in a Blister Pack GRAY 0173-0714 Manufactured under agreement from Shire Pharmaceuticals Group plc Basingstoke, UK GlaxoSmithKline Research Triangle Park, NC 27709 Made in Singapore This Product was Repackaged By: State of Florida DOH Central Pharmacy 104-2 Hamilton Park Drive Tallahassee, FL 32304 United States
RECENT MAJOR CHANGES
Dosage and Administration, Pediatric Patients (2.2) February 2008
GERIATRIC USE
8.5 Geriatric Use Clinical studies of EPIVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
DOSAGE FORMS AND STRENGTHS
3 EPIVIR Scored Tablets 150 mg, are white, diamond-shaped, scored, film-coated tablets debossed with “GX CJ7” on both sides.
EPIVIR Tablets 300 mg, are gray, modified diamond-shaped, film-coated tablets engraved with “GX EJ7” on one side and plain on the reverse side.
EPIVIR Oral Solution A clear, colorless to pale yellow, strawberry-banana flavored liquid, containing 10 mg of lamivudine per 1 mL.
Tablets: 300 mg (3) Tablets: Scored 150 mg (3) Oral Solution: 10 mg/mL (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Lamivudine is an antiviral agent [see Clinical Pharmacology (12.4)].
INDICATIONS AND USAGE
1 EPIVIR is a nucleoside analogue indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection.
Limitation of use: The dosage of this product is for HIV-1 and not for HBV.
EPIVIR is a nucleoside analogue reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Limitation of Use: The dosage of this product is for HIV-1 and not for HBV.
(1)
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of twice-daily EPIVIR in combination with other antiretroviral agents have been established in pediatric patients 3 months and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)].
PREGNANCY
8.1 Pregnancy Pregnancy Category C.
There are no adequate and well-controlled studies of EPIVIR in pregnant women.
Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity.
Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans.
EPIVIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical studies conducted in South Africa.
The study assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals.
These studies were not designed or powered to provide efficacy information.
Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women.
Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.
In a subset of subjects, lamivudine amniotic fluid specimens were collected following natural rupture of membranes.
Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily).
It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients.
Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine.
Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans.
However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans.
Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus [see Nonclinical Toxicology (13.2)].
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established.
Physicians are encouraged to register patients by calling 1-800-258-4263.
NUSRING MOTHERS
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
Because of the potential for serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine.
Lamivudine is excreted into human milk.
Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.
BOXED WARNING
WARNING: RISK OF LACTIC ACIDOSIS, EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS UPON DISCONTINUATION OF EPIVIR , DIFFERENT FORMULATIONS OF EPIVIR.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals.
Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.1)].
Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued EPIVIR.
Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPIVIR and are co-infected with HIV-1 and HBV.
If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.2)].
EPIVIR Tablets and Oral Solution (used to treat HIV-1 infection) contain a higher dose of the active ingredient (lamivudine) than EPIVIR-HBV® Tablets and Oral Solution (used to treat chronic HBV infection).
Patients with HIV-1 infection should receive only dosage forms appropriate for treatment of HIV-1 [see Warnings and Precautions (5.2)] .
WARNING: LACTIC ACIDOSIS, POSTTREATMENT EXACERBATIONS OF HEPATITIS B IN CO-INFECTED PATIENTS, DIFFERENT FORMULATIONS OF EPIVIR See full prescribing information for complete boxed warning Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues.
Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.
(5.1) Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued EPIVIR.
Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment.
(5.2) Patients with HIV-1 infection should receive only dosage forms of EPIVIR appropriate for treatment of HIV-1.
(5.2)
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Lactic acidosis and severe hepatomegaly with steatosis: Reported with the use of nucleoside analogues.
Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatoxicity occur.
(5.1) Severe acute exacerbations of hepatitis: Reported in patients who are co-infected with hepatitis B virus and HIV-1 and discontinued EPIVIR.
Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment.
(5.2) Patients with HIV-1 infection should receive only dosage forms of EPIVIR appropriate for treatment of HIV-1.
(5.2) Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported.
(5.2) Emtricitabine should not be administered concomitantly with lamivudine-containing products.
(5.3) Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based regimens.
Monitor for treatment-associated toxicities.
Discontinue EPIVIR as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both.
(5.4) Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis.
Discontinue treatment as clinically appropriate.
(5.5) Immune reconstitution syndrome (5.6) and redistribution/accumulation of body fat (5.7) have been reported in patients treated with combination antiretroviral therapy.
5.1 Lactic Acidosis/Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals.
A majority of these cases have been in women.
Obesity and prolonged nucleoside exposure may be risk factors.
Particular caution should be exercised when administering EPIVIR to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors.
Treatment with EPIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
5.2 Patients With HIV-1 and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis: In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine.
These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA.
Although most events appear to have been self-limited, fatalities have been reported in some cases.
Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV.
The causal relationship to discontinuation of lamivudine treatment is unknown.
Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.
There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.
Important Differences Among Lamivudine-Containing Products: EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than EPIVIR-HBV Tablets and EPIVIR-HBV Oral Solution.
EPIVIR-HBV was developed for patients with chronic hepatitis B.
The formulation and dosage of lamivudine in EPIVIR-HBV are not appropriate for patients co-infected with HIV-1 and HBV.
Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV.
If treatment with EPIVIR-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment.
If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, EPIVIR Tablets, EPIVIR Oral Solution, COMBIVIR® (lamivudine/zidovudine) Tablets, EPZICOM® (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR® (abacavir sulfate, lamivudine, and zidovudine) Tablets should be used as part of an appropriate combination regimen.
