Drug Safety-related Labeling Changes (SrLC)
Get Email Alerts |
Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
TYZEKA (NDA-022011)
(TELBIVUDINE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/27/2018 (SUPPL-22)
4 Contraindications
4 CONTRAINDICATIONS(Additions and/or revisions are underlined)
TYZEKA is contraindicated in combination with pegylated interferon alfa-2a because of increased risk of peripheral neuropathy.
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
…
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 [estimated glomerular filtration rate (eGFR) 60- 90 mL per min)] at baseline, mean estimated GFR assessed by modification of diet in renal disease (MDRD) did not decline.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes
in women exposed to TYZEKA
during pregnancy. Healthcare providers
are encouraged to register
patients by calling
the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Prospective pregnancy data from the APR are insufficient to adequately assess the risk of birth defects, miscarriage or adverse maternal or fetal outcomes. Available data from the APR show no increase in the overall risk of major birth defects of telbivudine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of miscarriage is 15%-20% of clinically recognized pregnancies.
In animal reproduction studies, no adverse developmental effects were observed in rats and rabbits at exposures 6- and 37-times higher, respectively, than those observed at the recommended human dose (RHD) of 600 mg per day.
Data
Human Data
Based on prospective reports to the APR of live births following exposure to telbivudine-containing regimens during pregnancy (including 245 exposed in the first trimester and 13 exposed in the second/third trimester), the prevalence of birth defects in live births was 1.2% (95% confidence interval [CI]: 0.3% to 3.5%) for telbivudine with first trimester exposures; the 13 second/third trimester exposures reported to the APR are insufficient to make a risk assessment. Prospective reports from the APR of overall major birth defects in pregnancies exposed TYZEKA is compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
Animal Data
In an embryo-fetal development study, pregnant rabbits received telbivudine at oral doses of 50, 250 or 1000 mg/kg/day during the period of organogenesis (gestation Day 6 to 18). No adverse embryo-fetal effects were observed at doses up to 1000 mg/kg/day. At this dose level, an increased incidence of abortions associated with maternal toxicity was observed at an exposure approximately 37 times the systemic exposure at the RHD of 600 mg per day.
In a prenatal and postnatal development study, pregnant rats received oral doses of telbivudine at 100, 250, or 1000 mg/kg/day from organogenesis, through late gestation, delivery, and lactation (gestation Day 7 to lactation/postpartum Day 20). No adverse effects were observed at doses up to 1000 mg/kg/day, at exposures approximately 6 times the systemic exposure at the RHD.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Risk Summary
It is not known whether TYZEKA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. Telbivudine is present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TYZEKA and any potential adverse effects on the breastfed infant from TYZEKA or from the underlying maternal condition. Data
Telbivudine was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 10 mg per kg on lactation Day 12, with milk concentrations of up to approximately 2.8 times that of maternal plasma concentrations observed 3 hours post-dose.
(Additions and/or revisions are underlined)
Safety and effectiveness of TYZEKA in pediatric patients have not been established.
Juvenile Animal Toxicity Data
In a juvenile animal study, reduced fertility associated with oral telbivudine doses ? 1000 mg/kg/day was observed when administered to sexually immature rats (from postpartum Day 14 to 70). No fertility effects were observed in sexually mature animals.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
See FDA-approved patient labeling (Medication Guide and Instructions for Use) Severe Acute Exacerbation of Hepatitis after Discontinuation of Treatment
Inform patients that discontinuation of anti-hepatitis B therapy, including TYZEKA, may result in severe acute exacerbations of hepatitis B. Advise the patient to not discontinue TYZEKA without first informing their healthcare provider.
Lactic Acidosis and Severe Hepatomegaly
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to TYZEKA. Advise patients to contact their healthcare provider immediately and stop TYZEKA if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.
Myopathy and Rhabdomyolysis
Advise patients that cases of myopathy/myositis have been reported with TYZEKA and to report promptly unexplained muscle weakness, tenderness, or pain.
Peripheral Neuropathy
Inform patients that peripheral neuropathy has been reported with TYZEKA alone or in combination with pegylated interferon alfa-2a and other interferons. Advise patients to report promptly any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without difficulty walking.
Important Administration Instructions
Inform patients that it is important to take TYZEKA on a regular dosing schedule with or without food and to avoid missing doses as it can result in the development of resistance. Inform patients to discuss with their physician any changes in their regimen or discontinuation as deterioration of liver disease may occur in some cases with treatment discontinuation. Advise patients on a low sodium diet that TYZEKA oral solution contains approximately 47 mg of sodium per 600 mg dose (30 mL).
Treatment Duration
Advise patients that in the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. The relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known.
Pregnancy Registry
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TYZEKA during pregnancy.
(Additions and/or revisions are underlined)
…
How should I store TYZEKA?
- Store TYZEKA tablets and TYZEKA oral solution in their original container at room temperature
- 68°F to 77°F (20°C to 25°C).
- Do not freeze TYZEKA oral solution.
- Use TYZEKA oral solution within 2 months after opening the bottle.
- Keep the bottle closed tightly.
- Throw away TYZEKA when it is outdated or no longer needed by taking TYZEKA to a community take- back disposal program, if available, or by placing TYZEKA in a closed container (such as a sealed bag) in the household trash. Remove all identifying information from the original TYZEKA container before throwing it out.
Keep TYZEKA and all medicines out of the reach of children.
…