Epivir HBV

The most severe side effects of lamivudine are:

• pancreatitis,
• liver failure,
• metabolic disturbance (lactic acidosis),
• a decrease in blood cells,
• muscle pain,
• weakness, and
• nerve damage in the extremities (peripheral neuropathy). Symptoms of peripheral neuropathy are tingling, numbness and pain in the feet or hands.

Other important side effects are

• fever,
• abdominal pain,
• weight loss,
• nausea,
• vomiting,
• diarrhea,
• hair loss, and
• difficulty sleeping.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Epivir HBV there are no specific foods that you must exclude from your diet when receiving Epivir HBV.

Before receiving Epivir HBV, tell your doctor if you:

• are allergic to Epivir HBV or any of the other ingredients in Epivir HBV
• have HIV-1 infection
• have ever had liver disease such as liver failure, cirrhosis, or hepatitis
• are seriously overweight (especially if you’re a woman)
• are diabetic (Epivir HBV contains sucrose)
• use insulin
• have kidney disease
• have had pancreatitis (inflammation of the pancreas) in the past, particularly children

Tell your doctor if you are pregnant or breastfeeding.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

You should not take Epivir-HBV (for treating hepatitis B) if you also take other medicine that contains lamivudine or emtricitabine. This includes Atripla, Combivir, Complera, Emtriva, Epzicom, Stribild, Trizivir, and Truvada.

Lamivudine may cause a serious condition called lactic acidosis. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

Lamivudine can also cause severe or life-threatening effects on your liver or pancreas. Call your doctor at once if you have: severe pain in your upper stomach spreading to your back, nausea, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

If you have hepatitis B you may develop liver symptoms after you stop taking lamivudine. Your liver function may need to be checked for several months after you stop using lamivudine.

Taking this medicine will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

It is very important that your doctor check the progress of you or your child at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Do not use this medicine if you or your child is also taking zalcitabine or medicines containing emtricitabine or lamivudine (eg, Atripla®, Combivir®, Complera®, Emtriva®, Epzicom®, Stribild®, Trizivir®, Truvada®). Tell your doctor right away if you are using any of these medicines.

Two rare but serious reactions to this medicine are lactic acidosis (build-up of acid in the blood) and liver toxicity, including an enlarged liver. These are more common if you are female, very overweight (obese), or have been taking anti-HIV medicines for a long time. Call your doctor right away if you or your child has stomach discomfort or cramping, nausea, vomiting, or diarrhea, a decreased appetite, a general feeling of discomfort, muscle cramping or pain, unusual tiredness or weakness, trouble breathing, or yellow skin or eyes.

This medicine may cause worsening of hepatitis B infection when treatment is stopped.

Pancreatitis may occur while you are using Epivir®. Tell your doctor right away if you or your child has sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

Your immune system may get stronger when you start taking Epivir®. This could cause a hidden infection in your body to become active. Tell your doctor right away if you or your child notice any changes in your health.

Epivir® may cause you or your child to have excess body fat. Tell your doctor right away if you notice changes in your body shape, including an increased amount of body fat in the neck or upper back, face, around the chest, or stomach area. You might also lose fat from your legs, arms, or face.

Lamivudine does not decrease the risk of transmitting HIV infection to others through sexual contact or by contamination through blood. HIV may be acquired from or spread to others through infected body fluids, including blood, vaginal fluid, or semen. If you are infected, it is best to avoid any sexual activity involving an exchange of body fluids with other people. If you do have sex, always wear (or have your partner wear) a condom (“rubber”). Only use condoms made of latex or polyurethane and use them every time you have contact with semen, vaginal secretions, or blood. Also, do not re-use or share needles or equipment with anyone. If you have any questions about this, check with your doctor.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Epivir-HBV is contraindicated in patients who have experienced a previous hypersensitivity reaction (e.g., anaphylaxis) to lamivudine or to any component of the tablets or oral solution.

Epivir-HBV is a synthetic nucleoside analogue with activity against 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. It has the following structural formula:

Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg per mL in water at 20°C.

Epivir-HBV tablets are for oral administration. Each tablet contains 100 mg of lamivudine and the inactive ingredients hypromellose, macrogol 400, magnesium stearate, microcrystalline cellulose, polysorbate 80, red iron oxide, sodium starch glycolate, titanium dioxide, and yellow iron oxide.

