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ANTIVIRAL NUCLEOSIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Adefovir is an acyclic nucleotide analogue antiviral agent with activity against human hepatitis B virus. Adefovir dipivoxil (Hepsera(R) is a diester prodrug of adefovir.
    B) Entecavir is a guanosine nucleoside analogue antiviral agent with selective activity against hepatitis B virus.
    C) Telbivudine (beta-L-2'-deoxythymidine) is a synthetic hymidine nucleoside analog with activity against hepatitis B virus by competitive inhibition of both viral reverse transcriptase and DNA polymerase.

Specific Substances

    A) ADEFOVIR
    1) GS-0393
    2) PMEA
    3) ((2-(6-Amino-9H-purin-9-yl)ethoxy)methyl)phosphonic acid
    4) 9-(2-Phosphonylmethoxyethyl-adenine
    5) 9-((2-Phosphonylmethoxy)ethyl)adenine
    6) Phosphonic acid, ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)-
    7) Molecular Formula: C8-H12-N5-O4-P
    8) CAS 106941-25-7
    ADEFOVIR DIPIVOXIL
    1) GS-840
    2) Bis-POM PMEA
    3) 9-[2-[[bis[(pivaloyloxy)methoxy]-phosphinyl]methoxy]ethyl]adenine
    4) Propanoic acid, 2,2-dimethyl-, ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphinylidene)bis (oxymethylene) ester
    5) Molecular Formula: C20-H32-N5-O8-P
    6) CAS 142340-99-6
    ENTECAVIR
    1) 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate
    2) Molecular Formula: C12-H15-N5-O3.H2O
    3) CAS 142217-69-4 (anhydrous entecavir)
    4) CAS 209216-23-9 (entecavir monohydrate)
    TELBIVUDINE
    1) Telbivudina
    2) Telbivudinum
    3) Molecular Formula: C10-H14-N2-O5
    4) CAS 3424-98-4

Available Forms Sources

    A) FORMS
    1) Adefovir dipivoxil is available as 10 mg tablets (Prod Info HEPSERA oral tablets, 2009).
    2) Entecavir is available as 0.5 and 1 mg film-coated tablets and 0.05 mg/mL oral solution (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    3) Telbivudine is available as 600 mg tablets and 100 mg per 5 mL oral solution (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).
    B) USES
    1) Adefovir dipivoxil, entecavir, and telbivudine are antiviral agents used to treat chronic hepatitis B in patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease (Prod Info Tyzeka(R) oral tablets, oral solution, 2011; Prod Info BARACLUDE(R) oral solution, oral tablets, 2010; Prod Info HEPSERA oral tablets, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Adefovir dipivoxil, entecavir, and telbivudine are antiviral agents used to treat chronic hepatitis B in patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
    B) PHARMACOLOGY: Adefovir is an acyclic nucleotide analogue of adenosine monophosphate. It is phosphorylated via cellular enzymes to active form, adefovir diphosphate, and inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. Entecavir is a guanosine nucleoside analogue antiviral agent with selective activity against HBV polymerase. It is phosphorylated to active form, entecavir triphosphate and inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): [1-base priming, 2-reverse transcription of the negative strand from the pregenomic messenger RNA, and 3-synthesis of the positive strand of HBV DNA] by competing with the natural substrate deoxyguanosine triphosphate. Telbivudine (beta-L-2'-deoxythymidine) is a synthetic thymidine nucleoside analog with activity against hepatitis B virus by competitive inhibition of both viral reverse transcriptase and DNA polymerase. Like other nucleoside analogues, the antiviral activity of telbivudine is dependent on its conversion intracellulary to telbivudine triphosphate. Once incorporated into viral DNA (anti-complement or second-strand DNA) by hepatitis B polymerase, DNA chain termination results.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported in patients taking nucleoside analogues alone or in combination with antiretroviral.
    2) ADEFOVIR: Asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, and dyspepsia have been reported in patients receiving adefovir in clinical trials. However, the incidence of these adverse events was similar in the placebo group. Other adverse effects included rash, pruritus, vomiting, abnormal renal function, elevation in serum transaminases, cough, pharyngitis, sinusitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic failure, and fever. Nephrotoxicity has been reported during adefovir therapy, particularly using doses higher than 10 mg daily. It is characterized primarily by rises in serum creatinine and decreases in serum phosphorus levels; patients with underlying renal dysfunction are at greater risk.
    3) ENTECAVIR: COMMON: Headache, fatigue, dizziness, and nausea. OTHER EFFECTS: Hyperglycemia, glycosuria, dyspepsia, vomiting, elevated serum amylase and lipase, hematuria, and photophobia.
    4) TELBIVUDINE: COMMON: Abdominal pain, transient increase in creatine kinase, myopathy, headache, nasopharyngitis, upper respiratory infection, malaise, and fatigue. Increases in ALT as high as ten times the upper limit of normal have been reported but may have been associated with resistance. Isolated cases of rhabdomyolysis have been reported with postmarketing use of telbivudine.
    E) WITH POISONING/EXPOSURE
    1) ADEFOVIR: Gastrointestinal side effects have been reported in patients following doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks.
    2) ENTECAVIR: Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days did not experience any unexpected adverse events.
    3) TELBIVUDINE: One patient received an unintentional overdose and was asymptomatic. The dose was not reported. No increase in or unexpected adverse effects were reported in healthy subjects who received 1800 milligram/day for 4 days.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) ADEFOVIR: Fever has been reported (2% or higher) in pre- and post-liver transplantation patients treated with adefovir (Prod Info HEPSERA oral tablets, 2009).
    0.2.20) REPRODUCTIVE
    A) ADEFOVIR and ENTECAVIR are classified as FDA pregnancy category C. TELBIVUDINE is classified as FDA pregnancy category B. In animal studies, embryotoxicity, maternal toxicity, and an increased incidence of fetal malformations were observed following the administration of intravenous ADEFOVIR to pregnant rats. Following ENTECAVIR exposures, rats and rabbits experienced maternal toxicity, embryofetal toxicity, lower fetal body weights, tail and vertebral malformations, reduced ossifications, and extra lumbar vertebrae and ribs. TELBIVUDINE was shown to be safe and effective during all trimesters of pregnancy in a study of 86 pregnant women who had hepatitis B virus (HBV), in a total of 89 pregnancies. TELBIVUDINE has been shown to cross the placenta in studies involving pregnant rats and rabbits. ENTECAVIR and TELBIVUDINE have been shown to be excreted in the milk of rats. Seminiferous tubular degeneration was noted in rodents and dogs and testicular degeneration was noted in dogs following ENTECAVIR exposure.

