Sebivo

Chronic Hepatitis B

Sebivo is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

The following points should be considered when initiating therapy with Sebivo:

• This indication is based on virologic, serologic, biochemical and histologic responses in nucleoside treatment naïve adult patients with HBeAg positive and HBeAg negative chronic hepatitis B with compensated liver disease.
• For HBeAg-positive patients, Sebivo should only be initiated in patients with HBV DNA less than 9 log₁₀ copies per mL and ALT greater than or equal to 2x Upper Limit of Normal (ULN) prior to treatment.
• For HBeAg-negative patients, Sebivo should only be initiated in patients with HBV DNA less than 7 log₁₀ copies per mL prior to treatment.
• On-treatment response should guide continued therapy.
• Sebivo has not been evaluated in patients co-infected with HIV, HCV or HDV.
• Sebivo has not been evaluated in liver transplant recipients or in patients with decompensated liver disease.
• Sebivo has not been studied in well-controlled trials for the treatment of patients with established nucleoside analog reverse transcriptase inhibitor-resistant hepatitis B virus infection, but is expected to be cross-resistant to lamivudine.
• The safety and efficacy of Sebivo have not been evaluated in Black/African American or Hispanic patients.

Adults and Adolescents (16 years of age and older)

Due to higher rates of resistance that may develop with longer term treatment among patients with incomplete viral suppression, treatment should only be initiated, if pre-treatment HBV DNA and ALT measurements are known, in the following patient populations:

For HBeAg-positive patients, HBV DNA should be less than 9 log₁₀ copies per mL and ALT should be greater than or equal to 2x ULN prior to treatment with Sebivo.

For HBeAg-negative patients, HBV DNA should be less than 7 log₁₀ copies per mL prior to treatment with Sebivo.

HBV DNA levels should be monitored at 24 weeks of treatment to assure complete viral suppression (HBV DNA less than 300 copies per mL). Alternate therapy should be initiated for patients who have detectable HBV DNA after 24 weeks of treatment. Optimal therapy should be guided by further resistance testing.

The recommended dose of Sebivo for the treatment of chronic hepatitis B is 600 mg once daily, taken orally, with or without food.

Sebivo Oral Solution (30 mL) may be considered for patients who have difficulty with swallowing tablets.

Renal Impairment

Sebivo may be used for the treatment of chronic hepatitis B in patients with impaired renal function. No adjustment to the recommended dose of Sebivo is necessary in patients whose creatinine clearance is greater than or equal to 50 mL per min. Adjustment of the total daily dose of Sebivo Oral Solution or of the interval for administration of Sebivo tablets is required in patients with creatinine clearance less than 50 mL per min including those with ESRD on hemodialysis (Table 1).

Table 1 : Dose Adjustment of Sebivo in Patients with Renal Impairment

Hepatic Impairment

No adjustment to the recommended dose of Sebivo is necessary in patients with hepatic impairment.

Duration of Therapy

For patients with incomplete viral suppression (HBV DNA greater than or equal to 300 copies per mL) after 24 weeks of treatment, alternate therapy should be instituted. HBV DNA should be monitored every 6 months to assure continued response. If patients test positive for HBV DNA at any time after their initial response, alternate treatment should be instituted. Optimal therapy should be guided by resistance testing.

The optimal duration of therapy with Sebivo for patients with chronic hepatitis B is unknown.

Combination of Sebivo with pegylated interferon alfa-2a is contraindicated because of increased risk of peripheral neuropathy.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lactic Acidosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering HBV nucleoside analogue reverse transcriptase inhibitors to patients with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Sebivo should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Exacerbations of Hepatitis B after Discontinuation of Treatment

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Sebivo. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Myopathy

Cases of myopathy/myositis have been reported with Sebivo use several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class. Rhabdomyolysis has been reported during postmarketing use of Sebivo.

