Lamivudine (Page 2 of 7)

5.1 Patients with Hepatitis B Virus Co-infection

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

Lamivudine tablets 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, lamivudine 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 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.

5.3 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, 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)].

5.4 Immune Reconstitution Syndrome

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.

5.5 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 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 EPIVIR oral solution.

6 ADVERSE REACTIONS

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 BOXED WARNING, WARNINGS AND PRECAUTIONS (5.2)].
  • Pancreatitis [see WARNINGS AND PRECAUTIONS (5.3)].
  • Immune reconstitution syndrome[see WARNINGS AND PRECAUTIONS (5.4)].

6.1 Clinical Trials Experience

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)

a Either zidovudine monotherapy or zidovudine in combination with zalcitabine.

Adverse Reaction Lamivudine 150 mg Twice Daily plus RETROVIR ( n = 251 ) RETROVIRa ( n = 230 )
Body as a Whole
Headache 35% 27%
Malaise & fatigue 27% 23%
Fever or chills 10% 12%
Digestive
Nausea 33% 29%
Diarrhea 18% 22%
Nausea & vomiting 13% 12%
Anorexia and/or decreased appetite 10% 7%
Abdominal pain 9% 11%
Abdominal cramps 6% 3%
Dyspepsia 5% 5%
Nervous System
Neuropathy 12% 10%
Insomnia & other sleep disorders 11% 7%
Dizziness 10% 4%
Depressive disorders 9% 4%
Respiratory
Nasal signs & symptoms 20% 11%
Cough 18% 13%
Skin
Skin rashes 9% 6%
Musculoskeletal
Musculoskeletal pain 12% 10%
Myalgia 8% 6%
Arthralgia 5% 5%

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 to 4 Laboratory Abnormalities in Adults in Four 24-Week Surrogate Endpoint Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical Endpoint Trial (NUCB3007)

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.

24-Week Surrogate Endpoint Trialsa Clinical Endpoint Triala
Test (Threshold Level) 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%
Platelets (<50,000/mm3) 0.4% 1.3% 2.8% 3.8%
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%

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

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

a Includes pain, discharge, erythema, or swelling of an ear.

Adverse Reaction Lamivudine plus RETROVIR ® ( n = 236 ) Didanosine ( n = 235 )
Body as a Whole
Fever 25% 32%
Digestive
Hepatomegaly 11% 11%
Nausea & vomiting 8% 7%
Diarrhea 8% 6%
Stomatitis 6% 12%
Splenomegaly 5% 8%
Respiratory
Cough 15% 18%
Abnormal breath sounds/wheezing 7% 9%
Ear , Nose , and Throat
Signs or symptoms of earsa 7% 6%
Nasal discharge or congestion 8% 11%
Other
Skin rashes 12% 14%
Lymphadenopathy 9% 11%

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 to 4 Laboratory Abnormalities in Pediatric Subjects in Trial ACTG300

ULN = Upper limit of normal.

Test (Threshold Level) Lamivudine plus RETROVIR Didanosine
Absolute neutrophil count (<400/mm3) 8% 3%
Hemoglobin (<7 g/dL) 4% 2%
Platelets (<50,000/mm3) 1% 3%
ALT (>10 x ULN) 1% 3%
AST (>10 x ULN) 2% 4%
Lipase (>2.5 x ULN) 3% 3%
Total Amylase (>2.5 x ULN) 3% 3%

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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