HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use EPIVIR
`safely and effectively. See full prescribing information for EPIVIR.
`EPIVIR (lamivudine) tablets for oral use
`EPIVIR (lamivudine) oral solution
`Initial U.S. Approval: 1995
`
`09/2017
`
`WARNING: EXACERBATIONS OF HEPATITIS B, and DIFFERENT
`FORMULATIONS OF EPIVIR
`See full prescribing information for complete boxed warning.
`(cid:120) 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. (5.1)
`(cid:120) Patients with HIV-1 infection should receive only dosage forms of
`EPIVIR appropriate for treatment of HIV-1. (5.1)
`---------------------------RECENT MAJOR CHANGES ---------------------------
`Boxed Warning
`04/2018
`Dosage and Administration (2.2)
`09/2017
`Warnings and Precautions, Lactic Acidosis and Severe
`04/2018
`Hepatomegaly with Steatosis (5.2)
`Warnings and Precautions, Lower Virologic Suppression
`Rates and Increased Risk of Viral Resistance with Oral
`Solution (5.6)
`Removed –
`Warnings and Precautions, Fat Redistribution (previous
`04/2018
`5.7)
`--------------------------- INDICATIONS AND USAGE----------------------------
`EPIVIR is a nucleoside analogue reverse transcriptase inhibitor indicated in
`combination with other antiretroviral agents for the treatment of HIV-1
`infection.
`Limitations of Use: The dosage of this product is for HIV-1 and not for HBV.
`(1)
`-----------------------DOSAGE AND ADMINISTRATION -----------------------
`(cid:120) Adults: 300 mg daily, administered as either 150 mg twice daily or
`300 mg once daily. (2.1)
`(cid:120) Pediatric Patients Aged 3 Months and Older: Administered either once or
`twice daily. Dose should be calculated on body weight (kg) and should
`not exceed 300 mg daily. (2.2)
`(cid:120) Patients with Renal Impairment: Doses of EPIVIR must be adjusted in
`accordance with renal function. (2.3)
`--------------------- DOSAGE FORMS AND STRENGTHS----------------------
`(cid:120) Tablets: 150 mg, scored (3)
`(cid:120) Tablets: 300 mg (3)
`(cid:120) Oral Solution: 10 mg per mL (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: EXACERBATIONS OF HEPATITIS B, AND
`DIFFERENT FORMULATIONS OF EPIVIR.
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage for Adult Patients
`2.2 Recommended Dosage for Pediatric Patients
`2.3
`Patients with Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Patients with Hepatitis B Virus Co-infection
`5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis
`5.3 Use with Interferon- and Ribavirin-Based Regimens
`5.4
`Pancreatitis
`5.5
`Immune Reconstitution Syndrome
`5.6 Lower Virologic Suppression Rates and Increased Risk of
`Viral Resistance with Oral Solution
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`(cid:120)
`
`------------------------------ CONTRAINDICATIONS ------------------------------
`EPIVIR is contraindicated in patients with previous hypersensitivity reaction
`to lamivudine. (4)
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`(cid:120) Co-infected HIV-1/HBV Patients: Emergence of lamivudine-resistant
`HBV variants associated with lamivudine-containing antiretroviral
`regimens has been reported. (5.1)
`(cid:120) Lactic acidosis and severe hepatomegaly with steatosis, including fatal
`cases, have been reported with the use of nucleoside analogues. (5.2)
`(cid:120) 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. (5.3)
`(cid:120) Pancreatitis: Use with caution in pediatric patients with a history of
`pancreatitis or other significant risk factors for pancreatitis. Discontinue
`treatment as clinically appropriate. (5.4)
`Immune reconstitution syndrome has been reported in patients treated
`with combination antiretroviral therapy. (5.5)
`(cid:120) Lower virologic suppression rates and increased risk of viral resistance
`were observed in pediatric subjects who received EPIVIR oral solution
`concomitantly with other antiretroviral oral solutions compared with
`those who received tablets. An all-tablet regimen should be used when
`possible. (5.6)
`------------------------------ ADVERSE REACTIONS ------------------------------
`(cid:120) The most common reported adverse reactions (incidence greater than or
`equal to 15%) in adults were headache, nausea, malaise and fatigue, nasal
`signs and symptoms, diarrhea, and cough. (6.1)
`(cid:120) The most common reported adverse reactions (incidence greater than or
`equal to 15%) in pediatric subjects were fever and cough. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact ViiV
`Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`------------------------------ DRUG INTERACTIONS-------------------------------
`Sorbitol: Coadministration of lamivudine and sorbitol may decrease
`lamivudine concentrations; when possible, avoid chronic coadministration.
`(7.2)
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`(cid:120) Lactation: Women infected with HIV should be instructed not to
`breastfeed due to potential for HIV transmission. (8.2)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 04/2018
`
`7 DRUG INTERACTIONS
`7.1 Drugs Inhibiting Organic Cation Transporters
`7.2
`Sorbitol
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Lactation
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6
`Patients with Impaired Renal Function
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Adult Subjects
`14.2 Pediatric Subjects
`
`1
`
`Reference ID: 4253947
`
`BMS 2015
`MYLAN v. BMS
`IPR2018-00892
`
`