Uncomplicated myalgia has been reported in Sebivo-treated patients. Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness in conjunction with increases in creatine kinase (CK) values, should be considered in any patient with diffuse myalgias, muscle tenderness, or muscle weakness. Among patients with Sebivo-associated myopathy, no pattern with regard to the degree or timing of CK elevations has been observed. In addition, the predisposing factors for the development of myopathy among Sebivo recipients are unknown. Patients should be advised to report promptly unexplained muscle aches, pain, tenderness, or weakness. Sebivo therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is confirmed. It is unknown whether the risk of myopathy during treatment with drugs in this class is increased with concurrent administration of other drugs associated with myopathy, including but not limited to: corticosteroids, chloroquine, hydroxychloroquine, certain HMGCoA reductase inhibitors, fibric acid derivatives, penicillamine, zidovudine, cyclosporine, erythromycin, niacin, and certain azole antifungals. Physicians initiating concomitant treatment with any drug associated with myopathy should monitor patients closely for any signs or symptoms of unexplained muscle pain, tenderness, or weakness.

Peripheral Neuropathy

Peripheral neuropathy has been reported with Sebivo alone or in combination with pegylated interferon alfa-2a and other interferons. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of Sebivo 600mg daily and pegylated interferon alfa-2a 180 micrograms once weekly compared to Sebivo or pegylated interferon alfa-2a alone. Such risk cannot be excluded for other dose regimens of pegylated interferon alfa-2a, or other alfa interferons (pegylated or standard). The safety and efficacy of Sebivo in combination with pegylated interferons or other interferons for the treatment of chronic hepatitis B have not been demonstrated. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Sebivo therapy should be interrupted if peripheral neuropathy is suspected, and discontinued if peripheral neuropathy is confirmed.

Patient Counseling Information

• See FDA-approved patient labeling (Medication Guide and Instructions for Use)

Patients should remain under the care of a physician while taking Sebivo. They should discuss any new symptoms or concurrent medications with their physician.

Patients should be advised to report promptly unexplained muscle weakness, tenderness, or pain.

Patients should be advised to report promptly any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without difficulty walking.

Patients should be advised that Sebivo is not a cure for hepatitis B, that the long-term treatment benefits of Sebivo are unknown at this time. In particular, the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown.

Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician.

Patients should be advised that treatment with Sebivo has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. HBV prevention strategies should be discussed with patients, including safe sexual practices, and avoidance of needle sharing or sharing any personal items which may contain residual blood or body fluids, such as razor blades or toothbrushes. Additionally, a vaccine is available for prevention of hepatitis B infection in susceptible individuals.

Patients on a low sodium diet should be advised that Sebivo oral solution contains approximately 47 mg of sodium per 600 mg dose (30 mL).

Patients should be advised to dispose of unused or expired Sebivo by using a community pharmaceutical take-back disposal program, or by placing unused Sebivo in a closed container, such as a sealed bag, into household trash. All identifying information should be removed from the original Sebivo container prior to disposal.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Telbivudine has shown no carcinogenic potential. Long term oral carcinogenicity studies with telbivudine were negative in mice and rats at exposures up to 14 times those observed in humans at the therapeutic dose of 600 mg per day.

There was no evidence of genotoxicity based on in vitro or in vivo tests. Telbivudine was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains with or without metabolic activation. Telbivudine was not clastogenic in mammalian-cell gene mutation assays, including human lymphocyte cultures and an assay with Chinese hamster ovary cells with or without metabolic activation. Furthermore, telbivudine showed no effect in an in vivo micronucleus study in mice.

Effects on fertility were studied in rats administered telbivudine as juveniles or adults. Juvenile rats were treated with telbivudine at doses of 0, 250, 1000, and 2000 mg per kg per day from post natal days 14 to 70. These rats were mated following a 5 week drug-free recovery period. Up to 50% reduction of fertility was associated with doses 1000 mg per kg per day and higher, which was equivalent to a systemic exposure approximately 7.5 times that achieved in humans at the therapeutic dose. The no observed adverse effect level (NOAEL) for effects on fertility or mating parameters was 250 mg per kg per day, which was equivalent to systemic exposure levels 2.5 to 2.8 times that achieved in humans at the therapeutic dose. In contrast, such reduction of fertility was absent in adult rats treated with telbivudine at doses up to 2000 mg per kg per day, equivalent to a systemic exposure approximately 14 times that achieved in humans at the therapeutic dose.

