Lamivudine

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# Black Box Warning

# Overview
Lamivudine is a nucleoside analogue reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### Human immunodeficiency virus (HIV-1) infection
- Dosage: 300 mg daily or 150 mg q12h
- In combination with other antiretroviral agents.

### Chronic Hepatitis B (HBV) infection
- Dosage: 100 mg daily

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of lamivudine in adult patients.

### NonGuideline-Supported Use

### Posttransplant Prophylaxis for Hepatitis B
- Dosage: 100mg daily 
- In combination with HBIG.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

### Human immunodeficiency virus (HIV-1) infection

### Chronic Hepatitis B (HBV) infection
- Dosage: patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dosage of 100 mg.
- The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of lamivudine in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of lamivudine in pediatric patients.

# Contraindications
- Hypersensitivity to lamivudine or to any component of the tablets or oral solution.

# Warnings

### 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 alone or in combination, including lamivudine and other antiretrovirals.
- A majority of these cases have been in women.
- Obesity and prolonged nucleoside exposure may be risk factors.
- Particular caution should be exercised when administering lamivudine to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. 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).

### Patients With HIV-1 and Hepatitis B Virus Co-infection
Posttreatment Exacerbations of Hepatitis
- In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, 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.
- There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis.
Important Differences Among Lamivudine-Containing Products
- lamivudine Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than lamivudine-HBV Tablets and lamivudine-HBV Oral Solution.
- lamivudine-HBV was developed for patients with chronic hepatitis B.
- The formulation and dosage of lamivudine in lamivudine-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 lamivudine-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, lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine) Tablets, or abacavir sulfate, lamivudine, and zidovudine) Tablets should be used as part of an appropriate combination regimen.
Emergence of Lamivudine-Resistant HBV
- In nonHIV-1-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response.
- Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus.

### Use With Other Lamivudine- and Emtricitabine-Containing Products
- lamivudine should not be administered concomitantly with other lamivudine-containing products including lamivudine-HBV Tablets, lamivudine Oral Solution, lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine Tablets, or abacavir sulfate, lamivudine, and zidovudine or emtricitabine-containing products, including efavirenz, emtricitabine, and tenofovir, emtricitabine, emtricitabine and tenofovir, or rilpivirine/emtricitabine/tenofovir.

### 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-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.
- 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).

### 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.

### 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 system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre 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.

### 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.

# Adverse Reactions

## 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 Population
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 5% of subjects 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.
Pancreatitis:
Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received lamivudine in controlled clinical trials.
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.
The frequencies of selected laboratory abnormalities reported subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar.

### Pediatric Population
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 5% frequency during therapy with lamivudine 4 mg/kg twice daily plus zidovudine 160 mg/m2 3 times daily in therapy-naive (56 days of antiretroviral therapy) pediatric subjects are listed in Table 5.
Pancreatitis:
Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleosideexperienced pediatric subjects receiving lamivudine alone or in combination with other antiretroviral agents. In an openlabel doseescalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these subjects died of complications of pancreatitis. In a second openlabel trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to lamivudine plus zidovudine. Pancreatitis was observed in 1 subject in this trial who received openlabel lamivudine in combination with zidovudin and ritonavir following discontinuation of didanosine monotherapy.
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 (<1%) in Trial ACTG300.
Selected laboratory abnormalities experienced by therapynaive (56 days of antiretroviral therapy) pediatric subjects are listed in Table 6.
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. 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.

## Postmarketing Experience
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of lamivudine.
Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made.
Body as a Whole
- Redistribution/accumulation of body fat.
General
- Weakness.
Endocrine and Metabolic
- Hyperglycemia.
Hemic and Lymphatic
- Anemia (including pure red cell aplasia and severe anemias progressing on therapy).
Hepatic and Pancreatic
- Lactic acidosis and hepatic steatosis
- Posttreatment exacerbation of hepatitis B
Hypersensitivity
- Anaphylaxis
- Urticaria.
Musculoskeletal
- Muscle weakness
- CPK elevation
- Rhabdomyolysis
Skin
- Alopecia
- Pruritus

# Drug Interactions
- 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.
- 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.
- Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another.
- 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.
- A drug interaction trial showed no clinically significant interaction between lamivudine and zidovudine.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled trials of lamivudine in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. Lamivudine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, lamivudine amniotic fluid specimens were collected following natural rupture of membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients.
Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus.
Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established.
Pregnancy Category (AUS): B3
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lamivudine in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Lamivudine during labor and delivery.

### Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine.
Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine.

### Pediatric Use
The safety and effectiveness of twice-daily lamivudine in combination with other antiretroviral agents have been established in pediatric patients 3 months and older.

### Geriatic Use
Clinical trials of lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly.

### Gender
There is no FDA guidance on the use of Lamivudine with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Lamivudine with respect to specific racial populations.

### Renal Impairment
Dosing of lamivudine is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2.
No additional dosing of lamivudine is required after routine (4-hour) hemodialysis or peritoneal dialysis.
Although there are insufficient data to recommend a specific dose adjustment of lamivudine in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered.

### Hepatic Impairment
There is no FDA guidance on the use of Lamivudine in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lamivudine in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Lamivudine in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
- Patients with HIV-1 and Hepatitis B Virus Co-infection should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

# IV Compatibility
There is limited information regarding the compatibility of Lamivudine and IV administrations.

# Overdosage
There is no known antidote for lamivudine. One case of an adult ingesting 6 g of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in Trial ACTG300. One case involved a single dose of 7 mg/kg of lamivudine; the second case involved use of 5 mg/kg of lamivudine twice daily for 30 days. There were no clinical signs or symptoms noted in either case. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.

# Pharmacology

## Mechanism of Action
- Lamivudine is an antiviral agent.
- Intracellularly, lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP).
- The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA.
- 3TC-TP is a weak inhibitor of mammalian DNA polymerases , , and .

## Structure
- Lamivudine is a synthetic nucleoside analogue with activity against HIV-1 and HBV.
- The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one.
- Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. *Lamivudine has also been referred to as (-)2,3-dideoxy, 3-thiacytidine.
- It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3.
- Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20C.

## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of lamivudine in the drug label.

## Pharmacokinetics

### Pharmacokinetics in Adults
- The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg.
- The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected subjects.
- The steady-state pharmacokinetic properties of the lamivudine 300-mg tablet once daily for 7 days compared with the lamivudine 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects.
- Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen.
- Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared with the 150-mg twice-daily regimen. *Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations.
- The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known.
- Lamivudine was rapidly absorbed after oral administration in HIV-1-infected subjects.
- Absolute bioavailability in 12 adult subjects was 86%  16% (mean  SD) for the 150-mg tablet and 87%  13% for the oral solution.
- After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5  0.5 mcg/mL (mean  SD).
- The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg.
- The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily.
- An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2  1.3 hours) compared with the fasted state (Tmax: 0.9  0.3 hours); Cmax in the fed state was 40%  23% (mean  SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC) in the fed and fasted states; therefore, lamivudine Tablets and Oral Solution may be administered with or without food.
- The apparent volume of distribution after IV administration of lamivudine to 20 subjects was 1.3  0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces.
- Volume of distribution was independent of dose and did not correlate with body weight.
- Binding of lamivudine to human plasma proteins is low (<36%).
- In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.
- Metabolism of lamivudine is a minor route of elimination.
- In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-1-infected adults, 5.2%  1.4% (mean  SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined.
- The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion.
- In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7  56.9 mL/min (mean  SD).
- In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4  75.2 mL/min (mean  SD), representing 71%  16% (mean  SD) of total clearance of lamivudine.
- In most single-dose trials in HIV-1-infected subjects, HBVinfected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t12) ranged from 5 to 7 hours.
- In HIV-1-infected subjects, total clearance was 398.5  69.1 mL/min (mean  SD).
- Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg/kg.

### Special Populations
- The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7).
- Exposure (AUC), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance).
- Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. *Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment.
- Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration.
- Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.
- It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis.
- The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.
- The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function.
- Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function.
- Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.

### Pharmacokinetics in Pediatric Patients
- In Trial NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric subjects (age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day.
- In the 9 infants and children (age range: 5 months to 12 years) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66%  26% (mean  SD), which was less than the 86%  16% (mean  SD) observed in adults.
- The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown.
Systemic clearance decreased with increasing age in pediatric subjects, as shown in Figure 1.
- After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric subjects ranging in age from 4 months to 14 years, Cmax was 1.1  0.6 mcg/mL and half-life was 2.0  0.6 hours. (In adults with similar blood sampling, the halflife was 3.7  1 hours.)
- Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric subjects receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose.
- Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine.
- CSF samples were collected between 2 and 4 hours postdose.
- At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean  SD of 14.2%  7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL.
- Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged >3 months) studied previously.
- There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old.