Laboratory Monitoring

    A) Monitor vital signs, renal function, and liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    C) Monitor serum lactate and arterial blood gases in symptomatic patients.
    D) Monitor CK; monitor renal function, and urine output in patients with rhabdomyolysis. Isolated cases of rhabdomyolysis have been reported with postmarketing use of telbivudine.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is very unlikely to be necessary unless other toxic agents have been administered concurrently.
    E) ANTIDOTE
    1) None
    F) ACIDOSIS
    1) Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg.
    G) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    H) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis is UNLIKELY to be of value for entecavir or telbivudine because of the large volume of distribution of these agents. Hemodialysis would likely be effective for adefovir.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe vomiting, profuse diarrhea, electrolyte abnormalities, lactic acidosis, hepatic failure, or renal failure.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PHARMACOKINETICS
    1) ADEFOVIR: Bilavailability 59%, protein binding 4% or less, Vd 400 mL/kg, renal excretion, half-life 7.5 hours. ENTECAVIR: Well absorbed. Protein binding 13%, Vd in excess of total body water, renal excretion, half-life 128 to 149 hours. TELBIVUDINE: Protein binding 3.3%, Vd in excess of total body water. Renal clearance. Half-life 40 to 49 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause renal dysfunction or lactic acidosis.

Range Of Toxicity

    A) ADEFOVIR: Gastrointestinal side effects have been reported in patients following doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks.
    B) ENTECAVIR: Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days did not experience any unexpected adverse events.
    C) TELBIVUDINE: Healthy subjects who received telbivudine at doses up to 1800 mg/day for 4 days did not experience any unexpected adverse events.
    D) THERAPEUTIC DOSES: ADULTS: ADEFOVIR: 10 mg orally once daily. ENTECAVIR: Varies by indication; 0.5 mg to 1 mg orally once daily. TELBIVUDINE: 600 mg orally once daily. CHILDREN: ADEFOVIR: (12 years and older) 10 mg orally once daily. Safety and efficacy of adefovir in pediatric patients below the age of 12 years have not been established. ENTECAVIR: (16 years and older): Varies by indication; 0.5 mg to 1 mg orally once daily. Safety and efficacy of entecavir in pediatric patients below the age of 16 years have not been established. TELBIVUDINE: (16 years and older) 600 mg orally once daily. Safety and efficacy of telbivudine in pediatric patients below the age of 16 years have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Adefovir dipivoxil, entecavir, and telbivudine are antiviral agents used to treat chronic hepatitis B in patients with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
    B) PHARMACOLOGY: Adefovir is an acyclic nucleotide analogue of adenosine monophosphate. It is phosphorylated via cellular enzymes to active form, adefovir diphosphate, and inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. Entecavir is a guanosine nucleoside analogue antiviral agent with selective activity against HBV polymerase. It is phosphorylated to active form, entecavir triphosphate and inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): [1-base priming, 2-reverse transcription of the negative strand from the pregenomic messenger RNA, and 3-synthesis of the positive strand of HBV DNA] by competing with the natural substrate deoxyguanosine triphosphate. Telbivudine (beta-L-2'-deoxythymidine) is a synthetic thymidine nucleoside analog with activity against hepatitis B virus by competitive inhibition of both viral reverse transcriptase and DNA polymerase. Like other nucleoside analogues, the antiviral activity of telbivudine is dependent on its conversion intracellulary to telbivudine triphosphate. Once incorporated into viral DNA (anti-complement or second-strand DNA) by hepatitis B polymerase, DNA chain termination results.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported in patients taking nucleoside analogues alone or in combination with antiretroviral.
    2) ADEFOVIR: Asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, and dyspepsia have been reported in patients receiving adefovir in clinical trials. However, the incidence of these adverse events was similar in the placebo group. Other adverse effects included rash, pruritus, vomiting, abnormal renal function, elevation in serum transaminases, cough, pharyngitis, sinusitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic failure, and fever. Nephrotoxicity has been reported during adefovir therapy, particularly using doses higher than 10 mg daily. It is characterized primarily by rises in serum creatinine and decreases in serum phosphorus levels; patients with underlying renal dysfunction are at greater risk.
    3) ENTECAVIR: COMMON: Headache, fatigue, dizziness, and nausea. OTHER EFFECTS: Hyperglycemia, glycosuria, dyspepsia, vomiting, elevated serum amylase and lipase, hematuria, and photophobia.
    4) TELBIVUDINE: COMMON: Abdominal pain, transient increase in creatine kinase, myopathy, headache, nasopharyngitis, upper respiratory infection, malaise, and fatigue. Increases in ALT as high as ten times the upper limit of normal have been reported but may have been associated with resistance. Isolated cases of rhabdomyolysis have been reported with postmarketing use of telbivudine.
    E) WITH POISONING/EXPOSURE
    1) ADEFOVIR: Gastrointestinal side effects have been reported in patients following doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks.
    2) ENTECAVIR: Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days did not experience any unexpected adverse events.
    3) TELBIVUDINE: One patient received an unintentional overdose and was asymptomatic. The dose was not reported. No increase in or unexpected adverse effects were reported in healthy subjects who received 1800 milligram/day for 4 days.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) ADEFOVIR: Fever has been reported (2% or higher) in pre- and post-liver transplantation patients treated with adefovir (Prod Info HEPSERA oral tablets, 2009).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) ENTECAVIR: Photophobia has been reported in studies (Galan et al, 2001).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: Increased cough, pharyngitis, and sinusitis have been reported (2% or higher) in pre- and post-liver transplantation patients treated with adefovir (Prod Info HEPSERA oral tablets, 2009).
    b) TELBIVUDINE: Increased cough, nasopharyngitis, and upper respiratory infection were observed with telbivudine therapy. Most events were mild to moderate in severity(Prod Info Tyzeka(R) oral tablets, oral solution, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: In hepatitis B clinical trials, headache has been reported in 9% of patients (n=294) receiving adefovir compared with 10% of patients in the placebo group (n=228) (Prod Info HEPSERA oral tablets, 2009).
    b) ENTECAVIR: In clinical trials, headache was reported in 2% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 2% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, headache was reported in 4% of patients (n=183) receiving entecavir 1 mg and 1% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010; Galan et al, 2001).
    c) TELBIVUDINE: Incidence of headaches, regardless of attributability, was 11% among chronic hepatitis B patients receiving telbivudine 600 mg orally compared with 14% among those receiving lamivudine 100 mg orally once daily in the phase III, randomized, double-blind 007 GLOBE study (n=1,367) after 52 weeks. Most events were mild to moderate in severity (Prod Info Tyzeka(R) oral tablets, oral solution, 2011). One of the most common adverse event reported, regardless of attributability to the drugs, was headache in a multicenter, double-blind, randomized phase IIb trial (n=104) evaluating daily oral treatments of telbivudine 400 mg, telbivudine 600 mg, telbivudine 400 mg plus lamivudine 100 mg, telbivudine 600 mg plus lamivudine 100 mg, or lamivudine 100 mg for 52 weeks for the treatment of chronic hepatitis B. The respective frequencies of headache were 5% (1/22), 14% (3/22), 19% (4/21), 10% (2/20), and 26% (5/19) (Lai et al, 2005).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: In hepatitis B clinical trials, asthenia has been reported in 13% of patients (n=294) receiving adefovir compared with 14% of patients in the placebo group (n=228) (Prod Info HEPSERA oral tablets, 2009).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) ENTECAVIR: Dizziness and photophobia have been reported in studies (Galan et al, 2001).