Epivir-HBV oral solution is for oral administration. One milliliter (1 mL) of Epivir-HBV oral solution contains 5 mg of lamivudine (5 mg per mL) in an aqueous solution and the inactive ingredients artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben, propylene glycol, propylparaben, sodium citrate (dihydrate), and sucrose (200 mg).

Mechanism of Action

Lamivudine is an antiviral agent [see Microbiology (12.4)].

Pharmacokinetics

Pharmacokinetics in Adults

The pharmacokinetic properties of lamivudine have been studied as single and multiple oral doses ranging from 5 mg to 600 mg per day administered to HBV-infected subjects.

Absorption and Bioavailability: Following single oral doses of 100 mg, the peak serum lamivudine concentration (Cmax) in HBV-infected patients (steady state) and healthy subjects (single dose) was 1.28 ± 0.56 mcg per mL and 1.05 ± 0.32 mcg per mL (mean ± SD), respectively, which occurred between 0.5 and 2 hours after administration. The area under the plasma concentration versus time curve (AUC[0-24 h]) following 100-mg lamivudine oral single and repeated daily doses to steady state was 4.3 ± 1.4 (mean ± SD) and 4.7 ± 1.7 mcg•hour per mL, respectively. The relative bioavailability of the tablet and oral solution were demonstrated in healthy subjects. Although the solution demonstrated a slightly higher peak serum concentration (Cmax), there was no significant difference in systemic exposure (AUC) between the oral solution and the tablet. Therefore, the oral solution and the tablet may be used interchangeably.

After oral administration of lamivudine once daily to HBV-infected adults, the AUC and Cmax increased in proportion to dose over the range from 5 mg to 600 mg once daily.

Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the 10-mg per mL oral solution.

Effects of Food on Oral Absorption: The 100-mg tablet was administered orally to 24 healthy subjects on 2 occasions, once in the fasted state and once with food (standard meal: 967 kcal; 67 grams fat, 33 grams protein, 58 grams carbohydrate). There was no significant difference in systemic exposure (AUC) in the fed and fasted states.

Distribution: The apparent volume of distribution after IV administration of lamivudine to 20 asymptomatic HIV-1-infected subjects was 1.3 ± 0.4 L per 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 less than 36% and independent of dose. In vitro studies showed that over the concentration range of 0.1 to 100 mcg per mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration.

Metabolism: Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. In 9 healthy subjects receiving 300 mg of lamivudine as single oral doses, a total of 4.2% (range: 1.5% to 7.5%) of the dose was excreted as the trans-sulfoxide metabolite in the urine, the majority of which was excreted in the first 12 hours. Serum concentrations of the trans-sulfoxide metabolite have not been determined.

Elimination: 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 per min (mean ± SD). In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL per min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine.

In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL per 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 per kg.

Special Populations

Adults with Renal Impairment: The pharmacokinetic properties of lamivudine have been determined in healthy subjects and in subjects with impaired renal function, with and without hemodialysis (Table 5).

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 [see Dosage and Administration (2.4)].

Hemodialysis increases lamivudine clearance from a mean of 64 to 88 mL per 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.

Pediatric Patients with Renal Impairment: The effect of renal impairment on lamivudine pharmacokinetics in pediatric patients with chronic hepatitis B is not known.

Adults with Hepatic Impairment: The pharmacokinetic properties of lamivudine in adults with hepatic impairment are shown in Table 6. Subjects were stratified by severity of hepatic impairment.

Pharmacokinetic parameters were not altered by diminishing hepatic impairment. Therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. Safety and efficacy of Epivir-HBV have not been established in the presence of decompensated liver disease [see Indications and Usage (1)].

Adults Post-Hepatic Transplant: Fourteen HBV-infected subjects received liver transplant following lamivudine therapy and completed pharmacokinetic assessments at enrollment, 2 weeks after 100-mg once-daily dosing (pre-transplant), and 3 months following transplant; there were no significant differences in pharmacokinetic parameters. The overall exposure of lamivudine is primarily affected by renal impairment; consequently, transplant patients with renal impairment had generally higher exposure than patients with normal renal function. Safety and efficacy of Epivir-HBV have not been established in this population [see Indications and Usage (1)].

