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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.
PEGASYS (BLA-103964)
(PEGINTERFERON ALFA-2A)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
12/11/2023 (SUPPL-5276)
Boxed Warning
5.15 Impact on Growth in Pediatric Patients
(Additions and/or revisions underlined)
Growth inhibition was observed in CHC pediatric subjects 5 to 17 years of age during combination therapy for up to 48 weeks with PEGASYS plus ribavirin. At the end of treatment, 43% of subjects were more than 15 percentiles below their baseline weight curve, and 25% of subjects were more than 15 percentiles below their baseline height curve. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight and height; 16% of subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.
The available longer-term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients [see Clinical Trials Experience (6.1)].
Growth inhibition was also observed in CHB pediatric subjects 3 to 17 years of age during therapy with PEGASYS lasting up to 48 weeks. At Week 48 of treatment 13% of subjects were more than 15 percentiles below their baseline weight curve and 6% were more than 15 percentiles below their baseline height curve. At 24 weeks after the end of treatment, 11% of subjects were more than 15 percentiles below their baseline weight curve and 12% were more than 15 percentiles below their baseline height curve. At 5 years post-treatment the percentage of subjects with decrease of more than 15 percentiles from baseline was 29% for weight and 18% for height. [see Clinical Trials Experience (6.1)].
6 Adverse Reactions
6.1 Clinical Trials Experience
Chronic Hepatitis B
Pediatric Subjects
(Additions and/or revisions underlined)
In a clinical trial with 111 subjects 3 to 17 years of age treated with PEGASYS for 48 weeks, the safety profile was consistent with that seen in adults with CHB and in pediatric subjects with CHC. The most commonly observed adverse reactions in PEGASYS-treated patients were pyrexia (51%), headache (21%), abdominal pain (17%), cough (15%), vomiting (15%), influenza-like illness (14%), alanine aminotransferase increased (10%),aspartate aminotransferase increased (10%), rash (10%), asthenia (9.0%), epistaxis (9.0%), nausea (9.0%), fatigue (8%), upper respiratory tract infection (8%), alopecia (6%), decreased appetite (6%), dizziness (6%), and nasopharyngitis (6%).
Growth inhibition in CHB pediatric subjects [see Warnings and Precautions (5.15)].
The mean changes from baseline in z-scores for height and weight for age were -0.07 and -0.21 for PEGASYS- treated subjects at Week 48. Comparable findings were observed in untreated patients at Week 48 (changes in z- scores for height and weight for age were -0.01 and -0.08, respectively). At Week 48 of PEGASYS treatment, a height or weight decrease of more than 15 percentiles on the normative growth curves was observed in 6% of subjects for height and 13% of subjects for weight. At 24 weeks after the end of PEGASYS treatment the percentage of subjects with decrease of more than 15 percentiles from baseline was 12% for height and 11% for weight. At 5 years post-treatment, the percentage of subjects with decrease of more than 15 percentiles from baseline was 18% for height and 29% for weight.
Other
(COPEGUS revised to read ribavirin thorough out labeling)
10/13/2017 (SUPPL-5270)
5 Warnings and Precautions
5.15 Impact on Growth in Pediatric Patients(Additions and/or revisions are underlined)
Growth inhibition was observed in CHC pediatric subjects 5 to 17 years of age during combination therapy for up to 48 weeks with PEGASYS plus ribavirin. At the end of treatment, 43% of subjects were more than 15 percentiles below their baseline weight curve, and 25% of subjects were more than 15 percentiles below their baseline height curve. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight and height; 16% of subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.
The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients.
Growth inhibition was also observed in CHB pediatric subjects 3 to 17 years of age during therapy with PEGASYS lasting up to 48 weeks. At Week 48 of treatment 11% of subjects were more than 15 percentiles below their baseline weight curve and 6% were more than 15 percentiles below their baseline height curve. At 24 weeks after the end of treatment, 12% of subjects were more than 15 percentiles below their baseline weight curve and 12% were more than 15 percentiles below their baseline height curve. No data are available on longer term follow-up post-treatment in these patients.
6 Adverse Reactions
6.1 Clinical Trials Experience(Additions and/or revisions are underlined)
Chronic Hepatitis C
Adult Subjects
In all hepatitis C studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS alone or in combination with COPEGUS…
Pediatric Subjects
In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with PEGASYS alone or in combination with COPEGUS, dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia…
Growth inhibition in CHC pediatric subjects
Pediatric subjects treated with PEGASYS plus ribavirin combination therapy showed a delay in weight and height increases up to 48 weeks of therapy compared with baseline…
Chronic Hepatitis B
Adult Subjects
In clinical trials of 48 week treatment duration, the adverse reaction profile of PEGASYS in CHB was similar to that seen in CHC PEGASYS monotherapy use, except for exacerbations of hepatitis…
Pediatric Subjects
In a clinical trial with 111 subjects 3 to 17 years of age treated with PEGASYS for 48 weeks, the safety profile was consistent with that seen in adults with CHB and in pediatric subjects with CHC. The most commonly observed adverse reactions in PEGASYS-treated patients were pyrexia (51%), headache (21%), abdominal pain (17%), cough (15%), vomiting (15%), influenza-like illness (14%), alanine aminotransferase increased (10%), aspartate aminotransferase increased (10%), rash (10%), asthenia (9.0%), epistaxis (9.0%), nausea (9.0%), fatigue (8%), upper respiratory tract infection (8%), alopecia (6%), decreased appetite (6%), dizziness (6%), and nasopharyngitis (6%).