    b) TELBIVUDINE: Incidence of dizziness, regardless of attributability, was similar among chronic hepatitis B patients receiving telbivudine 600 mg orally and those receiving lamivudine 100 mg orally once daily (4% vs 5%) in the phase III, randomized, double-blind 007 GLOBE study (n=1,367) after 52 weeks. Most events were mild to moderate in severity (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).
    D) FATIGUE
    1) WITH THERAPEUTIC USE
    a) TELBIVUDINE: In a pooled analysis of 2, double-blind, clinical studies (007 GLOBE and NV-02B-015) in patients with chronic hepatitis B treated with either telbivudine 600 mg/day (n=847) or lamivudine 100 mg/day (n=852) for a median of 104 weeks, the incidence of fatigue was 13% vs 11% respectively. Fatigue was a common adverse event in clinical trials leading to telbivudine discontinuation (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: Oral adefovir can cause nausea and other mild-to-moderate gastrointestinal symptoms such as diarrhea, vomiting, and dyspepsia (Kahn et al, 1999; Anon, 1996b; Anon, 1995). In hepatitis B clinical trials, abdominal pain, nausea, flatulence, diarrhea, and dyspepsia have been reported in 9%, 5%, 4%, 3%, and 3% of patients (n=294) receiving adefovir, respectively, compared with 11%, 8%, 4%, 4%, and 2% of patients in the placebo group (n=228), respectively (Prod Info HEPSERA oral tablets, 2009). In a randomized, placebo-controlled trial, the incidence of these adverse events was 57% in patients receiving adefovir 120 mg/day and 29% in those receiving placebo (p less than 0.001) (Kahn et al, 1999).
    b) ENTECAVIR: In clinical trials, dyspepsia, diarrhea, nausea, and vomiting were reported rarely in patients taking entecavir (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    c) TELBIVUDINE: Abdominal pain, diarrhea, nausea, and vomiting were reported with therapeutic use of telbivudine and were mild to moderate in severity (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).
    2) WITH POISONING/EXPOSURE
    a) ADEFOVIR: Gastrointestinal side effects have been reported in patients following doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks (Prod Info HEPSERA oral tablets, 2009).
    B) SERUM AMYLASE RAISED
    1) WITH THERAPEUTIC USE
    a) In clinical trials, elevated serum amylase (greater than 2 x ULN) was reported in 2% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 2% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, elevated serum amylase was reported in 3% of patients (n=183) receiving entecavir 1 mg and 3% of patients (n=190) receiving lamivudine 100 mg. Elevated serum lipase (greater than 2 x ULN) was reported in 7% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 6% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, elevated serum amylase was reported in 8% of patients (n=183) receiving entecavir 1 mg and 7% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: Hepatic failure has been reported in association with adefovir therapy (Prod Info HEPSERA oral tablets, 2009).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: Adefovir dipivoxil can cause serum transaminase elevations. At doses of 10 milligrams/day for the treatment of hepatitis B, increases in ALT and AST occurred in 20% and 8% of patients, respectively. These increases were not greater than in patients receiving placebo. In a randomized, placebo-controlled trial, the incidence of AST and ALT elevation in patients receiving oral adefovir was 20% and 28%, respectively. These rates were significantly greater than those patients randomized to placebo (p less than or equal to 0.001) (Prod Info HEPSERA oral tablets, 2009; Galan et al, 2001; Kahn et al, 1999; Arends et al, 1996; Gilson et al, 1995).
    b) ENTECAVIR: In clinical trials, increases in ALT (greater than 10 x ULN and greater than 2 x baseline) were reported in 2% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 4% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, increases in ALT were reported in 2% of patients (n=183) receiving entecavir 1 mg and 11% of patients (n=190) receiving lamivudine 100 mg. The manufacturer reported that on-treatment values worsened from baseline to Grade 3 or Grade 4 for all parameters except albumin (any on-treatment value less than 2.5 g/dL). On-treatment ALT elevations (greater than 10 x ULN and greater than 2 x baseline) generally resolved with continued treatment (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    1) In clinical trials, increases in ALT (greater than 5 x ULN) were reported in 11% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 16% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, increases in ALT were reported in 12% of patients (n=183) receiving entecavir 1 mg and 24% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    2) In clinical trials, increases in AST (greater than 5 x ULN) were reported in 5% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 8% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, increases in AST were reported in 5% of patients (n=183) receiving entecavir 1 mg and 17% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    3) In clinical trials, elevated total bilirubin (greater than 2.5 x ULN) was reported in 2% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 2% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, elevated total bilirubin was reported in 3% of patients (n=183) receiving entecavir 1 mg and 2% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    c) TELBIVUDINE: After 52 weeks, an increase in ALT of greater than 10 times the upper limit of normal (ULN) and bilirubin of greater than 2 times the ULN was reported in 3 patients on lamivudine and 0 patients on telbivudine in a randomized, international, blinded 2-year trial (The GLOBE study). Patients (n=1,367) with compensated chronic hepatitis B were randomized to daily oral doses of telbivudine 600 milligrams (mg) or lamivudine 100 mg. ALT flares were mostly associated with resistance (Lai et al, 2005).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: Nephrotoxicity has been reported during adefovir therapy, particularly using doses higher than 10 mg daily. It is characterized primarily by rises in serum creatinine and decreases in serum phosphorus levels; patients with underlying renal dysfunction are at greater risk (Prod Info HEPSERA oral tablets, 2009; Galan et al, 2001; Kahn et al, 1999).
    1) Data provided by the manufacturer for adefovir are of limited usefulness in discerning the severity of renal impairment during therapy. Studies cited in the product information indicate increases in serum creatinine of at least 0.3 mg/dL in 4% of chronic hepatitis B patients treated with adefovir 10 mg daily for up to 48 weeks; this was seen in 2% of patients receiving placebo. By week 96 of therapy with this dose, creatinine increases of at least 0.3 mg/dL were evident in 10% of patients, with 2% experiencing rises of at least 0.5 mg/dL (placebo data unavailable). However, the range of creatinine increases or highest increase (eg; 4 mg/dL), or instances of renal failure, were not provided (Prod Info HEPSERA oral tablets, 2009). In other unpublished studies in the product information involving liver transplantation patients with preexisting renal impairment or risk factors for renal impairment, increases in serum creatinine of at least 0.3 mg/dL were reported in 26% and 37% by week 48 and week 96 of treatment, respectively; creatinine increases of at least 0.5 mg/dL occurred in 16% and 31% of patients at these respective times. In the group of patients with rises of at least 0.5 mg/dL, this increase remained in most during continued therapy. Discontinuation was required in 1% due to renal events (Prod Info HEPSERA oral tablets, 2009). However, the magnitude of increases and resultant morbidity resulting from these increases was again not provided.