Pregnancy: The pharmacokinetics of lamivudine in patients with HBV or HIV-1 infection and in healthy volunteers were similar at similar doses. Lamivudine pharmacokinetics were studied in 36 pregnant women with HIV during 2 clinical trials conducted in South Africa (3 to 6 times the recommended daily dosage for HBV). 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.

Pediatric Subjects: Lamivudine pharmacokinetics were evaluated in a 28-day dose-ranging trial in 53 pediatric subjects with chronic hepatitis B. Subjects aged 2 to 12 years were randomized to receive lamivudine 0.35 mg per kg twice daily, 3 mg per kg once daily, 1.5 mg per kg twice daily, or 4 mg per kg twice daily. Subjects aged 13 to 17 years received lamivudine 100 mg once daily. Lamivudine Tmax was 0.5 to 1 hour. In general, both Cmax and exposure (AUC) showed dose proportionality in the dosing range studied. Weight-corrected oral clearance was highest at age 2 and declined from 2 to 12 years, where values were then similar to those seen in adults. A dose of 3 mg per kg given once daily produced a steady-state lamivudine AUC (mean 5,953 ng•hour per mL ± 1,562 SD) similar to that associated with a dose of 100 mg per day in adults.

Gender: There are no significant gender differences in lamivudine pharmacokinetics.

Race: There are no significant racial differences in lamivudine pharmacokinetics.

Drug Interactions

Interferon Alfa: Multiple doses of lamivudine and a single dose of interferon were coadministered to 19 healthy male subjects in a pharmacokinetics trial. Results indicated a 10% reduction in lamivudine AUC, but no change in interferon pharmacokinetic parameters when the 2 drugs were given in combination. All other pharmacokinetic parameters (Cmax, Tmax, and t½) were unchanged. There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in this trial.

Ribavirin: 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.

Trimethoprim/Sulfamethoxazole: Lamivudine and trimethoprim/sulfamethoxazole (TMP/SMX) were coadministered to 14 HIV-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 44% ± 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.

Zidovudine: Lamivudine and zidovudine were coadministered to 12 asymptomatic HIV-positive adult subjects in a single-center, open-label, randomized, crossover trial. No significant differences were observed in AUC or total clearance for lamivudine or zidovudine when the 2 drugs were administered together. Coadministration of lamivudine with zidovudine resulted in an increase of 39% ± 62% (mean ± SD) in Cmax of zidovudine.

Microbiology

Mechanism of Action

Lamivudine is a synthetic nucleoside analogue. 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 the RNA- and DNA-dependent polymerase activities of HBV reverse transcriptase (rt) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. 3TC-TP is a weak inhibitor of mammalian α, β, and γ-DNA polymerases.

Antiviral Activity

Activity of lamivudine against HBV in cell culture was assessed in HBV DNA-transfected 2.2.15 cells, HB611 cells, and infected human primary hepatocytes. EC50 values (the concentration of drug needed to reduce the level of extracellular HBV DNA by 50%) varied from 0.01 μM (2.3 ng per mL) to 5.6 μM (1.3 mcg per mL) depending upon the duration of exposure of cells to lamivudine, the cell model system, and the protocol used. See the EPIVIR prescribing information for information regarding activity of lamivudine against HIV.

Resistance

Lamivudine-resistant isolates were identified in subjects with virologic breakthrough, defined when using solution hybridization assay as the detection of HBV DNA in serum on 2 or more occasions after failing to detect HBV DNA on 2 or more occasions and defined when using PCR assay as a greater than 1 log10 (10-fold) increase in serum HBV DNA from nadir during treatment in a subject who had an initial virologic response.

Lamivudine-resistant HBV isolates develop rtM204V/I substitutions in the YMDD motif of the catalytic domain of the viral reverse transcriptase. rtM204V/I substitutions are frequently accompanied by other substitutions (rtV173L, rtL180M) which enhance the level of lamivudine resistance or act as compensatory substitutions improving replication efficiency. Other substitutions detected in lamivudine-resistant HBV isolates include rtL80I and rtA181T.