`

`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: EXACERBATIONS OF HEPATITIS B, and DIFFERENT
`FORMULATIONS OF EPIVIR.
`
`Exacerbations of Hepatitis B
`Severe acute exacerbations of hepatitis B have been reported in patients who are
`co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and
`have discontinued 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 (5.1)].
`Important Differences among Lamivudine-Containing Products
`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 (5.1)].
`
`INDICATIONS AND USAGE
`1
`EPIVIR is a nucleoside analogue indicated in combination with other antiretroviral agents for the
`treatment of human immunodeficiency virus type 1 (HIV-1) infection.
`Limitations of Use:
`The dosage of this product is for HIV-1 and not for HBV.
`(cid:120)
`
`DOSAGE AND ADMINISTRATION
`2
`Recommended Dosage for Adult Patients
`2.1
`The recommended dosage of EPIVIR in HIV-1-infected adults is 300 mg daily, administered as
`either 150 mg taken orally twice daily or 300 mg taken orally once daily with or without food. 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 (5.1)].
`2.2
`Recommended Dosage for Pediatric Patients
`EPIVIR scored tablet is the preferred formulation for HIV-1-infected pediatric patients who
`weigh at least 14 kg and for whom a solid dosage form is appropriate. Before prescribing
`EPIVIR scored tablets, pediatric patients should be assessed for the ability to swallow tablets.
`For patients unable to safely and reliably swallow EPIVIR tablets, the oral solution formulation
`may be prescribed [see Warnings and Precautions (5.6)]. The recommended oral dosage of
`EPIVIR tablets for HIV-1-infected pediatric patients is presented in Table 1.
`
`Reference ID: 4253947
`
`2
`
`