    2) Direct tubular injury ranging from proximal tubular damage (Fanconi-like syndrome) to acute tubular necrosis has been reported in patients taking adefovir. These patients may develop glycosuria, phosphaturia, aminoaciduria, renal tubular acidosis and increase in serum creatinine. Renal effects may occur in 12% to 24% of patients and are usually reversible following the discontinuation of adefovir. However, end stage renal failure has been reported. These drugs are similar to naturally occurring nucleotides. They are taken up by organic anion transporters located in the basolateral membrane of proximal tubules and secreted via the apical membrane into the urine. While inside the cells, they interfere with synthesis and degradation of membrane phospholipids, as well as ATP dependent processes and mitochondrial function and cause cell necrosis (Joannidis, 2004).
    3) Following 24 weeks of oral adefovir therapy (120 mg/day), an increased incidence of renal toxic effects was noted, manifested primarily by elevations in serum creatinine or hypophosphatemia. A serum creatinine increase more than 0.5 mg/dL from baseline can be expected in 35% of patients after 48 weeks and 50% after 72 weeks of adefovir therapy. Management consists of drug discontinuation (Kahn et al, 1999).
    B) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: In clinical trials, hematuria was reported in 11% of patients (n=294) receiving adefovir 10 mg and 10% of patients (n=228) receiving placebo (Prod Info HEPSERA oral tablets, 2009).
    b) ENTECAVIR: In clinical trials, hematuria was reported in 9% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 10% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, hematuria was reported in 9% of patients (n=183) receiving entecavir 1 mg and 6% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported in patients taking nucleoside analogues alone or in combination with antiretroviral (Prod Info Tyzeka(R) oral tablets, oral solution, 2011; Prod Info BARACLUDE(R) oral solution, oral tablets, 2010; Prod Info HEPSERA oral tablets, 2009).
    b) The development of lactic acidosis was significantly correlated (p=0.002) with a Model for End-Stage Liver Disease (MELD) score of at least 20 and insufficiently correlated with Child-Pugh score in 5 patients who developed lactic acidosis during entecavir treatment. In a study of 16 adult patients between the ages of 24 and 80 yr (mean age 50.25 yr, 62% male) with chronic hepatitis B and associated liver cirrhosis (MELD scores between 6 and 38) treated with standard doses of entecavir, severe lactic acidoses occurred in 3 patients (5 days, 8 days, and 8 months after initiation of therapy), and compensated lactic acidosis in 2 patients (4 and 31 days after initiation of therapy). Maximal blood lactate concentrations ranged between 26 and 200 mg/dL, minimal arterial pH values were between 7.02 and 7.4, and the maximal anionic gap was between 20 and 28 mmol/L. Patients with severe lactic acidosis complained of nausea, dyspnea, and weakness, and exhibited impaired consciousness and tachypnea. Lactic acidosis was fatal in 1 patient, and resolved in the other 4 cases following discontinuation and/or interruption of entecavir treatment. Increased serum lactate concentrations were not observed in any of the 11 patients who had MELD scores below 18. Of the 5 patients who developed lactic acidosis, 2 had Child-Pugh class B cirrhosis, while 4 of the 11 patients who exhibited no change in serum lactate concentrations had Child-Pugh class B cirrhosis (Lange et al, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: Pruritus has been reported in association with adefovir therapy (Prod Info HEPSERA oral tablets, 2009).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: Rash have been reported in association with adefovir therapy (Prod Info HEPSERA oral tablets, 2009).
    b) ENTECAVIR: Rash has been reported with entecavir therapy during postmarketing surveillance (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    c) ENTECAVIR: A case report described development of a maculopapular rash in a 62-year-old after receiving entecavir therapy for a fulminant hepatitis B infection. Generalized erythema developed 7 days after starting entecavir 0.5 mg daily and the patient presented with an eruption on his trunk and extremities. Blood chemistries revealed significantly elevated liver enzymes, total bilirubin, and lactate dehydrogenase. A lymphocyte stimulation test yielded positive results for entecavir, which was consequently discontinued. Treatment with topical betamethasone led to improvement of the rash within a week. The patient declined an entecavir rechallenge (Yamada et al, 2011).
    d) TELBIVUDINE: In a pooled analysis of 2 double-blind, clinical studies (007 GLOBE and NV-02B-015) in patients with chronic hepatitis B treated with either telbivudine 600 mg/day (n=847) or lamivudine 100 mg/day (n=852) for a median of 104 weeks, the incidence of rash was 4% vs 3%, respectively. Most adverse events reported were considered mild to moderate in severity and were not attributed to telbivudine (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).
    C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) ADEFOVIR: A 59-year-old man developed Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) overlap syndrome following adefovir dipivoxil treatment for chronic hepatitis B infection. The patient presented for hospitalization on day 28 of adefovir therapy (10 mg daily) with a 3-day history of fever, chills, malaise, headache, and nausea that progressed to include the appearance of a rash over the skin and mucosa. Physical examination revealed widespread papules and multiple erythematous dusky patches, very loosely attached to the skin (covering the back, trunk, external ears, and upper and lower limbs), as well as mucosal involvement (ocular, oral, and genital) with hemorrhagic crusts on the lips comprising in total less than 30% of the body surface area. The central portion of many lesions showed flaccid vesiculation. The only change to the patient's medication regimen in the prior 2 months was the addition of adefovir dipivoxil. Skin biopsy taken from a nonbullous lesion on the patient's back showed mild hyperkeratosis, a normal spinous cell later with basal cell degeneration, and an unremarkable dermis with minimal inflammation. A diagnosis of SJS-TEN overlap syndrome was made, and the patient was managed with supportive care and treatment (antihistamines, sterile dressing changes, temperature control, and electrolyte monitoring) until the lesions improved. Following discontinuation of adefovir, the patient improved and the rash began to resolve within one week; the patient was discharged home in stable condition (Chattopadhyay & Sarma, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) TELBIVUDINE: Isolated cases of rhabdomyolysis have been reported with postmarketing use of telbivudine (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).
    B) FINDING OF CREATINE KINASE LEVEL
    1) WITH THERAPEUTIC USE
    a) TELBIVUDINE: In a pooled analysis of 2, double-blind, clinical studies (007 GLOBE and NV-02B-015) in patients with chronic hepatitis B treated with either telbivudine 600 mg/day (n=847) or lamivudine 100 mg/day (n=852) for a median of 104 weeks, the incidence of elevated creatine kinase was 11% vs 6%, respectively. The incidence of a grade 3/4 increase in creatine kinase (CK) levels (greater than 7 times the ULN) was 13% vs 4%, respectively. Elevated creatine kinase was a common adverse event leading to telbivudine discontinuation (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) ENTECAVIR: In clinical trials, hyperglycemia (fasting glucose greater than 250 mg/dL) was reported in 2% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 1% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, hyperglycemia was reported in 2% of patients (n=183) receiving entecavir 1 mg and 1% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    1) ENTECAVIR: In clinical trials, glycosuria was reported in 4% of nucleoside-naive patients (n=679) receiving entecavir 0.5 mg and 3% of patients (n=668) receiving lamivudine 100 mg. In lamivudine-refractory patients, glycosuria was reported in 4% of patients (n=183) receiving entecavir 1 mg and 6% of patients (n=190) receiving lamivudine 100 mg (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010)

