Tyzeka

Telbivudine comes as a tablet to take by mouth. It is usually taken once a day with or without food. Take telbivudine at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take telbivudine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Ask your pharmacist or doctor for a copy of the manufacturer's information for the patient.

Before taking telbivudine,

• tell your doctor and pharmacist if you are allergic to telbivudine or any other medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: chloroquine (Aralen);erythromycin (E.E.S., E-Mycin, Erythrocin); fenofibrate (Antara, Lofibra, Triglide); gemfibrozil (Lopid); hydroxychloroquine (Plaquenil); medications to prevent rejection of a transplanted organ, such as cyclosporine (Neoral, Sandimmune) or tacrolimus (Prograf); medications to treat fungal infections such as fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), posaconazole (Noxafil), or voriconazole (Vfend); oral steroids such as dexamethasone (Decadron, Dexone), methylprednisolone (Medrol), and prednisone; (Deltasone), penicillamine (Cuprimine); probenecid; or zidovudine (AZT, Retrovir, in Combivir, in Trizivir). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• Tell your doctor if you have or have ever had a liver transplant (surgery to replace a diseased liver), or kidney disease.
• Tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking telbivudine, call your doctor. Do not breastfeed while you are taking telbivudine.
• If you are having surgery, including dental surgery, tell the doctor or dentist that you are taking telbivudine.

You should not take telbivudine if you are allergic to it, or if you are also using peginterferon alfa-2b (PegIntron, PegIntron Redipen, Sylatron).

To make sure you can safely take telbivudine, tell your doctor if you have any of these other conditions:

• kidney disease;
• other types of hepatitis (C or D);
• HIV or AIDS;
• if you have received a liver transplant; or
• if any hepatitis B medications you received in the past did not work well in treating your condition.

Some people develop a life-threatening condition called lactic acidosis while taking telbivudine. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk.

It is not known whether this medication is safe to use while you are pregnant. Telbivudine may not keep you from passing hepatitis B to your unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while you are taking telbivudine.

If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of telbivudine on the baby.

It is not known whether telbivudine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give telbivudine to a child younger than 16 years old without the advice of a doctor.

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Peginterferon Alfa-2a

Tyzeka is part of the drug class:

• Nucleoside and nucleotide reverse transcriptase inhibitors

Tell your healthcare provider about all of your medical conditions, including if you:

• have kidney problems. You may need a lower dose of Tyzeka.
• have any allergies.
• are pregnant or planning to become pregnant. It is not known if Tyzeka is safe to use during pregnancy. It is not known whether Tyzeka helps prevent a pregnant mother from passing HBV to her baby. You and your healthcare provider will need to decide if Tyzeka is right for you. If you use Tyzeka while you are pregnant, talk to your healthcare provider.
• are breastfeeding. It is not known if Tyzeka can pass into your breast milk or if it can harm your baby. Do not breastfeed if you are taking Tyzeka.

Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements.

If you take too much Tyzeka, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If Tyzeka is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Telbivudine is an antiviral medication. It works by preventing viral cells from multiplying in the body and infecting new liver cells.

Telbivudine is used to treat chronic hepatitis B in adults. This medicine will not cure hepatitis.

Telbivudine may also be used for purposes not listed in this medication guide.

In the U.S.

• Tyzeka

Available Dosage Forms:

• Tablet
• Solution

Therapeutic Class: Antiviral

Chemical Class: Thymidine Nucleoside Analog

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

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

• Chills
• cough
• diarrhea
• fever
• general feeling of discomfort or illness
• headache
• joint pain
• loss of appetite
• muscle aches and pains
• nausea
• runny nose
• shivering
• sore throat
• stomach pain
• sweating
• trouble with sleeping
• unusual tiredness or weakness
• vomiting

• Back pain
• chest pain
• difficulty with moving
• muscle cramping
• muscle stiffness
• muscle tenderness, wasting, or weakness
• pain
• pain in the extremity
• swollen joints

• Burning feeling in the chest or stomach
• indigestion
• loose stools
• stomach upset
• tenderness in the stomach area

• Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• dark-colored urine
• decreased appetite
• fast, shallow breathing
• muscle pain or spasms
• shortness of breath
• sleepiness

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

• Body aches or pain
• difficulty with breathing
• ear congestion
• loss of voice
• nasal congestion
• sneezing
• stuffy nose

• Acid or sour stomach
• belching
• dizziness
• heartburn
• rash
• sleeplessness
• stomach discomfort
• unable to sleep

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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)].

     Clinical Experience in Nucleoside-Naïve Adults

The safety and efficacy of long-term (104-week) Tyzeka treatment were evaluated in one active-controlled, clinical trial (NV-02B-007 GLOBE Trial) that included 1,367 subjects with chronic hepatitis B and a smaller supportive trial (NV-02B-015) that included 332 subjects. Subjects were 16 years of age or older, with chronic hepatitis B, evidence of HBV infection with viral replication (HBsAg-positive, HBeAg-positive or HBeAg-negative, HBV DNA detectable by a PCR assay), and elevated ALT levels greater than or equal to 1.3 x ULN, no evidence of hepatic decompensation, and chronic inflammation on liver biopsy compatible with chronic viral hepatitis.

NV-02B-007 GLOBE Trial

The Week 52 and Week 104 results of the 007 GLOBE trial are summarized below.