`

`Table 1. Dosing Recommendations for EPIVIR Scored (150-mg) Tablets in Pediatric
`Patients
`
`Twice-Daily Dosing Regimen Using Scored 150-mg
`Tablet
`
`Weight
`(kg)
`14 to <20
`
`(cid:116)20 to <25
`
`PM Dose
`AM Dose
`½ tablet (75 mg) ½ tablet (75 mg)
`
`Total Daily Dose
`150 mg
`
`½ tablet (75 mg)
`
`1 tablet (150 mg)
`
`225 mg
`
`Once-Daily
`Dosing
`Regimena
`1 tablet
`(150 mg)
`1½ tablets
`(225 mg)
`2 tablets
`(cid:116)25
`300 mg
`1 tablet (150 mg)
`1 tablet (150 mg)
`(300 mg)b
`a Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from
`twice-daily dosing to once-daily dosing after 36 weeks of treatment [see Clinical Studies
`(14.2)].
`b Patients may alternatively take one 300-mg tablet, which is not scored.
`Oral Solution
`The recommended dosage of EPIVIR oral solution in HIV-1-infected pediatric patients aged
`3 months and older is 5 mg per kg taken orally twice daily or 10 mg per kg taken orally once
`daily (up to a maximum of 300 mg daily), administered in combination with other antiretroviral
`agents [see Clinical Pharmacology (12.3)]. Consider HIV-1 viral load and CD4+ cell
`count/percentage when selecting the dosing interval for patients initiating treatment with oral
`solution [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].
`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 (Greater than or
`Equal to 25 kg) in Accordance with Creatinine Clearance
`Creatinine Clearance
`(mL/min)
`
`Recommended Dosage of EPIVIR
`150 mg twice daily or 300 mg once daily
`150 mg once daily
`150 mg first dose, then 100 mg once daily
`150 mg first dose, then 50 mg once daily
`50 mg first dose, then 25 mg once daily
`
`(cid:116)50
`30-49
`15-29
`5-14
`<5
`
`No additional dosing of EPIVIR is required after routine (4-hour) hemodialysis or peritoneal
`dialysis.
`
`Reference ID: 4253947
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`3
`
`

`

`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.
`
`DOSAGE FORMS AND STRENGTHS
`3
`EPIVIR Scored Tablets
`(cid:120)
`EPIVIR scored tablets contain 150 mg of lamivudine. The tablets are white, diamond-shaped,
`scored, film-coated tablets debossed with “GX CJ7” on both sides.
`EPIVIR Tablets
`(cid:120)
`EPIVIR tablets contain 300 mg of lamivudine. The tablets are gray, modified diamond-shaped,
`film-coated, and engraved with “GX EJ7” on one side and plain on the reverse side.
`EPIVIR Oral Solution
`(cid:120)
`EPIVIR oral solution contains 10 mg of lamivudine per 1 mL. The solution is a clear, colorless
`to pale yellow, strawberry-banana flavored liquid.
`
`CONTRAINDICATIONS
`4
`EPIVIR is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.
`
`WARNINGS AND PRECAUTIONS
`5
`Patients with Hepatitis B Virus Co-infection
`5.1
`Posttreatment Exacerbations of Hepatitis
`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.
`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
`
`Reference ID: 4253947
`
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`
`

`

`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, or another product
`containing the higher dose of lamivudine should be used as part of an appropriate combination
`regimen.
`Emergence of Lamivudine-Resistant HBV
`Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B
`in subjects dually infected with HIV-1 and HBV (see full prescribing information for
`EPIVIR-HBV). Emergence of hepatitis B virus variants associated with resistance to lamivudine
`has also been reported in HIV-1-infected subjects who have received lamivudine-containing
`antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.
`5.2
`Lactic Acidosis and Severe Hepatomegaly with Steatosis
`Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported
`with the use of nucleoside analogues, including EPIVIR. A majority of these cases have been in
`women. Female sex and obesity may be risk factors for the development of lactic acidosis and
`severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues.
`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.
`5.3
`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 greater than
`6). See the full prescribing information for interferon and ribavirin.
`5.4
`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,
`
`Reference ID: 4253947
`
`5
`
`