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) ENTECAVIR: Anaphylactoid reaction has been reported with entecavir therapy during postmarketing surveillance (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).

Reproductive

    3.20.1) SUMMARY
    A) ADEFOVIR and ENTECAVIR are classified as FDA pregnancy category C. TELBIVUDINE is classified as FDA pregnancy category B. In animal studies, embryotoxicity, maternal toxicity, and an increased incidence of fetal malformations were observed following the administration of intravenous ADEFOVIR to pregnant rats. Following ENTECAVIR exposures, rats and rabbits experienced maternal toxicity, embryofetal toxicity, lower fetal body weights, tail and vertebral malformations, reduced ossifications, and extra lumbar vertebrae and ribs. TELBIVUDINE was shown to be safe and effective during all trimesters of pregnancy in a study of 86 pregnant women who had hepatitis B virus (HBV), in a total of 89 pregnancies. TELBIVUDINE has been shown to cross the placenta in studies involving pregnant rats and rabbits. ENTECAVIR and TELBIVUDINE have been shown to be excreted in the milk of rats. Seminiferous tubular degeneration was noted in rodents and dogs and testicular degeneration was noted in dogs following ENTECAVIR exposure.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of antiviral nucleoside agents (Prod Info BARACLUDE(R) oral tablets, solution, 2008; Prod Info TYZEKA oral solution, oral tablets, 2009).
    B) ADEFOVIR
    1) Paternal administration of adefovir may be associated with a case of human fetal complex congenital heart defects. The patient's 32-year-old husband was perinatally infected with hepatitis B virus and was receiving treatment with adefovir 10 mg/day prior to and during the pregnancy. A detailed fetal echocardiography performed at 24-weeks gestation in a 28-year-old woman revealed fetal dextrocardia with a double-outlet right ventricle, pulmonary stenosis, a ventricular septum defect, discordant atrioventricular connection, and mitral stenosis. The pregnancy was voluntarily terminated and an autopsy was performed. The autopsy confirmed the findings and also discovered bilaterally trilobed lungs. All prenatal serologic tests were normal, there was no family history of congenital heart disease, and there was no known exposure to other teratogens prior to or during the pregnancy (Gu et al, 2014).
    C) ANIMAL STUDIES
    1) ADEFOVIR ORAL ADMINISTRATION
    a) RATS - When adefovir dipivoxil was administered orally to pregnant rats at doses producing systemic exposures (approximately 23 times that achieved in humans at the therapeutic dose of 10 mg/day) and in rabbits (40 times that in the human) no embryotoxicity or teratogenicity were observed (Prod Info HEPSERA(R) oral tablets, 2008).
    2) ADEFOVIR INTRAVENOUS ADMINISTRATION
    a) RATS - When adefovir was administered intravenously to pregnant rats at a systemic exposure 12 times that in humans, no adverse effects on development were observed. An increased incidence of fetal malformations (anasarca, depressed eye bulge, umbilical hernia and kinked tail) were observed following the administration of adefovir to pregnant rats at intravenous doses 38 times that in humans (Prod Info HEPSERA(R) oral tablets, 2008).
    3) ENTECAVIR
    a) RATS, RABBITS - In a peri-postnatal animal study, no adverse effects on offspring were observed with entecavir administered orally at exposures 28 times and 212 times those in humans in rats and rabbits, respectively (Prod Info BARACLUDE(R) oral tablets, solution, 2008).
    4) TELBIVUDINE
    a) RATS, RABBITS - Telbivudine has been shown to cross the placenta in studies involving pregnant rats and rabbits. Developmental studies exposing rats and rabbits to telbivudine at doses up to 1000 mg/kg/day, 6 and 37 times, respectively, higher than doses used in humans (600 mg/day) showed no signs of harm to the fetus (Prod Info TYZEKA oral solution, oral tablets, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to antiviral nucleoside agents during pregnancy in humans (Prod Info HEPSERA(R) oral tablets, 2008; Prod Info BARACLUDE(R) oral tablets, solution, 2008; Prod Info TYZEKA oral solution, oral tablets, 2009).
    B) PREGNANCY CATEGORY
    1) ADEFOVIR and ENTECAVIR are classified by their manufacturers as FDA pregnancy category C (Prod Info HEPSERA(R) oral tablets, 2008; Prod Info BARACLUDE(R) oral tablets, solution, 2008).
    2) TELBIVUDINE is classified by the manufacturer as FDA pregnancy category B (Prod Info TYZEKA oral solution, oral tablets, 2009).
    C) TELBIVUDINE
    1) Telbivudine therapy was administered to 86 pregnant women who had hepatitis B virus (HBV), in a total of 89 pregnancies. Prior to 20 weeks of gestation, 6.7% of women reported spontaneous abortion or early embryonic death, 1.1% reported ectopic pregnancy, with an overall pregnancy failure rate of 7.9%. During the study period, 52 full-term live infants were born to 50 mothers; of those infants, 3.8% had congenital abnormalities. At delivery, 86% of mothers who delivered full-term infants had HBV DNA less than 500 copies/mL. Out of 15 mothers with HBV DNA greater than 500 copies/mL prior to pregnancy, 60% achieved HBV DNA less than 500 copies/mL. Of the 5 patients who received no antiviral treatment prior to pregnancy, 4 had abnormal ALT (greater than or equal to 2 times the ULN) and high replication of HBV DNA within 12 weeks of gestation. Telbivudine administration also resulted in rapid suppression of HBV DNA and ALT normalization. During telbivudine therapy, all patients maintained normal ALT levels, and there were no reports of liver disease progression. Telbivudine resistance was reported in 31.6% of lamivudine-experienced patients compared with 6.5% of lamivudine-naive patients. Of the 52 full-term, live-birth infants, 5.8% had low birth weight (less than 2500 g) and 1 infant had macrosomia (greater than or equal to 4000 g). All other infants were of normal weight and there were no reports of abnormal hearing, congenital phenylketonuria, or hypothyroidism. There were no obvious developmental or intellectual abnormalities in infants followed for more than 1 and 2 years. During a 6-month follow-up period, there were no reports of HBV surface antigen positivity. This indicates a 100% success rate in blocking mother-to-infant transmission (Liu et al, 2013).
    D) ANIMAL STUDIES
    1) ADEFOVIR
    a) RATS - Embryotoxicity and maternal toxicity were observed following the administration of adefovir to pregnant rats at intravenous doses 38 times that in humans (Prod Info HEPSERA(R) oral tablets, 2008).
    2) ENTECAVIR
    a) RATS, RABBITS - No embryotoxicity or maternal toxicity was observed following systemic exposures approximately 28 and 212 times those achieved at the highest recommended dose of 1 mg/day in humans in rats and rabbits, respectively. Following exposures 3100 times those in humans, rats experienced maternal toxicity, embryo-fetal toxicity (resorptions), lower fetal body weights, tail and vertebral malformations, reduced ossifications (vertebrae, sternebrae, and phalanges), and extra lumbar vertebrae and ribs. Following exposures 883 times those in humans, rabbits experienced embryo-fetal toxicity (resorptions), reduced ossification (hyoid), and an increased incidence of 13th rib (Prod Info BARACLUDE(R) oral tablets, solution, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) At the time of this review, no data were available to assess the potential effects of exposure to antiviral nucleoside agents during lactation in humans (Prod Info HEPSERA(R) oral tablets, 2008; Prod Info BARACLUDE(R) oral tablets, solution, 2008; Prod Info TYZEKA oral solution, oral tablets, 2009).
    B) ANIMAL STUDIES
    1) ENTECAVIR and TELBIVUDINE have been shown to be excreted in the milk of rats (Prod Info BARACLUDE(R) oral tablets, solution, 2008; Prod Info TYZEKA oral solution, oral tablets, 2009).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to antiviral nucleoside agents in humans (Prod Info HEPSERA(R) oral tablets, 2008; Prod Info BARACLUDE(R) oral tablets, solution, 2008; Prod Info TYZEKA oral solution, oral tablets, 2009).
    B) ANIMAL STUDIES
    1) ADEFOVIR
    a) RATS - Impaired fertility was not observed in male or female rats at systemic exposure approximately 19 times that achieved in humans at the therapeutic dose (Prod Info HEPSERA(R) oral tablets, 2008).
    2) ENTECAVIR
    a) DOGS - In a 2-week study, dogs developed testicular degeneration after receiving 10 mg/kg of entecavir (Billich, 2001).
    b) MONKEYS- No testicular changes were observed in monkeys following exposure to entecavir (Prod Info BARACLUDE(R) oral tablets, solution, 2008).
    c) RATS - In animal studies, animals were administered entecavir at up to 30 mg/kg for up to 4 weeks. Following systemic exposures greater than 90 times those achieved in humans at the highest recommended dose of 1 mg/day, no evidence of impaired fertility was observed in male or female rats (Prod Info BARACLUDE(R) oral tablets, solution, 2008).
    d) RODENTS, DOGS - In rodents and dogs, seminiferous tubular degeneration was noted at exposures equal to or greater than 35 times those achieved in human (Prod Info BARACLUDE(R) oral tablets, solution, 2008).
    3) TELBIVUDINE
    a) RATS - No evidence of impaired fertility was observed in male or female rats exposed to doses 14 times the therapeutic dose of humans (Prod Info TYZEKA(TM) oral tablets, 2006).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) ENTECAVIR - In mouse and rat studies, entecavir was carcinogenic after exposures up to approximately 42 times (mice) and 35 times (rats) those observed in humans at the highest recommended dose of 1 mg/day (Prod Info Baraclude(TM), 2005).
    a) Following exposures 3 and 40 times those in humans, lung adenomas were increased in male and female mice (Prod Info Baraclude(TM), 2005).
    b) Following exposures 40 times those in humans, vascular tumors in female mice (hemangiomas of ovaries and uterus and hemangiosarcomas of spleen) were increased (Prod Info Baraclude(TM), 2005).
    c) Following exposures 42 times those in humans, increased incidence of hepatocellular carcinomas in males and increased incidence of combined liver adenomas and carcinomas were observed. Increased incidence of hepatocellular adenomas were observed in rats at exposures 24 times those in humans; increased incidence of combined adenomas and carcinomas were also observed at exposures 24 times those in humans(Prod Info Baraclude(TM), 2005).
    d) Following exposures 35 and 24 times those in humans, brain gliomas were observed in both males and females, respectively (Prod Info Baraclude(TM), 2005).
    e) Following exposures 4 times those in humans, skin fibromas were observed in females (Prod Info Baraclude(TM), 2005).
    B) LACK OF EFFECT
    1) ADEFOVIR - In long-term animal studies, no carcinogenic effects were observed in rats and mice following adefovir dipivoxil exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the therapeutic dose for HBV infection (Prod Info Hepsera(R), 2004).
    2) TELBIVUDINE - In long-term studies, no carcinogenic effects were observed in rats and mice at exposures up to 14 times those observed in humans (600 milligrams/day) (Prod Info TYZEKA(TM) oral tablets, 2006).

