"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
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].
- Severe acute exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
- Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see WARNINGS AND PRECAUTIONS].
- Pancreatitis [see WARNINGS AND PRECAUTIONS].
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 with 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 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)
|Adverse Reaction||EPIVIR 150 mg Twice Daily plus RETROVIR
(n = 251)
(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 EPIVIR in controlled clinical trials EPV20001, NUCA3001, NUCB3001, NUCA3002, NUCB3002, and NUCB3007 [see WARNINGS AND PRECAUTIONS].
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)
|Test (Threshold Level)||24-Week Surrogate Endpoint Trialsa||Clinical Endpoint Triala|
|EPIVIR plus RETROVIR||RETROVIRb||EPIVIR plus Current Therapy||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%|
|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 EPIVIR 300 mg once daily or EPIVIR 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.
Pediatric Subjects - Clinical Trials in HIV-1
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
|Adverse Reaction||EPIVIR plus RETROVIR
(n = 236)
(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 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%) 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].
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)||EPIVIR plus|
|Absolute neutrophil count ( < 400/mm³)||8%||3%|
|Hemoglobin ( < 7.0 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%|
|ULN = Upper limit of normal.|
Neonates - Clinical Trials in HIV-1
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]. 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.
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 [see WARNINGS AND PRECAUTIONS].
Endocrine and Metabolic
Hemic and Lymphatic
Anemia (including pure red cell aplasia and severe anemias progressing on therapy).
Hepatic and Pancreatic
Muscle weakness, CPK elevation, rhabdomyolysis.
Read the Epivir (lamivudine) Side Effects Center for a complete guide to possible side effects
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). No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.
Interferon- And Ribavirin-Based Regimens
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, 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 [see WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].
Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. Therefore, use of lamivudine in combination with zalcitabine is not recommended.
No change in dose of either drug is recommended. There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP/SMX such as those used to treat PCP.
Drugs With No Observed Interactions With EPIVIR
A drug interaction trial showed no clinically significant interaction between EPIVIR and zidovudine.
Read the Epivir Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/6/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Epivir Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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