Emergence of Lamivudine-Resistant HBV: In non–HIV-1-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 full prescribing information for EPIVIR-HBV for additional information).
Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.
5.3 Use With Other Lamivudine- and Emtricitabine-Containing Products EPIVIR should not be administered concomitantly with other lamivudine-containing products including EPIVIR-HBV Tablets, EPIVIR Oral Solution, COMBIVIR (lamivudine/zidovudine) Tablets, EPZICOM (abacavir sulfate and lamivudine) Tablets, or TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine) or emtricitabine-containing products, including ATRIPLA® (efavirenz, emtricitabine, and tenofovir), EMTRIVA® (emtricitabine), or TRUVADA® (emtricitabine and tenofovir).
5.4 Use With Interferon- and Ribavirin-Based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine.
Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin.
Patients receiving interferon alfa with or without ribavirin and EPIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation.
Discontinuation of EPIVIR should be considered as medically appropriate.
Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6).
See the complete prescribing information for interferon and ribavirin.
5.5 Pancreatitis In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, EPIVIR should be used with caution.
Treatment with EPIVIR should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].
5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPIVIR.
During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
5.7 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION 17.1 Advice for the Patient Information About Therapy With EPIVIR: EPIVIR is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.
Patients should remain under the care of a physician when using EPIVIR.
Patients should be advised that the use of EPIVIR has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
Patients should be advised that the long-term effects of EPIVIR are unknown at this time.
Patients should be advised of the importance of taking EPIVIR with combination therapy on a regular dosing schedule and to avoid missing doses.
EPIVIR should not be coadministered with drugs containing lamivudine or emtricitabine, including COMBIVIR (lamivudine/zidovudine) Tablets, EPZICOM (abacavir sulfate and lamivudine) Tablets, TRIZIVIR (abacavir sulfate, lamivudine, and zidovudine), ATRIPLA (efavirenz, emtricitabine, and tenofovir), EMTRIVA (emtricitabine) or TRUVADA (emtricitabine and tenofovir) [see Warnings and Precautions (5.3)].
Redistribution/Accumulation of Body Fat: Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including EPIVIR, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.7)].
Differences in Formulations of EPIVIR: Patients should be advised that EPIVIR Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) as EPIVIR-HBV Tablets and Oral Solution.
If a decision is made to include lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of lamivudine in EPIVIR (not EPIVIR-HBV) should be used [see Warnings and Precautions (5.2)].
Co-infection With HIV-1 and HBV: Patients co-infected with HIV-1 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 [see Warnings and Precautions (5.2)].
Risk of Pancreatitis: Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)].
Sucrose Content of EPIVIR Oral Solution: Diabetic patients should be advised that each 15-mL dose of EPIVIR Oral Solution contains 3 grams of sucrose [see Description (11)].
COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, and TRIZIVIR are registered trademarks of GlaxoSmithKline.
ATRIPLA, EMTRIVA, and TRUVADA are trademarks of their respective owners and are not trademarks of GlaxoSmithKline.
The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.
DOSAGE AND ADMINISTRATION
2 Adults and adolescents >16 years of age: 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily.
(2.1) Pediatric patients 3 months up to 16 years of age: Dosage should be based on body weight.
(2.2) Patients With Renal Impairment: Doses of EPIVIR must be adjusted in accordance with renal function.
(2.3) 2.1 Adults and Adolescents >16 years of age The recommended oral dose of EPIVIR in HIV-1-infected adults and adolescents >16 years of age is 300 mg daily, administered as either 150 mg twice daily or 300 mg once daily, in combination with other antiretroviral agents.
If lamivudine is administered to a patient infected with HIV-1 and HBV, the dosage indicated for HIV-1 therapy should be used as part of an appropriate combination regimen [see Warnings and Precautions (5.2)].
2.2 Pediatric Patients The recommended oral dose of EPIVIR Oral Solution in HIV-1-infected pediatric patients 3 months to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day), administered in combination with other antiretroviral agents.
EPIVIR is also available as a scored tablet for HIV-1-infected pediatric patients who weigh ≥14 kg and for whom a solid dosage form is appropriate.
Before prescribing EPIVIR Tablets, children should be assessed for the ability to swallow tablets.
If a child is unable to reliably swallow EPIVIR Tablets, the oral solution formulation should be prescribed.
The recommended oral dosage of EPIVIR Tablets for HIV-1-infected pediatric patients is presented in Table 1.
Table 1.
Dosing Recommendations for EPIVIR Tablets in Pediatric Patients Weight (kg) Dosage Regimen Using Scored 150-mg Tablet Total Daily Dose AM Dose PM Dose 14 to 21 ½ tablet (75 mg) ½ tablet (75 mg) 150 mg >21 to <30 ½ tablet (75 mg) 1 tablet (150 mg) 225 mg ≥30 1 tablet (150 mg) 1 tablet (150 mg) 300 mg 2.3 Patients With Renal Impairment Dosing of EPIVIR is adjusted in accordance with renal function.
Dosage adjustments are listed in Table 2 [see Clinical Pharmacology (12.3)].
Table 2.
Adjustment of Dosage of EPIVIR in Adults and Adolescents (≥30 kg) in Accordance With Creatinine Clearance Creatinine Clearance (mL/min) Recommended Dosage of EPIVIR ≥50 150 mg twice daily or 300 mg once daily 30-49 150 mg once daily 15-29 150 mg first dose, then 100 mg once daily 5-14 150 mg first dose, then 50 mg once daily <5 50 mg first dose, then 25 mg once daily No additional dosing of EPIVIR is required after routine (4-hour) hemodialysis or peritoneal dialysis.
Although there are insufficient data to recommend a specific dose adjustment of EPIVIR in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.