Genotoxicity

    A) ADEFOVIR - In the in vitro human peripheral blood lymphocyte assay, adefovir induced chromosomal aberrations without metabolic activation (Prod Info Hepsera(R), 2004).
    B) ADEFOVIR - In the in vitro mouse lymphoma cell assay, adefovir dipivoxil was mutagenic with or without metabolic activation. In the in vivo mouse micronucleus assay, adefovir dipivoxil was not clastogenic. In the Ames bacterial reverse mutation assay using S typhimurium and E coli strains, adefovir was not mutagenic in the presence or absence of metabolic activation (Prod Info Hepsera(R), 2004).
    C) ENTECAVIR - In studies, entecavir was clastogenic to human lymphocyte cultures (Prod Info Baraclude(TM), 2005).
    D) ENTECAVIR - In a gene toxicity study, entecavir caused chromosomal aberrations (Billich, 2001).
    E) ENTECAVIR - In studies, entecavir was not mutagenic in the Ames bacterial reverse mutation assay using S typhimurium and E coli strains in the presence or absence of metabolic activation, a mammalian-cell gene mutation assay, and a transformation assay with Syrian hamster embryo cells (Prod Info Baraclude(TM), 2005).
    F) TELBIVUDINE - No evidence of genotoxicity was shown on in vitro or in vivo tests. Telbivudine was not mutagenic using the Ames bacterial reverse mutation assay, with or without metabolic activation. No clastogenic activity was seen in the mammalian-cell gene assay with or without activation. No effects were observed in a micronucleus study in mice (Prod Info TYZEKA(TM) oral tablets, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, renal function, and liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    C) Monitor serum lactate and arterial blood gases in symptomatic patients.
    D) Monitor CK; monitor renal function, and urine output in patients with rhabdomyolysis. Isolated cases of rhabdomyolysis have been reported with postmarketing use of telbivudine.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe vomiting, profuse diarrhea, electrolyte abnormalities, lactic acidosis, hepatic failure, or renal failure.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours to assess electrolyte and fluid balance. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs, renal function, and liver enzymes in symptomatic patients.
    B) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    C) Monitor serum lactate and arterial blood gases in symptomatic patients.
    D) Monitor CK; monitor renal function, and urine output in patients with rhabdomyolysis. Isolated cases of rhabdomyolysis have been reported with postmarketing use of telbivudine.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs, renal function, and liver enzymes in symptomatic patients.
    2) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    3) Monitor serum lactate and arterial blood gases in symptomatic patients.
    4) Monitor CK; monitor renal function, and urine output in patients with rhabdomyolysis. Isolated cases of rhabdomyolysis have been reported with postmarketing use of telbivudine.
    B) ACIDOSIS
    1) Untreated patients with lactic acidosis may develop confusion, hypotension, coma, and circulatory collapse.
    2) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    3) Monitor serum sodium to avoid overload.
    4) L-CARNITINE: Preliminary data from a pilot study of 6 patients suggested that L-carnitine may be helpful for patients with symptomatic nucleoside-analog-related lactic acidosis (Claessens et al, 2003). The dose used by these authors was L-carnitine 50 milligrams/kilogram/day as a 2 hour infusion 3 times/day in patients not receiving dialysis. For patients receiving continuous hemodiafiltration the dose was 100 mg/kg/day by continuous infusion.
    5) RIBOFLAVIN: Riboflavin deficiency has been proposed as a mechanism in AIDS patients who develop lactic acidosis and hepatic steatosis while taking antiretroviral nucleoside analogues (Fouty et al, 1998). These authors have treated 3 patients with this syndrome with riboflavin 50 mg and reported return of serum lactate levels to normal. In another case, resistant lactic acidosis improved within 4 days after treatment with riboflavin 50 mg/day orally(Luzzati et al, 1999).
    C) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value for entecavir or telbivudine because of the large volume of distribution of these agents. Hemodialysis would likely be effective for adefovir.
    2) ADEFOVIR: Approximately 35% of a single 10 mg dose of adefovir has been removed by 4 hours of hemodialysis (Prod Info Hepsera(R), 2004).
    3) ENTECAVIR: Approximately 13% of a single 1-mg dose of entecavir has been removed by 4 hours of hemodialysis (Prod Info Baraclude(TM), 2005).
    4) TELBIVUDINE: Approximately 23% of a single 200-mg dose of telbivudine has been removed by 4 hours of hemodialysis (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).