`

`symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions
`(6.1)].
`Immune Reconstitution Syndrome
`5.5
`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 systems respond may develop an inflammatory response to
`indolent or residual opportunistic infections (such as Mycobacterium avium infection,
`cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may
`necessitate further evaluation and treatment.
`Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome)
`have also been reported to occur in the setting of immune reconstitution, however, the time to
`onset is more variable, and can occur many months after initiation of treatment.
`5.6
`Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with
`Oral Solution
`Pediatric subjects who received EPIVIR oral solution (at weight band-based doses
`approximating 8 mg per kg per day) concomitantly with other antiretroviral oral solutions at any
`time in the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine
`exposure, and developed viral resistance more frequently than those receiving EPIVIR tablets
`[see Clinical Pharmacology (12.3), Microbiology (12.4), Clinical Studies (14.2)].
`EPIVIR scored tablet is the preferred formulation for HIV-1-infected pediatric patients who
`weigh at least 14 kg and for whom a solid dosage form is appropriate. An all-tablet regimen
`should be used when possible to avoid a potential interaction with sorbitol [see Clinical
`Pharmacology (12.3)]. Consider more frequent monitoring of HIV-1 viral load when treating
`with EPIVIR oral solution.
`
`ADVERSE REACTIONS
`6
`The following adverse reactions are discussed in other sections of the labeling:
`(cid:120) Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1)].
`(cid:120) Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions
`(5.2)].
`(cid:120) Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see Warnings
`and Precautions (5.3)].
`(cid:120) Pancreatitis [see Warnings and Precautions (5.4)].
`Immune reconstitution syndrome [see Warnings and Precautions (5.5)].
`(cid:120)
`
`Reference ID: 4253947
`
`6
`
`

`

`Clinical Trials Experience
`6.1
`Clinical Trials Experience in Adult Subjects
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared with rates in the clinical
`trials of another drug and may not reflect the rates observed in clinical practice.
`The safety profile of EPIVIR in adults is primarily based on 3,568 HIV-1-infected subjects in
`7 clinical trials.
`The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and
`symptoms, diarrhea, and cough.
`Selected clinical adverse reactions in greater than or equal to 5% of subjects during therapy with
`EPIVIR 150 mg twice daily plus RETROVIR 200 mg 3 times daily for up to 24 weeks are listed
`in Table 3.
`
`Table 3. Selected Clinical Adverse Reactions (Greater than or Equal to 5% Frequency)
`in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)
`EPIVIR 150 mg
`Twice Daily
`plus RETROVIR
`(n = 251)
`
`RETROVIRa
`(n = 230)
`
`Adverse Reaction
`Body as a Whole
`Headache
`Malaise & fatigue
`Fever or chills
`Digestive
`Nausea
`Diarrhea
`Nausea & vomiting
`Anorexia and/or decreased appetite
`Abdominal pain
`Abdominal cramps
`Dyspepsia
`Nervous System
`Neuropathy
`Insomnia & other sleep disorders
`Dizziness
`Depressive disorders
`Respiratory
`Nasal signs & symptoms
`
`Reference ID: 4253947
`
`7
`
`35%
`27%
`10%
`
`33%
`18%
`13%
`10%
`9%
`6%
`5%
`
`12%
`11%
`10%
`9%
`
`20%
`
`27%
`23%
`12%
`
`29%
`22%
`12%
`7%
`11%
`3%
`5%
`
`10%
`7%
`4%
`4%
`
`11%
`
`

`

`18%
`
`9%
`
`13%
`
`6%
`
`10%
`6%
`5%
`
`Cough
`Skin
`Skin rashes
`Musculoskeletal
`12%
`Musculoskeletal pain
`8%
`Myalgia
`5%
`Arthralgia
`a Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
`Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received
`EPIVIR in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002,
`NUCB3002, and NUCB3007 [see Warnings and Precautions (5.4)].
`EPIVIR 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in
`subjects receiving EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug
`combination regimens in EPV20001 and EPV40001) for 48 weeks were similar.
`Selected laboratory abnormalities observed during therapy are summarized in Table 4.
`
`Table 4. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Adults in Four
`24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)
`and a Clinical Endpoint Trial (NUCB3007)
`24-Week Surrogate Endpoint
`Trialsa
`
`Test
`(Threshold Level)
`Absolute neutrophil count
`(<750/mm3)
`2.9%
`Hemoglobin (<8.0 g/dL)
`Platelets (<50,000/mm3)
`0.4%
`3.7%
`ALT (>5.0 x ULN)
`1.7%
`AST (>5.0 x ULN)
`0.8%
`Bilirubin (>2.5 x ULN)
`4.2%
`Amylase (>2.0 x ULN)
`a The median duration on study was 12 months.
`b Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
`c Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus
`zalcitabine.
`ULN = Upper limit of normal.
`ND = Not done.
`
`1.8%
`1.3%
`3.6%
`1.8%
`0.4%
`1.5%
`
`2.2%
`2.8%
`3.8%
`4.0%
`ND
`2.2%
`
`3.4%
`3.8%
`1.9%
`2.1%
`ND
`1.1%
`
`Reference ID: 4253947
`
`8
`
`Clinical Endpoint
`Triala
`EPIVIR
`plus
`Current
`Therapyc
`15%
`
`Placebo
`plus
`Current
`Therapyc
`13%
`
`EPIVIR plus
`RETROVIR RETROVIRb
`7.2%
`5.4%
`
`