In 4 controlled clinical trials in adults with HBeAg-positive chronic hepatitis B virus infection (CHB), YMDD-mutant HBV was detected in 81 of 335 subjects receiving Epivir-HBV 100 mg once daily for 52 weeks. The prevalence of YMDD substitutions was less than 10% in each of these trials for subjects studied at 24 weeks and increased to an average of 24% (range in 4 trials: 16% to 32%) at 52 weeks. In limited data from a long-term follow-up trial in subjects who continued 100 mg per day Epivir-HBV after one of these trials, YMDD substitutions further increased from 18% (10 of 57) at 1 year to 41% (20 of 49), 53% (27 of 51), and 69% (31 of 45) after 2, 3, and 4 years of treatment, respectively. Over the 5-year treatment period, the proportion of subjects who developed YMDD-mutant HBV at any time was 69% (40 of 58).

In a controlled trial, treatment-naive subjects with HBeAg-positive CHB were treated with Epivir-HBV or Epivir-HBV plus adefovir dipivoxil combination therapy. Following 104 weeks of therapy, YMDD-mutant HBV was detected in 7 of 40 (18%) subjects receiving combination therapy compared with 15 of 35 (43%) subjects receiving therapy with only Epivir-HBV. In another controlled trial, combination therapy was evaluated in adult subjects with HBeAg-positive CHB who had YMDD-mutant HBV and diminished clinical and virologic response to Epivir-HBV. Following 52 weeks of Epivir-HBV plus adefovir dipivoxil combination therapy (n = 46) or therapy with only Epivir-HBV (n = 49), YMDD‑mutant HBV was detected less frequently in subjects receiving combination therapy, 62% versus 96%.

A published trial suggested that the rates of lamivudine resistance in subjects treated for HBeAg-negative CHB appear to be more variable (0% to 27% at 1 year and 10% to 56% at 2 years).

Pediatric Subjects: In a controlled trial in pediatric subjects, YMDD-mutant HBV was detected in 31 of 166 (19%) subjects receiving Epivir-HBV for 52 weeks. For a subgroup that remained on therapy with Epivir-HBV in a follow-up trial, YMDD substitutions increased from 24% (29 of 121) at 12 months to 59% (68 of 115) at 24 months and 64% (66 of 103) at 36 months of treatment with Epivir-HBV.

Cross-Resistance

HBV containing lamivudine resistance-associated substitutions (rtL180M, rtM204I, rtM204V, rtL180M and rtM204V, rtV173L and rtL180M and rtM204V) retain susceptibility to adefovir dipivoxil but have reduced susceptibility to entecavir (30-fold) and telbivudine (greater than 100-fold). The lamivudine resistance-associated substitution rtA181T results in diminished response to adefovir and telbivudine. Similarly, HBV with entecavir resistance-associated substitutions (I169T/M250V and T184G/S202I) have greater than 1,000-fold reductions in susceptibility to lamivudine.

Applies to lamivudine: oral solution, oral tablet

Along with its needed effects, lamivudine (the active ingredient contained in Epivir-HBV) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking lamivudine:

• Abdominal or stomach discomfort
• black, tarry stools
• bleeding gums
• bloating
• blood in the urine or stools
• chills
• constipation
• cough
• darkened urine
• decreased appetite
• diarrhea
• difficulty with swallowing
• dizziness
• fast heartbeat
• fast, shallow breathing
• fever
• general feeling of discomfort
• general tiredness and weakness
• indigestion
• light-colored stools
• loss of appetite
• muscle cramps or spasms
• muscle pain or stiffness
• nausea and vomiting
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pinpoint red spots on the skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• right upper abdominal or stomach pain and fullness
• skin rash, hives, or itching
• sleepiness
• tightness in the chest
• unusual bleeding or bruising
• unusual tiredness or weakness
• upper right abdominal or stomach pain
• yellow eyes or skin

Some side effects of lamivudine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• burning, tingling, numbness or pain in the hands, arms, feet, or legs
• depression
• general feeling of discomfort or illness
• headache
• heartburn
• indigestion
• muscle or joint pain
• sensation of pins and needles
• sore throat
• stabbing pain
• stomach discomfort, upset, or pain
• stuffy or runny nose
• trouble sleeping
• weight loss

• Blurred vision
• dry mouth
• flushed, dry skin
• fruit-like breath odor
• hair loss or thinning of the hair
• increased hunger
• increased thirst
• increased urination
• pale skin
• sweating
• troubled breathing with exertion
• unexplained weight loss
• weight gain around your neck, upper back, breast, face, or waist