Lamivudine (Page 2 of 7)

5.3 Use With Other Lamivudine- and Emtricitabine-Containing Products

Lamivudine should not be administered concomitantly with other lamivudine- containing products including EPIVIR-HBV Tablets,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), or COMPLERA TM (rilpivirine/emtricitabine/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-l/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-l/HCV co-infected patients [see Clinical Pharmacology (12.3) ], hepatic decompensation (some fatal) has occurred in HIV-l/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 lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine 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, 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)] .

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretrovira1 therapy, including lamivudine. 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. 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.

5.7 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.

 

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:
• Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)].
• Severe acute exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.2)].
• Hepatic decompensation in patients co-infected with HIV-l and Hepatitis C [see Warnings and Precautions (5.4)]. • Pancreatitis [see Warnings and Precautions (5.5)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults — Clinical Trials in HIV-1: The safety profile of lamivudine in adults is primarily based on 3,568 HIV-l-infected patients 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 of in ≥5% of patients during therapy with lamivudine 150 mg twice daily plus zidovudine 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Table 3. Selected Clinical Adverse Reactions (≥5% Frequency) in Four Controlled Clinical Trials (NUCA3001, NUCA3002, NUCB3001, NUCB3002)

Adverse Reaction Lamivudine 150 mg Twice Daily plus Zidovudine (n = 251) Zidovudine a (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%

a Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult patients (0.3%) who received lamivudine in the controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see Warnings and Precautions (5.5)].
Lamivudine 300 mg Once Daily : The types and frequencies of clinical adverse reactions reported in patients receiving lamivudine 300 mg once daily or lamivudine
150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for48 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 Studies (NUCA3001, NUCA3002, NUCB3001, NUCB3002) and a Clinical End point Study (NUCB3007)

Test (Threshold Level) 24-Week Surogate Endpoint Studies a Clinical Endpoint Study a
Lamivudine plus Zidovudine Zidovudine b Lamivudine plus Current Therapy Placebo plus Current Therapy c
Absolute neutrophil count (<750/mm 3) 7.2% 5.4% 15% 13%
Hemoglobin (<8.0 g/dL) 2.9% 1.8% 2.2% 3.4%
Platelets (<50,000/mm 3) 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%

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 didonasine, or zidovudine plus zalcitabine
ULN = Upper limit of normal. ND = Not done.
The frequencies of selected laboratory abnormalities reported in patients receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.

Pediatric Patients — Clinical Trials in HIV-1: Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with lamivudine 4 mg/kg twice daily plus zidovudine 160 mg/m 2 3 times daily in therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 5. Table 5. Seleted Clinical Adverse Reactions and Physical Findings (≥5% frequency) in Pediatric Patients in Study ACTG300

Adverse Reaction Lamivudine plus Zidovudine (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/wheezling 7% 9%
Ear, Nose, and Throat
Signs or symptoms of ears a 7% 6%
Nasal discharge or congestion 8% 11%
Other
Skin rashes 12% 14%
Lymphadenopathy 9% 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 patients receiving lamivudine alone or in combination with other antiretroviral agents. In an open-label dose-escalation study (NUCA2002), 14 patients (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these patients died of complications of pancreatitis. In a second open-label study (NUCA2005), 12 patients (18%) developed pancreatitis. In Study ACTG300, pancreatitis was not observed in 236 patients randomized to lamivudine plus zidovudine. Pancreatitis was observed in 1 patient in this study who received open- label lamivudine in combination with zidovudine and ritonavir following discontinuation of didanosine monotherapy [see Warnings and Precautions (5.5)].

Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 patients (15%) in Study NUCA2002, 6 patients (9%) in Study NUCA2005, and 2 patients (<1%) in Study ACTG300.
Selected laboratory abnormalities experienced by therapy-naive (≤56 days of antiretroviral therapy) pediatric patients are listed in Table 6. Table 6. Frequencies of Selected Grade 3 to 4 Laboratory Abnormalities in Pediatric Patients in Study ACTG300

Test (Threshold Level) Lamivudine plus Zidovudine Didanosine
Absolute neutrophil count (<400/mm 3) 8% 3%
Hemoglobin (<7.0 g/dL) 4% 2%
Platelets (<50,000/mm 3) 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%

ULN = Upper limit of normal. Neonates — Clinical Trials in HIV-1: Limited short-term safety information is available from 2 small, uncontrolled studies 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 (1from 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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