Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine. 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 lamivudine 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.
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, lamivudine should be used with caution. Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine. 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.
Pediatric subjects who received lamivudine 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 lamivudine tablets [see Clinical Pharmacology (12.3), Microbiology (12.4), Clinical Studies (14.2)].
Lamivudine 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 lamivudine oral solution.
The following adverse reactions are discussed in other sections of the labeling:
• Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.1)].
• Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.2)].
• Pancreatitis [see Warnings and Precautions (5.3)].
• Immune reconstitution syndrome [see Warnings and Precautions (5.4)].
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 lamivudine 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 lamivudine 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)
|Adverse Reaction||LAMIVUDINE 150 mg Twice Daily plus RETROVIR (n = 251)||RETROVIRa (n = 230)|
|Body as a Whole|
|Malaise & fatigue||27%||23%|
|Fever or chills||10%||12%|
|Nausea & vomiting||13%||12%|
|Anorexia and/or decreased appetite||10%||7%|
|Insomnia & other sleep disorders||11%||7%|
|Nasal signs & symptoms||20%||11%|
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 lamivudine in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.4)].
Lamivudine 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving lamivudine 300 mg once daily or lamivudine 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)
|Test (Threshold Level)||24-Week Surrogate Endpoint Trialsa||Clinical Endpoint Triala|
|LAMIVUDINE plus RETROVIR||RETROVIRb||LAMIVUDINE plus Current Therapyc||Placebo plus Current Therapyc|
|Absolute neutrophil count (<750/mm3)||7.2%||5.4%||15%||13%|
|Hemoglobin (<8.0 g/dL)||2.9%||1.8%||2.2%||3.4%|
|ALT (>5.0 x ULN)||3.7%||3.6%||3.8%||1.9%|
|AST (>5.0 x ULN)||1.7%||1.8%||4.0%||2.1%|
|Bilirubin (>2.5 x ULN)||0.8%||0.4%||ND||ND|
|Amylase (>2.0 x ULN)||4.2%||1.5%||2.2%||1.1%|
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.
The frequencies of selected laboratory abnormalities reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.
Clinical Trials Experience in Pediatric Subjects
Lamivudine 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 lamivudine 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
|Adverse Reaction||LAMIVUDINE plus RETROVIR (n = 236)||Didanosine (n = 235)|
|Body as a Whole|
|Nausea & vomiting||8%||7%|
|Abnormal breath sounds/wheezing||7%||9%|
|Ear, Nose, and Throat|
|Signs or symptoms of earsa||7%||6%|
|Nasal discharge or congestion||8%||11%|
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 lamivudine 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 lamivudine. Three of these subjects died of complications of pancreatitis. In a second open-label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to lamivudine plus RETROVIR. Pancreatitis was observed in 1 subject in this trial who received open-label lamivudine 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.
Table 6. Frequencies of Selected Grade 3-4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300
|Test (Threshold Level)||LAMIVUDINE plus RETROVIR||Didanosine|
|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)||8% 4%1%1%2%3%3%||3%2%3%3%4%3%3%|
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 lamivudine 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 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.
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