The 007 GLOBE trial was a Phase III, randomized, double-blind, multinational trial of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 1,367 (n= 680 Tyzeka; n=687 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative subjects. The primary data analysis was conducted after all subjects had reached Week 52.

HBeAg-positive Subjects: (n= 458 Tyzeka; n= 463 lamivudine) The mean age of subjects was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.52 log10 copies per mL; and mean serum ALT was 153 IU per L. Pre- and post-liver biopsy samples were adequate for 86% of subjects.

HBeAg-negative Subjects: (n=222 Tyzeka; n= 224 lamivudine)The mean age of subjects was 43 years, 77% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 7.54 log10 copies per mL; and mean serum ALT was 140 IU per L. Pre- and post-liver biopsy samples were adequate for 92% of subjects.

Clinical Results 

Clinical and virologic efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative subject populations. 

The primary endpoint of Therapeutic Response at Week 52 was a composite endpoint requiring suppression of HBV DNA to less than 5 log10 copies per mL in conjunction with either loss of serum HBeAg or ALT normalization. Key secondary endpoints included histologic response, ALT normalization, and measures of virologic response.

At Week 52, in HBeAg-positive subjects, 75% of Tyzeka subjects and 67% of lamivudine subjects had a Therapeutic Response; in HBeAg-negative subjects, 75% of Tyzeka subjects and 77% of lamivudine subjects had a Therapeutic Response.

Analysis of the histological response at Week 52 is shown in Table 6.

Subjects were eligible to continue blinded treatment to Week 104. In the ITT population, 624/680 (92%) Tyzeka recipients and 599/687 (87%) lamivudine recipients completed trial treatment to Week 104. At Week 104, in HBeAg-positive subjects, 63% of Tyzeka subjects and 48% of lamivudine subjects had a Therapeutic Response, while in HBeAg-negative subjects 78% of Tyzeka subjects and 66% of lamivudine subjects had a Therapeutic Response.

Selected virologic, biochemical, and serologic outcome measures at Weeks 52 and 104 are shown in Table 7.

Subjects who achieved non-detectable HBV DNA levels at 24 weeks were more likely to undergo e-antigen seroconversion, achieve undetectable levels of HBV DNA, normalize ALT, and were less likely to develop resistance at one and two years.

NV-02B-015 Trial

The efficacy results of the 007 GLOBE trial were supported by results of trial NV-02B-015. This was a Phase III, randomized, double-blind, trial of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 (n=167 Tyzeka; n=165 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese subjects. The primary efficacy endpoint was serum HBV DNA reduction from baseline. In this trial, the composite endpoint Therapeutic Response was a key secondary endpoint. Histological response was not assessed as an outcome measure in this trial.

Clinical Results 

Among HBeAg-positive subjects (n=147 Tyzeka; n=143 lamivudine) results for key endpoints at Week 104 included Therapeutic Response (66% vs. 41%), mean HBV DNA reduction (-5.47 vs. -3.97 log10 copies per mL), HBV DNA PCR negativity (58% vs. 34%), ALT normalization (73% vs. 59%), HBeAg loss (40% vs. 28%) and HBeAg seroconversion (29% vs. 20%), for Tyzeka and lamivudine, respectively. Because the number of HBeAg-negative subjects in this trial was small (n=42), definitive conclusions could not be drawn regarding efficacy outcomes in this subpopulation.

Taking Tyzeka will not prevent you from passing hepatitis B to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Get emergency medical help if you have any of these signs of an allergic reaction to Tyzeka: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. This medication may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time.

Get emergency medical help if you have even mild symptoms of lactic acidosis, such as:

• muscle pain or weakness;

• numb or cold feeling in your arms and legs;

• trouble breathing;

• feeling dizzy, light-headed, tired, or very weak;

• stomach pain, nausea with vomiting; or

• fast or uneven heart rate.

Call your doctor at once if you have any other serious side effects, such as:

• muscle tenderness, or weakness (may occur several weeks or months after you start taking Tyzeka);

• fever or flu symptoms and dark colored urine;

• burning, pain or tingly feeling in your arms or legs; or

• liver symptoms - nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Less serious Tyzeka side effects may include:

• cough, sore throat;

• headache, tired feeling;

• dizziness;

• muscle aches;

• low fever;

• bloating, mild nausea, vomiting, diarrhea;

• itching or mild skin rash;

• joint pain, back pain; or

• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Applies to telbivudine: oral solution, oral tablet

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

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

• Chills
• cough
• diarrhea
• fever
• general feeling of discomfort or illness
• headache
• joint pain
• loss of appetite
• muscle aches and pains
• nausea
• runny nose
• shivering
• sore throat
• stomach pain
• sweating
• trouble with sleeping
• unusual tiredness or weakness
• vomiting

• Back pain
• chest pain
• difficulty with moving
• muscle cramping
• muscle stiffness
• muscle tenderness, wasting, or weakness
• pain
• pain in the extremity
• swollen joints

• Burning feeling in the chest or stomach
• indigestion
• loose stools
• stomach upset
• tenderness in the stomach area

• Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• dark-colored urine
• decreased appetite
• fast, shallow breathing
• muscle pain or spasms
• shortness of breath
• sleepiness

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

• Body aches or pain
• difficulty with breathing
• ear congestion
• loss of voice
• nasal congestion
• sneezing
• stuffy nose

• Acid or sour stomach
• belching
• dizziness
• heartburn
• rash
• sleeplessness
• stomach discomfort
• unable to sleep