Data from FDA - Curated by EPG Health - Last updated 25 January 2018

Indication(s)

1 INDICATIONS AND USAGE Tyzeka is an HBV nucleoside analogue reverse transcriptase inhibitor 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 (1.1). 1.1 Chronic Hepatitis B Tyzeka 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 Tyzeka: 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 [see Clinical Studies (14)]. For HBeAg-positive patients, Tyzeka 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, Tyzeka 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 [see Dosage and Administration (2.1) and Microbiology (12.4)]. Tyzeka has not been evaluated in patients co-infected with HIV, HCV, or HDV. Tyzeka has not been evaluated in liver transplant recipients or in patients with decompensated liver disease. Tyzeka 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 [see Microbiology (12.4)]. The safety and efficacy of Tyzeka have not been evaluated in Black/African American or Hispanic patients [see Use in Specific Populations (8.9)].

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Advisory information

contraindications
4 CONTRAINDICATIONS Combination of Tyzeka with pegylated interferon alfa-2a is contraindicated because of increased risk of peripheral neuropathy [see Warnings and Precautions (5.4) and Drug Interactions (7)]. Combination of Tyzeka with pegylated interferon alfa-2a: Increased risk of peripheral neuropathy (4).
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.1)] Severe acute exacerbations of hepatitis after discontinuation of treatment [see Boxed Warning, Warnings and Precautions (5.2)] Myopathy [see Warnings and Precautions (5.3)] Peripheral Neuropathy [see Warnings and Precautions (5.4)] In clinical trials, the most common adverse reactions (greater than or equal to 3%), of any severity, were: fatigue, increased creatine kinase (CK), headache, cough, diarrhea, abdominal pain, nausea, pharyngolaryngeal pain, arthralgia, pyrexia, rash, back pain, dizziness, myalgia, ALT increased, dyspepsia, insomnia, and abdominal distension (6.1). The most common adverse events resulting in Tyzeka discontinuation included increased CK, nausea, diarrhea, fatigue, myalgia, and myopathy (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 Tyzeka 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 Tyzeka were classified as mild or moderate in severity and were not attributed to Tyzeka. Selected adverse events of any severity which were reported in greater than or equal to 3% of Tyzeka and lamivudine recipients are shown in Table 2. With the exception of increased creatine kinase (CK), which was reported more frequently among Tyzeka recipients, the adverse event profile was similar for the two drugs. Table 2 Selected Common Adverse Eventsa in Pooled Trials 007 GLOBE and NV-02B-015 Adverse Event (Preferred Term) Tyzeka N=847 n (%) b Lamivudine N=852 n (%) b Fatigue 106 (13) 95 (11) CK increased 90 (11) 52 (6) Headache 83 (10) 95 (11) Cough 52 (6) 45 (5) Diarrhea 50 (6) 46 (5) Abdominal pain, upper 49 (6) 52 (6) Nausea 45 (5) 40 (5) Pharyngolaryngeal pain 38 (5) 31 (4) Arthralgia 37 (4) 38 (5) Pyrexia 34 (4) 27 (3) Rash 33 (4) 21 (3) Back pain 33 (4) 32 (4) Dizziness 32 (4) 43 (5) Abdominal pain 29 (3) 31 (4) Myalgia 27 (3) 17 (2) ALT increased 27 (3) 31 (4) Dyspepsia 24 (3) 39 (5) Insomnia 24 (3) 22 (3) Abdominal distension 22 (3) 19 (2) Pruritus 18 (2) 23 (3) Hepatitis B exacerbation 17 (2) 36 (4) a Adverse events reported in greater than or equal to 3% subjects in either treatment group b n (%) = the number and proportion of subjects in whom adverse event was reported Moderate to severe (Grade 2-4) adverse events were reported in 239/847 (28%) of Tyzeka 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 Tyzeka recipients and 4% of lamivudine recipients. The most common adverse events resulting in Tyzeka 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 Tyzeka monotherapy [see Warnings and Precautions (5.4)]. Of Tyzeka-treated subjects less than 1% (5/847) were diagnosed with myopathy/myositis (presenting with muscular weakness) [see Warnings and Precautions (5.3)]. 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 Abnormalitiesa in Patients with Chronic Hepatitis B in the 104-Week Pooled 007 GLOBE and NV-02B-015 Trials Test Tyzeka 600 mg (n=847) Lamivudine 100 mg (n=852) Creatine Kinase (CK) greater than 7.0 x ULN 13% 4% ALT greater than 10.0 x ULN and 2.0 x baselineb 5% 8% ALT greater than 3 x baseline 7% 13% AST (SGOT) greater than 3.0 x baseline 6% 10% Lipase greater than 2.5 x ULN 2% 4% Amylase greater than 3.0 x ULN less than 1% less than 1% Total Bilirubin greater than 5.0 x ULN less than 1% less than 1% Neutropenia (ANC less than or equal to 749/mm3) 2% 2% Thrombocytopenia (Platelets less than or equal to 49,999/mm3) less than 1% less than 1% a On-treatment value worsened from baseline to Grade 3 or Grade 4 during therapy b American Association for the Study of Liver Diseases (AASLD) definition of acute hepatitis flare Creatine Kinase (CK) Elevations Creatine kinase (CK) elevations were more frequent among subjects on Tyzeka treatment. By 104 weeks of treatment, Grade 1-4 CK elevations occurred in 79% of Tyzeka-treated subjects and 47% of lamivudine-treated subjects. Grade 3 or 4 CK elevations occurred in 13% of Tyzeka-treated subjects and 4% of lamivudine-treated subjects. Most CK elevations were asymptomatic, but the mean recovery time was longer for subjects on Tyzeka than subjects on lamivudine. Among Tyzeka-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) Tyzeka-treated subjects interrupted or discontinued trial drug due to CK elevation or musculoskeletal adverse events1. ______________________ 1 Includes 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. ______________________ 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 Tyzeka arm (2%) compared to the lamivudine arm (5%). Periodic monitoring of hepatic function is recommended during chronic hepatitis B treatment. Exacerbations of Hepatitis a fter Discontinuation of Treatment In the subset of subjects who discontinued treatment prematurely for reasons other than efficacy, or who elected not to continue Tyzeka in another clinical trial, 9/154 (6%) Tyzeka-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 Tyzeka in an open-label extension trial, CLDT600A2303. Of those initially randomized to Tyzeka 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 Tyzeka treatment for up to 208 weeks. The long-term Tyzeka 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 Tyzeka 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 Tyzeka-treated subjects. Among the cohort of 655 subjects continuing Tyzeka 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. 6.2 Postmarketing Experience The following adverse reactions have been reported during post approval use of Tyzeka. 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

