Lamivudine (Page 2 of 6)

5.2 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 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, lamivudine tablets, lamivudine 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.

5.3 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 pharmcodynamic 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 lamivudine should be closely monitored for treatment-assosicated toxicities, especially hepatic decompensation. Discontinuation of lamivudine tablets 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, 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)].

5.5 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine tablets. During the initial phase of combination antiretroviral treatment, patients whose immune system 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 Supression Rates and Increased Risk of Viral Resistance with Oral Solution

Pediatric subjects who received lamivudine oral solution 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. Consider more frequent monitoring of HIV-1 viral load when treating with lamivudine oral solution.

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 patient 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 other sections of the labeling:

  • Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)].
  • Exacerbations of hepatitis B [see Boxed Warning, Warnings and Precautions (5.2)].
  • Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.3)].
  • Pancreatitis [see Warnings and Precautions (5.4)].
  • Immune reconstitution syndrome [see Warnings and Precautions (5.5)].
  • Fat redistribution [see Warnings and Precautions (5.7)].

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 tablets 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 tablets 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 Tablets 150 mg Twice Daily plus RETROVIR ( n = 251 ) RETROVIRa ( n = 230 )
Body as a Whole Headache Malaise & fatigue Fever or chillsDigestive Nausea Diarrhea Nausea & vomiting Anorexia and/or decreased appetite Abdominal pain Abdominal cramps DyspepsiaNervous System Neuropathy Insomnia & other sleep disorders Dizziness Depressive disordersRespiratory Nasal signs & symptoms Cough Skin Skin rashesMusculoskeletal Musculoskeletal pain Myalgia Arthralgia 35%27%10%33%18%13%10%9%6%5%12%11%10%9%20%18%9%12%8%5% 27%23%12%29%22%12%7%11%3%5%10%7%4%4%11%13%6%10%6%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 Tablets 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving Lamivudine Tablets 300 mg once daily or Lamivudine Tablets 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)

ULN = Upper limit of normal.

ND = Not done.

*
The median duration on study was 12 months.
Either zidovudine monotherapy or zidovudine in combination with zalcitabine.
Current therapy was either zidovudine, zidovudine plus didanosine, or zidovudine plus zalcitabine.
TEST 24 Week Surrogate Endpoint Trials * Clinical Endpoint Trial *
( Threshold Level ) Lamivudine plus RETROVIR RETROVIR Lamivudine plus Current Therapy Placebo plus Current Therapy
Absolute neutrophil count (<750/mm3)Hemoglobin (<8.0 g/dL)Platelets (<50,000/mm3)ALT (>5.0 x ULN) AST (>5.0 x ULN) Bilirubin (>2.5 x ULN) Amylase (>2.0 x ULN) 7.2%2.9%0.4%3.7%1.7%0.8%4.2% 5.4%1.8%1.3%3.6%1.8%0.4%1.5% 15%2.2%2.8%3.8%4.0%ND2.2% 13%3.4%3.8%1.9%2.1%ND1.1%

The frequencies of selected laboratory abnormalities reported in subjects receiving lamivudine tablets 300 mg once daily or lamivudine tablets 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 Patients in Study 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 Digestive Hepatomegaly Nausea & vomiting Diarrhea Stomatitis SplenomegalyRespiratory Cough Abdominal breath sounds/wheezingEar , Nose , and Throat Signs or symptoms of earsa Nasal discharge or congestionOther Skin rashes Lymphadenopathy 25%11%8%8%6%5%15%7%7%8%12%9% 32%11%7%6%12%8%18%9%6%11%14%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 than1%) 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

ULN= Upper limit of normal.

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%

Additional pediatric use information for patients aged 3 months and above is approved for ViiV Healthcare Company’s EPIVIR® (lamivudine) tablets and oral solution. However, due to ViiV Healthcare Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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, anaemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions; 1from 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-1infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known.

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