Use In Specific Populations

Pregnancy

Category B

Telbivudine is not teratogenic and has shown no adverse effects in developing embryos and fetuses in preclinical studies. Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta. Developmental toxicity studies revealed no evidence of harm to the fetus in rats and rabbits at doses up to 1000 mg per kg per day, providing exposure levels 6- and 37-times higher, respectively, than those observed with the 600 mg per day dose in humans.

There are no adequate and well-controlled trials of Sebivo in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, Sebivo should be used during pregnancy only if potential benefits outweigh the risks.

Pregnancy Registry

To monitor fetal outcomes of pregnant women exposed to Sebivo, healthcare providers are encouraged to register such patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263.

Labor and Delivery

There are no trials in pregnant women and no data on the effect of Sebivo on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.

Nursing Mothers

Telbivudine is excreted in the milk of rats. It is not known whether Sebivo is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving Sebivo.

Pediatric Use

Safety and effectiveness of Sebivo in pediatric patients have not been established.

Geriatric Use

Clinical trials of Sebivo did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised when prescribing Sebivo to elderly patients, considering the greater frequency of decreased renal function due to concomitant disease or other drug therapy. Renal function should be monitored in elderly patients, and dosage adjustments should be made accordingly.

Renal Impairment

Sebivo is eliminated primarily by renal excretion, therefore dose regimen adjustment is recommended in patients with creatinine clearance less than 50 mL per min, including patients with ESRD requiring hemodialysis.

Liver Transplant Recipients

The safety and efficacy of Sebivo in liver transplant recipients have not been evaluated. The steady-state pharmacokinetics of Sebivo was not altered following multiple dose administration in combination with cyclosporine. If Sebivo treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function should be monitored both before and during treatment with Sebivo.

Co-infected Patients

Sebivo has not been investigated in co-infected hepatitis B patients (e.g., patients co-infected with HIV, HCV, or HDV).

Racial/Ethnic Minorities

The safety and efficacy of Sebivo have not been evaluated in Black/African American or Hispanic patients. It is not known if safety and efficacy can be extrapolated from studied populations.

The following adverse reactions are discussed in other sections of the labeling:

• Lactic acidosis and severe hepatomegaly with steatosis
• Severe acute exacerbations of hepatitis after discontinuation of treatment
• Myopathy
• Peripheral Neuropathy

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Assessment of adverse reactions is primarily based on two trials (007 GLOBE and NV-02B-015) in which 1,699 subjects with chronic hepatitis B received double-blind treatment with Sebivo 600 mg per day (n=847 subjects) or lamivudine (n=852 subjects) for 104 weeks. The median duration of therapy was 104 weeks for both treatment groups.

In the 104 week clinical trials, most adverse experiences reported with Sebivo were classified as mild or moderate in severity and were not attributed to Sebivo. Selected adverse events of any severity which were reported in greater than or equal to 3% of Sebivo and lamivudine recipients are shown in Table 2. With the exception of increased creatine kinase (CK), which was reported more frequently among Sebivo recipients, the adverse event profile was similar for the two drugs.

Table 2 : Selected Common Adverse Events^a in Pooled Trials 007 GLOBE and NV-02B-015

Moderate to severe (Grade 2-4) adverse events were reported in 239/847 (28%) of Sebivo recipients and 229/852 (27%) of lamivudine recipients. The profile of adverse events of moderate to severe intensity was similar in both treatment groups and no individual adverse event was reported in greater than 2% of subjects in either treatment group.

Discontinuations due to adverse events were reported in 4% of Sebivo recipients and 4% of lamivudine recipients. The most common adverse events resulting in Sebivo discontinuation included increased CK, nausea, diarrhea, fatigue, myalgia, and myopathy.

Peripheral neuropathy was reported as an adverse event in less than 1% (2/847) of subjects receiving Sebivo monotherapy. Of Sebivo-treated subjects less than 1% (5/847) were diagnosed with myopathy/myositis (presenting with muscular weakness).

Laboratory Abnormalities

Frequencies of selected treatment-emergent laboratory abnormalities in the 007 GLOBE and NV-02B-015 trials are listed in Table 3.