Growth inhibition in CHB pediatric subjects.
The mean changes from baseline in z-scores for height and weight for age were -0.07 and -0.21 for PEGASYS- treated subjects at Week 48. Comparable findings were observed in untreated patients at Week 48 (changes in z- scores for height and weight for age were -0.01 and -0.08, respectively). At Week 48 of PEGASYS treatment, a height or weight decrease of more than 15 percentiles on the normative growth curves was observed in 6% of subjects for height and 11% of subjects for weight. At 24 weeks after the end of PEGASYS treatment the percentage of subjects with decrease of more than 15 percentiles from baseline were 12% for height and 12% for weight. No data are available on longer term follow-up post-treatment in these subjects.
Laboratory Values
Pediatric Subjects
Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment in pediatric subjects. Most laboratory abnormalities noted during the CHC clinical trial (Table 9) returned to baseline levels shortly after completion of treatment.
Table 9 Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects with CHC (Table’s title has been revised)
…
The hematologic laboratory abnormalities observed in the CHB pediatric trial were similar to those observed in the CHC pediatric trial.
(Additions and/or revisions are underlined)
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to peginterferon alfa-2a in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
(Additions and/or revisions are underlined)
Infections and infestations: limb abscess
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Pregnancy Exposure Registry – Use with Ribavirin
A Ribavirin Pregnancy Registry has been established to monitor maternal and fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during pregnancy or who become pregnant within 6 months following cessation of treatment with ribavirin. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.
Risk Summary
There are no adequate and well-controlled studies of PEGASYS in pregnant women to inform a drug-associated risk. Based on animal reproduction studies, PEGASYS can cause fetal harm and should be assumed to have abortifacient potential. Non-pegylated interferon alfa-2a treatment caused abortion when given to pregnant rhesus monkeys. The background risk of major birth defects and miscarriage in the indicated population is 3% and 4-22%, respectively. In the U.S. general population, the estimated background risk for major birth defects and miscarriage in the clinically recognized pregnancies is 2-4% and 15-20%, respectively.
PEGASYS combination treatment with ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin.
Data
Animal Data – Groups of 8 or 9 pregnant rhesus monkeys were given non-pegylated interferon alfa-2a by daily intramuscular injection over days 22 to 70 of gestation at doses of 1, 5 and 25 million IU/day. Two, 3 and 6 monkeys aborted in the low, mid and high dose groups compared with 1 in the control group. Maternal toxicity, characterized by transient body weight loss, was seen at all dose levels. There were too few remaining pregnancies to assess teratogenic potential but no developmental abnormalities were observed in surviving fetuses.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
There is no information regarding the presence of peginterferon alfa-2a in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions from the drugs in nursing infants, a decision must be made whether to discontinue nursing or discontinue PEGASYS. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PEGASYS and any potential adverse effects on the breastfed child from PEGASYS or from the underlying maternal condition.
The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breastfeed their infants to avoid potential transmission of HIV; therefore, CHC- and CHB-infected mothers coinfected with HIV should not breastfeed their infants.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; newly added subsection)
Pregnancy Testing
Females of reproductive potential must undergo pregnancy testing before initiation of treatment with PEGASYS or with PEGASYS in combination with ribavirin or with other HCV drugs.
Females of reproductive potential receiving PEGASYS in combination with ribavirin must have a routine pregnancy test performed monthly during treatment and for at least 6 months following treatment. Female partners of male patients receiving PEGASYS in combination with ribavirin must have a routine pregnancy test performed monthly during treatment and for at least 6 months posttherapy.
Contraception
Females
Because of the abortifacient potential of PEGASYS, females of reproductive potential should be advised to use effective contraception during therapy. However, when receiving PEGASYS in combination with ribavirin, women of reproductive potential and their partners must use effective contraception during treatment and for at least 6 months after the last dose.
Infertility
Females
Based on its mechanism of action and studies in female monkeys, PEGASYS can cause disruption of the menstrual cycle. No female fertility study has been performed.
(Additions and/or revisions are underlined)
PEGASYS is indicated for the treatment of CHC in pediatric patients 5 to 17 years of age and for the treatment of CHB in pediatric patients 3 to 17 years of age.
The use of PEGASYS for the treatment of pediatric patients 5 to 17 years of age with CHC is based on one clinical trial in 114 previously untreated CHC subjects 5 to 17 years of age with compensated liver disease and detectable HCV RNA. The safety and efficacy of PEGASYS in pediatric patients with CHC below the age of 5 years have not been established.