Range Of Toxicity

Summary

    A) ADEFOVIR: Gastrointestinal side effects have been reported in patients following doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks.
    B) ENTECAVIR: Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days did not experience any unexpected adverse events.
    C) TELBIVUDINE: Healthy subjects who received telbivudine at doses up to 1800 mg/day for 4 days did not experience any unexpected adverse events.
    D) THERAPEUTIC DOSES: ADULTS: ADEFOVIR: 10 mg orally once daily. ENTECAVIR: Varies by indication; 0.5 mg to 1 mg orally once daily. TELBIVUDINE: 600 mg orally once daily. CHILDREN: ADEFOVIR: (12 years and older) 10 mg orally once daily. Safety and efficacy of adefovir in pediatric patients below the age of 12 years have not been established. ENTECAVIR: (16 years and older): Varies by indication; 0.5 mg to 1 mg orally once daily. Safety and efficacy of entecavir in pediatric patients below the age of 16 years have not been established. TELBIVUDINE: (16 years and older) 600 mg orally once daily. Safety and efficacy of telbivudine in pediatric patients below the age of 16 years have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ADEFOVIR: 10 mg orally once daily (Prod Info HEPSERA oral tablets, 2009).
    B) ENTECAVIR: Varies by indication; 0.5 mg to 1 mg orally once daily (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010)
    C) TELBIVUDINE: 600 mg orally once daily (Prod Info Tyzeka(R) oral tablets, oral solution, 2011)
    7.2.2) PEDIATRIC
    A) ADEFOVIR: (12 years and older) 10 mg orally once daily (Prod Info HEPSERA oral tablets, 2009).
    B) ADEFOVIR: Safety and efficacy of adefovir in pediatric patients below the age of 12 years have not been established (Prod Info HEPSERA oral tablets, 2009).
    C) ENTECAVIR: (16 years and older): Varies by indication; 0.5 mg to 1 mg orally once daily (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    D) ENTECAVIR: Safety and efficacy of entecavir in pediatric patients below the age of 16 years have not been established (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    E) TELBIVUDINE: (16 years and older) 600 mg orally once daily (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).
    F) TELBIVUDINE: Safety and efficacy of telbivudine in pediatric patients below the age of 16 years have not been established (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).

Maximum Tolerated Exposure

    A) ADEFOVIR: Gastrointestinal side effects have been reported in patients following doses of adefovir dipivoxil 500 mg daily for 2 weeks and 250 mg daily for 12 weeks (Prod Info HEPSERA oral tablets, 2009).
    B) ENTECAVIR: Healthy subjects who received single entecavir doses up to 40 mg or multiple doses up to 20 mg/day for up to 14 days did not experience any unexpected adverse events (Prod Info BARACLUDE(R) oral solution, oral tablets, 2010).
    C) TELBIVUDINE: Healthy subjects who received telbivudine at doses up to 1800 mg/day for 4 days did not experience any unexpected adverse events (Prod Info Tyzeka(R) oral tablets, oral solution, 2011).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADEFOVIR - Plasma level/efficacy correlations in clinical studies lacking. Hepatitis B in vitro data: concentrations of 0.2 to 2.5 micromoles inhibited 50% of viral DNA synthesis in HBV transfected human hepatoma cell lines (Prod Info Hepsera(R), 2004).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ADEFOVIR
    1) Adefovir dipivoxil is a diester prodrug of adefovir, and is rapidly converted to adefovir after oral doses. Adefovir is an acyclic nucleotide analogue of adenosine monophosphate. It is phosphorylated via cellular enzymes to active form, adefovir diphosphate. This active form inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. In HBV transfected human hepatoma cell lines, adefovir concentrations of 0.2 to 2.5 micromols/L inhibited 50% of viral DNA synthesis. Adefovir has shown activity in vitro and clinically against isolates of HBV containing lamivudine-resistance-associated mutations (Prod Info Hepsera(R), 2004).
    B) ENTECAVIR
    1) Entecavir is a guanosine nucleoside analogue antiviral agent with selective activity against HBV polymerase. It is phosphorylated to active form, entecavir triphosphate with an intracellular half-life of 15 hours. Entecavir triphosphate functionally inhibits all three activities of the HBV polymerase (reverse transcriptase, rt): [1-base priming, 2-reverse transcription of the negative strand from the pregenomic messenger RNA, and 3-synthesis of the positive strand of HBV DNA] by competing with the natural substrate deoxyguanosine triphosphate (Prod Info Baraclude(TM), 2005).
    C) TELBIVUDINE
    1) Telbivudine (beta-L-2'-deoxythymidine) is a synthetic thymidine nucleoside analog with activity against hepatitis B virus by competitive inhibition of both viral reverse transcriptase and DNA polymerase. Like other nucleoside analogues, the antiviral activity of telbivudine is dependent on its conversion intracellulary to telbivudine triphosphate. Once incorporated into viral DNA (anti-complement or second-strand DNA) by hepatitis B polymerase, DNA chain termination results. Evidence suggests telbivudine may be devoid of mitochondrial toxicity and subsequent outcomes of neuropathy, myopathy, and lactic acidemia because telbivudine does not inhibit human cellular polymerase alfa, beta, or gamma (Prod Info TYZEKA(TM) oral tablets, 2006; Kim et al, 2006).

Physicochemical

Physical Characteristics

    A) ADEFOVIR - A white to off-white crystalline powder with an aqueous solubility of 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2 (Prod Info Hepsera(R), 2004).
    B) ENTECAVIR - A white to off-white powder, slightly soluble in water (2.4 mg/mL) (Prod Info Baraclude(TM), 2005).
    C) TELBIVUDINE - Telbivudine is a white to slightly yellow powder that is sparingly soluble in water at concentrations greater than 20 mg/mL, and very slightly soluble in absolute ethanol (at a concentration of 0.7 mg/mL) and n-octanol (at a concentration of 0.1 mg/mL)(Prod Info TYZEKA(TM) oral tablets, 2006).