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Adults and Adolescents (16 years of age and older): 600 mg once daily, taken orally, with or without food (2.1). Renal Impairment: Dose adjustment required in patients with creatinine clearance less than 50 mL per min, (2.2) as follows: Creatinine Clearance (mL/min) Tyzeka Dose Oral Solution ( 100 mg/ 5 mL) Tablet (600 mg) greater than or equal to 50 30 mL once daily 1 tab every 24 hrs 30 – 49 20 mL once daily 1 tab every 48 hrs less than 30 (not requiring dialysis) 10 mL once daily 1 tab every 72 hrs End stage renal disease (ESRD) 6 mL once daily 1 tab every 96 hrs1 1When administered on hemodialysis days, administer Tyzeka after hemodialysis (2.2). 2.1 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 Tyzeka. For HBeAg-negative patients, HBV DNA should be less than 7 log10 copies per mL prior to treatment with Tyzeka. 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 Tyzeka for the treatment of chronic hepatitis B is 600 mg once daily, taken orally, with or without food. Tyzeka oral solution (30 mL) may be considered for patients who have difficulty with swallowing tablets. 2.2 Renal Impairment Tyzeka may be used for the treatment of chronic hepatitis B in patients with impaired renal function. No adjustment to the recommended dose of Tyzeka is necessary in patients whose creatinine clearance is greater than or equal to 50 mL per min. Adjustment of the total daily dose of Tyzeka oral solution or of the interval for administration of Tyzeka 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 Tyzeka in Patients with Renal Impairment Creatinine Clearance ( mL /min) Tyzeka Oral Solution Dose (5 mL = 100 mg) Tyzeka Tablet Dose (1 tablet = 600 mg) greater than or equal to 50 30 mL once daily 1 tablet every 24 hrs 30-49 20 mL once daily 1 tablet every 48 hrs less than 30 (not requiring dialysis) 10 mL once daily 1 tablet every 72 hrs ESRD 6 mL once daily 1 tablet every 96 hrs1 1When administered on hemodialysis days, Tyzeka should be administered after hemodialysis. 2.3 Hepatic Impairment No adjustment to the recommended dose of Tyzeka is necessary in patients with hepatic impairment. 2.4 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 Tyzeka for patients with chronic hepatitis B is unknown.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 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 Tyzeka in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, Tyzeka should be used during pregnancy only if potential benefits outweigh the risks. Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to Tyzeka, healthcare providers are encouraged to register such patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263. 8.2 Labor and Delivery There are no trials in pregnant women and no data on the effect of Tyzeka on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection. 8.3 Nursing Mothers Telbivudine is excreted in the milk of rats. It is not known whether Tyzeka is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving Tyzeka. 8.4 Pediatric Use Safety and effectiveness of Tyzeka in pediatric patients have not been established. 8.5 Geriatric Use Clinical trials of Tyzeka 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 Tyzeka 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 [see Clinical Pharmacology (12. 3 ) and Dosage and Administration (2.2)]. 8.6 Renal Impairment Tyzeka 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 [s ee Dosage and Administration (2.2) and Clinical Pharmacology (12. 3 )]. 8.7 Liver Transplant Recipients The safety and efficacy of Tyzeka in liver transplant recipients have not been evaluated. The steady-state pharmacokinetics of Tyzeka was not altered following multiple dose administration in combination with cyclosporine. If Tyzeka 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 Tyzeka [see Clinical Pharmacology (12.3) and Dosage and Administration (2.2)]. 8.8 Co-infected Patients Tyzeka has not been investigated in co-infected hepatitis B patients (e.g., patients co-infected with HIV, HCV, or HDV). 8.9 Racial/Ethnic Minorities The safety and efficacy of Tyzeka 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.
Pregnancy and lactation
8.3 Nursing Mothers Telbivudine is excreted in the milk of rats. It is not known whether Tyzeka is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving Tyzeka.