`

`The frequencies of selected laboratory abnormalities reported in subjects receiving EPIVIR
`300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in
`EPV20001 and EPV40001) were similar.
`Clinical Trials Experience in Pediatric Subjects
`EPIVIR oral solution has been studied in 638 pediatric subjects aged 3 months to 18 years in
`3 clinical trials.
`Selected clinical adverse reactions and physical findings with a greater than or equal to 5%
`frequency during therapy with EPIVIR 4 mg per kg twice daily plus RETROVIR 160 mg per m2
`3 times daily in therapy-naive (less than or equal to 56 days of antiretroviral therapy) pediatric
`subjects are listed in Table 5.
`
`Table 5. Selected Clinical Adverse Reactions and Physical Findings (Greater than or
`Equal to 5% Frequency) in Pediatric Subjects in Trial ACTG300
`EPIVIR plus
`RETROVIR
`(n = 236)
`
`Didanosine
`(n = 235)
`
`Adverse Reaction
`Body as a Whole
`Fever
`Digestive
`Hepatomegaly
`Nausea & vomiting
`Diarrhea
`Stomatitis
`Splenomegaly
`Respiratory
`Cough
`Abnormal breath sounds/wheezing
`Ear, Nose, and Throat
`Signs or symptoms of earsa
`Nasal discharge or congestion
`Other
`12%
`Skin rashes
`9%
`Lymphadenopathy
`a Includes pain, discharge, erythema, or swelling of an ear.
`Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral
`nucleoside-experienced pediatric subjects receiving EPIVIR alone or in combination with other
`antiretroviral agents. In an open-label dose-escalation trial (NUCA2002), 14 subjects (14%)
`developed pancreatitis while receiving monotherapy with EPIVIR. Three of these subjects died
`of complications of pancreatitis. In a second open-label trial (NUCA2005), 12 subjects (18%)
`
`25%
`
`11%
`8%
`8%
`6%
`5%
`
`15%
`7%
`
`7%
`8%
`
`32%
`
`11%
`7%
`6%
`12%
`8%
`
`18%
`9%
`
`6%
`11%
`
`14%
`11%
`
`Reference ID: 4253947
`
`9
`
`