Molecular Weight

    1) ADEFOVIR - 501.48 (Prod Info Hepsera(R), 2004)
    2) ENTECAVIR - 295.3 (Prod Info Baraclude(TM), 2005)
    3) TELBIVUDINE - 242.23 (Prod Info TYZEKA(TM) oral tablets, 2006)

References

General Bibliography

    1) Anon: GS840 - Hepatitis B infections (press release), Gilead Sciences, Foster City, CA, 1996b.
    2) Anon: GS840 - therapeutic trials - viral infections (press release), Gilead Sciences, Foster City, CA, 1995.
    3) Arends S, van Halteren E, Kamp W, et al: Safety of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in patients with human immunodeficiency virus infection. Pharm World Sci 1996; 18:30-34.
    4) Billich A: Entecavir. Current Opinion Invest Drugs 2001; 2(5):617-621.
    5) Brown CV, Rhee P, Chan L, et al: Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?. J Trauma 2004; 56(6):1191-1196.
    6) Camp NE: Drug- and toxin-induced Rhabdomyolysis. J Emerg Nurs 2009; 35(5):481-482.
    7) Chattopadhyay P & Sarma N: Adefovir-induced Stevens-Johnson syndrome and toxic epidermal necrolysis overlap syndrome. Singapore Med J 2011; 52(2):e31-e34.
    8) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    9) Claessens YE, Cariou A, Monchi M, et al: Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients, and treatment with L-carnitine. Crit Care Med 2003; 31:1042-1047.
    10) Criddle LM: Rhabdomyolysis. Pathophysiology, recognition, and management. Crit Care Nurse 2003; 23(6):14-22, 24-26, 28.
    11) Cundy KC, Barditch-Crovo P, Walker RE, et al: Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother 1995; 39:2401-2405.
    12) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    13) Erdman AR & Dart RC: Rhabdomyolysis. In: Dart RC, Caravati EM, McGuigan MA, et al, eds. Medical Toxicology, 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2004, pp 123-127.
    14) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    15) Fouty B, Frerman F, & Reves R: Riboflavin to treat nucleoside analogue-induced lactic acidosis. Lancet 1998; 352:291-292.
    16) Galan MV, Boyce D, Gordon SC, et al: Current pharmacotherapy for hepatitis B infection. Expert Opin Pharmacother 2001; 2(8):1289-1298.
    17) Gilson RI, Chopra K, Murray-Lyon I et al: Adefovir dipivoxil (bis-POM PMEA) treatment for chronic hepatitis B infection: a placebo-controlled phase#I/II study (abstract). Prog Abstr 36th Intersci Conf Antimicrob Agents Chemother (ICAAC), Sept 15-18, 1996, New Orleans, LA, Am Soc Microbiol (electronic version). Abstracts-On-Disk(R), Marathon Multimedia, Northfield, MN, 1995, 1995.
    18) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    19) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    20) Gu Y, Ru T, Zhou YH, et al: Adefovir as a possible teratogen: evidence from paternal exposure. Dig Liver Dis 2014; 46(12):1134-1135.
    21) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    22) Homsi E, Barreiro MF, Orlando JM, et al: Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail 1997; 19(2):283-288.
    23) Huerta-Alardin AL, Varon J, & Marik PE: Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care 2005; 9(2):158-169.
    24) Joannidis M: Drug-induced renal failure in the ICU. Ont J Artif Organs 2004; 27:1034-1042.
    25) Kahn J, Lagakos S, Wulfsohn M, et al: Efficacy and safety of adefovir dipivoxil with antiretroviral therapy. JAMA 1999; 282(24):2305-2312.
    26) Kim JW, Park SH, & Louie SG: Telbivudine: a novel nucleoside analog for chronic hepatitis B. Ann Pharmacother 2006; 40(3):472-478.
    27) Kraut JA & Madias NE: Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010; 6(5):274-285.
    28) Lai CL, Gane E, Liaw YF, et al: Telbivudine (LDT) vs. lamivudine for chronic hepatitis B: First-year results from the international phase III GLOBE trial. Hepatology 2005; 42(S1):748A-.
    29) Lange CM , Bojunga J , Hofmann WP , et al: Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology 2009; 50(6):2001-2006.
    30) Liu M, Cai H, & Yi W: Safety of telbivudine treatment for chronic hepatitis B for the entire pregnancy. J Viral Hepat 2013; 20 Suppl 1:65-70.
    31) Luzzati R, Bravo PD, & Perri GD: Riboflavine and severe lactic acidosis (letter). Lancet 1999; 353:901-902.
    32) Naesens L, Balzarini J, & De Clercq E: Pharmacokinetics in mice of the anti-retrovirus agent 9-(2-phosphonylmethoxyethyl)adenine. Drug Metab Disp 1992; 20:747-752.
    33) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    34) Polderman KH: Acute renal failure and rhabdomyolysis. Int J Artif Organs 2004; 27(12):1030-1033.
    35) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    36) Product Information: BARACLUDE(R) oral solution, oral tablets, entecavir oral solution, oral tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2010.
    37) Product Information: BARACLUDE(R) oral tablets, solution, entecavir oral tablets, solution. Bristol-Myers Squibb, Princeton, NJ, 2008.
    38) Product Information: Baraclude(TM), entecavir tablets, oral solution. Bristol-Myers Squibb Company, Princeton, NJ, 2005.
    39) Product Information: HEPSERA oral tablets, adefovir dipivoxil oral tablets. Gilead Sciences, Inc., Foster City, CA, 2009.
    40) Product Information: HEPSERA(R) oral tablets, adefovir dipivoxil oral tablets. Gilead Sciences,Inc., Foster City, CA, 2008.
    41) Product Information: Hepsera(R), Adefovir dipivoxil. Gilead Sciences, Inc, Foster City, CA, 2004.
    42) Product Information: TYZEKA oral solution, oral tablets, telbivudine oral solution, oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2009.
    43) Product Information: TYZEKA(TM) oral tablets, telbivudine oral tablets. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2006.
    44) Product Information: Tyzeka(R) oral tablets, oral solution, telbivudine oral tablets, oral solution. Novartis Pharmaceuticals, East Hanover, NJ, 2011.
    45) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    46) Vanholder R, Sever MS, Erek E, et al: Rhabdomyolysis. J Am Soc Nephrol 2000; 11(8):1553-1561.
    47) Walter LA & Catenacci MH: Rhabdomyolysis. Hosp Physician 2008; 44(1):25-31.
    48) Yamada S, Sawada Y, & Nakamura M: Maculopapular-type drug eruption caused by entecavir. Eur J Dermatol 2011; 21(4):635-636.
    49) Zhou XJ, Lim SG, Lloyd DM, et al: Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: pharmacodynamic implications. Antimicrob Agents Chemother 2006; 50(3):874-879.