### Pharmacokinetics in Geriatric Patients
- The pharmacokinetics of lamivudine after administration of lamivudine to patients over 65 years have not been studied.

### Drug Interactions
- There was no significant pharmacokineti interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.
- In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.
- Lamivudine and TMP-SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design.
- Coadministration of TMP-SMX with lamivudine resulted in an increase of 43%  23% (mean  SD) in lamivudine AUC, a decrease of 29%  13% in lamivudine oral clearance, and a decrease of 30%  36% in lamivudine renal clearance. *The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine.
- No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr).

## Nonclinical Toxicology
Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV-1 infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.
Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta.

# Clinical Studies
The use of lamivudine is based on the results of clinical trials in HIV1-infected subjects in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials.

### Adults
NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone  or zidovudine with didanosine or zalcitabine ) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells/mm3 (median = 122 cells/mm3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 8.
Dual Nucleoside Analogue Trials: 
Principal clinical trial in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression.
Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: 
EPV20001 was a multi-center, double-blind, controlled trial in which subjects were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm3 (median = 362 cells/mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9.
Roche AMPLICOR HIV-1 MONITOR.
Responders at each visit are subjects who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit.
The proportions of subjects with HIV-1 RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving lamivudine 300 mg once daily and 63% for subjects receiving lamivudine 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in subjects receiving lamivudine 300 mg once daily and 146 cells/mm3for subjects receiving lamivudine 150 mg twice daily.
A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm3, median plasma HIV-1 RNA 4.8 log10 copies/mL) were enrolled. Two of the treatment arms in this trial provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of subjects with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group.

### Pediatric Subjects
Clinical Endpoint Trial: 
ACTG300 was a multi-center, randomized, double-blind trial that provided for comparison of lamivudine plus zidovudine with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm3 (mean: 1,060 cells/mm3 and range:0 to 4,650 cells/mm3 for subjects aged 5 years; mean: 419 cells/mm3 and range: 0 to 1,555 cells/mm3 for subjects aged >5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration on trial was 10.1 months for the subjects receiving lamivudine plus zidovudine and 9.2 months for subjects receiving didanosine monotherapy. 
Results are summarized in Table 10.

# How Supplied
- White, diamond-shaped, scored, film-coated tablets debossed with GX CJ7 on both sides.
- Bottle of 60 tablets (NDC 49702-203-18) with child-resistant closure.
- Gray, modified diamond-shaped, film-coated tablets engraved with GX EJ7 on one side and plain on the reverse side.
- Bottle of 30 tablets (NDC 49702-204-13) with child-resistant closure.
- A clear, colorless to pale yellow, strawberry-banana-flavored liquid, contains 10 mg of lamivudine in each 1 mL.
- Plastic bottle of 240 mL (NDC 49702-205-48) with child-resistant closure. This product does not require reconstitution.

## Storage
- Store Lamivudine Tablets at 25C (77F); excursions permitted to 15 to 30C (59 to 86F).
- Store in tightly closed bottles at 25C (77F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Advice for the Patient
- Patients should be informed that some HIV medicines, including lamivudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).
- Patients co-infected with HIV-1 and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued.
- Patients should be advised to discuss any changes in regimen with their physician.
Patients should be advised that lamivudine Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) as lamivudine-HBV Tablets and Oral Solution. If a decision is made to include lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of lamivudine in lamivudine (not lamivudine-HBV) should be used.
Lamivudine should not be coadministered with drugs containing lamivudine or emtricitabine, including lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine Tablets, abacavir sulfate, lamivudine, and zidovudine, efavirenz, emtricitabine, and tenofovir,  , emtricitabine and tenofovir, or  rilpivirine/emtricitabine/tenofovir.
Patients with HIV-1/HCV co-infection should be informed that 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.
Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including lamivudine, and that the cause and long-term health effects of these conditions are not known at this time.
Diabetic patients should be advised that each 15-mL dose of lamivudine Oral Solution contains 3 grams of sucrose.
Lamivudine is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using lamivudine.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection.
- Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. Lamivudine is excreted in human breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- Patients should be informed to take all HIV medications exactly as prescribed.

# Precautions with Alcohol
Alcohol-lamivudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- EPIVIR
- EPIVIR HBV
- EPIVIR A/F

# Look-Alike Drug Names
There is limited information regarding Lamivudine Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price