`

`developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects
`randomized to EPIVIR plus RETROVIR. Pancreatitis was observed in 1 subject in this trial who
`received open-label EPIVIR in combination with RETROVIR and ritonavir following
`discontinuation of didanosine monotherapy [see Warnings and Precautions (5.4)].
`Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were
`reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and
`2 subjects (less than 1%) in Trial ACTG300.
`Selected laboratory abnormalities experienced by therapy-naive (less than or equal to 56 days of
`antiretroviral therapy) pediatric subjects are listed in Table 6.
`
`Didanosine
`3%
`2%
`3%
`3%
`4%
`3%
`3%
`
`EPIVIR plus
`RETROVIR
`8%
`4%
`1%
`1%
`2%
`3%
`3%
`
`Table 6. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric
`Subjects in Trial ACTG300
`Test
`(Threshold Level)
`Absolute neutrophil count (<400/mm3)
`Hemoglobin (<7.0 g/dL)
`Platelets (<50,000/mm3)
`ALT (>10 x ULN)
`AST (>10 x ULN)
`Lipase (>2.5 x ULN)
`Total Amylase (>2.5 x ULN)
`ULN = Upper limit of normal.
`Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): The safety of once-
`daily compared with twice-daily dosing of EPIVIR was assessed in the ARROW trial. Primary
`safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The
`frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily
`dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis
`in the once-daily cohort was considered as uncertain causality by the investigator and all other
`Grade 3 or 4 adverse events were considered not related by the investigator.
`Neonates: Limited short-term safety information is available from 2 small, uncontrolled trials in
`South Africa in neonates receiving lamivudine with or without zidovudine for the first week of
`life following maternal treatment starting at Week 38 or 36 of gestation [see Clinical
`Pharmacology (12.3)]. Selected adverse reactions reported in these neonates included increased
`liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and
`hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis
`with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes). Two other
`nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant
`had transient renal insufficiency associated with dehydration. The absence of control groups
`limits assessments of causality, but it should be assumed that perinatally exposed infants may be
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`at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected
`patients treated with lamivudine-containing combination regimens. Long-term effects of in utero
`and infant lamivudine exposure are not known.
`6.2
`Postmarketing Experience
`The following adverse reactions have been identified during post-approval use of EPIVIR.
`Because these reactions are reported voluntarily from a population of unknown size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure. These reactions have been chosen for inclusion due to a combination of their
`seriousness, frequency of reporting, or potential causal connection to lamivudine.
`Body as a Whole
`Redistribution/accumulation of body fat.
`Endocrine and Metabolic
`Hyperglycemia.
`General
`Weakness.
`Hemic and Lymphatic
`Anemia (including pure red cell aplasia and severe anemias progressing on therapy).
`Hepatic and Pancreatic
`Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.2)], posttreatment
`exacerbations of hepatitis B [see Warnings and Precautions (5.1)].
`Hypersensitivity
`Anaphylaxis, urticaria.
`Musculoskeletal
`Muscle weakness, CPK elevation, rhabdomyolysis.
`Skin
`Alopecia, pruritus.
`
`DRUG INTERACTIONS
`7
`Drugs Inhibiting Organic Cation Transporters
`7.1
`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) [see Clinical Pharmacology (12.3)]. No data are available
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`regarding interactions with other drugs that have renal clearance mechanisms similar to that of
`lamivudine.
`7.2
`Sorbitol
`Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent
`reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines
`with lamivudine [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Pregnancy Exposure Registry
`There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
`EPIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling
`the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
`Risk Summary
`Available data from the APR show no difference in the overall risk of birth defects for
`lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan
`Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses
`the MACDP as the U.S. reference population for birth defects in the general population. The
`MACDP evaluates women and infants from a limited geographic area and does not include
`outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not
`reported in the APR. The estimated background rate of miscarriage in clinically recognized
`pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth
`defects and miscarriage for the indicated population is unknown.
`In animal reproduction studies, oral administration of lamivudine to pregnant rabbits during
`organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the
`recommended clinical dose; however, no adverse development effects were observed with oral
`administration of lamivudine to pregnant rats during organogenesis at plasma concentrations
`(Cmax) 35 times the recommended clinical dose (see Data).
`Data
`Human Data: Based on prospective reports to the APR of over 11,000 exposures to lamivudine
`during pregnancy resulting in live births (including over 4,500 exposed in the first trimester),
`there was no difference between the overall risk of birth defects for lamivudine compared with
`the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The
`prevalence of defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester
`exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5% to 3.3%) following
`second/third trimester exposure to lamivudine-containing regimens.
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`Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted
`in South Africa. The trials 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 trials were not designed or powered to
`provide efficacy information. Lamivudine concentrations were generally similar in maternal,
`neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens
`were collected following natural rupture of membranes and confirmed that lamivudine crosses
`the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid
`concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal
`serum concentration (n = 8).
`Animal Data: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per
`kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg
`per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]).
`No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses
`producing plasma