Interactions

7 DRUG INTERACTIONS Tyzeka is excreted mainly by passive diffusion so the potential for interactions between Tyzeka and other drugs eliminated by renal excretion is low. However, because Tyzeka is eliminated primarily by renal excretion, coadministration of Tyzeka with drugs that alter renal function may alter plasma concentrations of Tyzeka [see Clinical Pharmacology (12.3)]. A clinical trial investigating the combination of Tyzeka, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of peripheral neuropathy occurrence and severity, in comparison to Tyzeka or pegylated interferon alfa-2a alone [see Contraindications (4) and Warnings and Precautions (5.4)]. Coadministration of Tyzeka with drugs that affect renal function may alter plasma concentrations of Tyzeka and/or coadministered drug (7). Coadministration of Tyzeka with pegylated interferon alfa-2a increases the risk and severity of peripheral neuropathy (7).

More information

Category Value
Authorisation number NDA022011
Agency product number 2OC4HKD3SF
Orphan designation No
Product NDC 0078-0538
Date Last Revised 22-12-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 665122
Marketing authorisation holder Novartis Pharmaceuticals Corporation
Warnings WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS AND SEVERE ACUTE EXACERBATIONS OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue s alone or in combination with antiretrovirals [ s ee Warnings and Precautions (5.1) ] . Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti - hepatitis B therapy, including Tyzeka. 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 [ see Warnings and Precautions (5 .2 ) ]. WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS AND SEVERE ACUTE EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. L actic acidosis and severe hepatomegaly with steatosis , including fatal cases, have been reported with the use of nucleoside analogu es (5.1) . Severe acute exacerbations of hepatitis B have been reported in patients who discontinue d anti-hepatitis B therapy , including Tyzeka. Hepatic function should be monitored closely in patients who discontinue therapy . Resumption of anti-hepatitis B therapy may be warranted (5.2).