Table 3 : Selected Treatment-Emergent Grade 3-4 Laboratory Abnormalities^a in Patients with Chronic Hepatitis B in the 104-Week Pooled 007 GLOBE and NV-02B-015 Trials

Creatine Kinase (CK) Elevations

Creatine kinase (CK) elevations were more frequent among subjects on Sebivo treatment. By 104 weeks of treatment, Grade 1-4 CK elevations occurred in 79% of Sebivo-treated subjects and 47% of lamivudine-treated subjects. Grade 3 or 4 CK elevations occurred in 13% of Sebivo-treated subjects and 4% of lamivudine-treated subjects. Most CK elevations were asymptomatic, but the mean recovery time was longer for subjects on Sebivo than subjects on lamivudine.

Among Sebivo-treated subjects with Grade 1-4 CK elevations, 10% developed a musculoskeletal adverse event compared to 5% of lamivudine-treated subjects. A total of 2% (13/847) Sebivo-treated subjects interrupted or discontinued trial drug due to CK elevation or musculoskeletal adverse events¹.

ALT Flares During Treatment

The incidence of ALT flares, defined as ALT greater than 10 x ULN and greater than 2 x baseline, was similar in the two treatment arms (3%) in the first six months. After week 24, ALT flares were reported less frequently in the Sebivo arm (2%) compared to the lamivudine arm (5%). Periodic monitoring of hepatic function is recommended during chronic hepatitis B treatment.

Exacerbations of Hepatitis after Discontinuation of Treatment

In the subset of subjects who discontinued treatment prematurely for reasons other than efficacy, or who elected not to continue Sebivo in another clinical trial, 9/154 (6%) Sebivo-treated and 10/180 (6%) lamivudine-treated subjects experienced an exacerbation of hepatitis (ALT elevation greater than 2 x baseline and greater than 10 x ULN) in the 4-month post-treatment period.

Results at 208 Weeks

After 104 weeks of blinded therapy in trials 007 GLOBE and NV-02B-015, 667 subjects received Sebivo in an open-label extension trial, CLDT600A2303. Of those initially randomized to Sebivo therapy, 78% of subjects (530/680) from trial 007 GLOBE and 82% (137/167) of subjects from trial NV-02B-015 enrolled into the extension trial and continued Sebivo treatment for up to 208 weeks. The long-term Sebivo safety population in trial CLDT600A2303 consisted of 655 subjects, including 518 subjects from trial 007 GLOBE and 137 subjects from trial NV-02B-015.

The overall safety profile from the pooled analysis up to 104 and 208 weeks was similar. Grade 3/4 CK elevations occurred in 16% of subjects (104/655) treated with Sebivo in trial CLDT600A2303. Most grade 3/4 CK elevations were asymptomatic (74% of subjects without any muscle related adverse reaction) and transient (98% of episodes lasted one or two visits (visit interval 2 - 12 weeks) and 87% of subjects had one or two episodes). Most grade 3/4 CK elevations (93%) resolved spontaneously or returned to baseline levels. Two cases of myopathy and two cases of myositis were reported in the 655 Sebivo-treated subjects.

Among the cohort of 655 subjects continuing Sebivo for up to 208 weeks in trial CLDT600A2303, including the subgroup of patients (n=223) with mild renal impairment (eGFR 60-90 mL per min) at baseline, mean estimated GFR assessed by MDRD did not decline.

Postmarketing Experience

The following adverse reactions have been reported during post approval use of Sebivo. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders

Rhabdomyolysis

Nervous System Disorders

Paraesthesia, hypoaesthesia

Metabolism and Nutrition Disorders

Lactic acidosis

¹Includes the Preferred Terms: back pain, chest wall pain, non-cardiac chest pain, chest discomfort, flank pain, muscle cramp, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, myofascial pain syndrome, myopathy, myositis, neck pain, and pain in extremity.

There is no information on intentional overdose of Sebivo, but one subject experienced an unintentional and asymptomatic overdose. Healthy subjects who received Sebivo doses up to 1800 mg per day for 4 days had no increase in or unexpected adverse events. A maximum tolerated dose for Sebivo has not been determined. In the event of an overdose, Sebivo should be discontinued, the patient must be monitored for evidence of toxicity, and appropriate general supportive treatment applied as necessary.

In case of overdosage, hemodialysis may be considered. Within 2 hours, following a single 200 mg dose of telbivudine, a 4-hour hemodialysis session removed approximately 23% of the telbivudine dose.