The use of PEGASYS for the treatment of pediatric patients 3 to 17 years of age with CHB is based on one clinical trial in 161 previously untreated CHB subjects 3 to 17 years of age of whom 111 were assigned to treatment with PEGASYS. PEGASYS has not been studied in pediatric CHB patients with liver cirrhosis and the safety and efficacy of PEGASYS in pediatric patients with CHB below the age of 3 years have not been established.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(Additions and/or revisions are underlined)
What is the most important information I should know about PEGASYS?
Ribavirin in combination with PEGASYS may cause birth defects or death of your unborn baby.
- If you or your female sexual partner becomes pregnant during treatment with PEGASYS and Ribavirin or within 6 months after you stop taking PEGASYS and Ribavirin, tell your healthcare provider right away. You or your healthcare provider should contact the Ribavirin Pregnancy Registry by calling 1-800-593-2214. The Ribavirin Pregnancy Registry collects information about the health of you and your baby if you take PEGASYS and Ribavirin during pregnancy or if you become pregnant within 6 months after you stop taking PEGASYS and Ribavirin.
Heart problems. PEGASYS may cause heart problems, including:
- trouble breathing
Before and during treatment with PEGASYS you will need to see your healthcare provider regularly and have blood tests to make sure that your treatment is working and to check for side effects.
PEGASYS can cause serious side effects. Some of these side effects may cause death. Tell your healthcare provider right away if you have any of these symptoms during treatment with PEGASYS.
For more information about side effects, see “What are the possible side effects of PEGASYS?”
What is PEGASYS?
PEGASYS is a prescription medicine that is:
- used with other hepatitis C virus (HCV) antiviral medicines to treat adults who have chronic (lasting a long time) hepatitis C infection and compensated liver disease.
- used alone to treat adults with chronic hepatitis C (CHC) and compensated liver disease, and who are not able to take other HCV antiviral medicines.
- used with Ribavirin to treat children 5 years of age and older who have CHC and compensated liver disease.
PEGASYS should not be used alone or with Ribavirin, without taking other HCV antiviral medicines, to treat people with CHC who have taken interferon-alfa and it did not work.
PEGASYS should not be used to treat people with CHC who have received an organ transplant.
PEGASYS is a prescription medicine that is:
- used alone to treat adults and children 3 years and older with chronic hepatitis B (CHB) virus who show signs that the virus is damaging the liver
It is not known if PEGASYS is safe and effective in:
- children with CHC under 5 years of age or children with CHB under 3 years of age.
- people with Hepatitis B virus (HBV) who also have HCV or HIV infection
- people with HCV who also have HBV, or HIV infection and their CD4+ cell count is less than 100 cells/mm3
Before taking PEGASYS tell your healthcare provider about all of your medical conditions, including if you :
- have or ever had any problems with your heart, including heart attack
- have high blood pressure
- have any kind of autoimmune disease (where the body’s immune system attacks the body’s own cells), such as psoriasis, systemic lupus erythematosus, or rheumatoid arthritis
- have or ever had low blood cell counts
- have or had blood disorders (bleeding problems or a blood clot, thalassemia major or sickle-cell anemia)
- have ever been addicted to drugs or alcohol
- are being treated for a mental illness or had treatment in the past for any mental illness, including depression and suicidal behavior.
- are breastfeeding or plan to breastfeed. It is not known if PEGASYS passes into your breast milk. You and your healthcare provider should decide if you will use PEGASYS or breastfeed. You should not do both.
- If you have HIV-1 infection and are being treated with PEGASYS, you should not breastfeed because of the risk of passing HIV-1 to your baby.
Tell your healthcare provider about all the medicines you take,…
- Do not start a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take PEGASYS with other medicines.
How should I take PEGASYS?
- Your healthcare provider will decide on your dose of PEGASYS and when you will take it. PEGASYS is usually injected 1 time each week. For children 3 years of age and older infected with hepatitis B virus or 5 years of age and older infected with hepatitis C virus, your healthcare provider will prescribe the dose of PEGASYS based on your child’s height and weight.
- When you get your prescription from the pharmacy, ask your pharmacist for the syringe and needle that you need to use to prepare and inject a dose of PEGASYS from the single-dose vial.
- If you will be injecting a child with PEGASYS, you will need a special syringe called a tuberculin syringe, which can measure doses of PEGASYS that are 1 milliliter (1mL) or less.
What should I avoid while taking PEGASYS?
- Avoid driving or operating machinery if you become dizzy, confused, very sleepy, or tired during treatment with PEGASYS.
What are the possible side effects of PEGASYS?
- Blood sugar problems…
Symptoms of low blood sugar may include:
- feeling faint
- headaches
- sweating
- anxiousness
- confusion
- weakness
- Inflammation of your intestines (colitis)…
- Fever
- Serious allergic reactions and skin reactions. Get medical help right away if you get any of the following symptoms: …
(additions underlined)
…
Flu-like symptoms
Inform patients that flu-like symptoms are very common in patients taking PEGASYS. Symptoms may include tiredness, weakness, fever, chills, muscle aches, joint pain, and headaches. Inform patients that some of these symptoms may be decreased by injecting PEGASYS in the evening. Also inform patients which over-the- counter medicines can be taken to help prevent or decrease some of the symptoms.
…
(Additions and/or revisions are underlined)
Flu-like symptoms
Inform patients that flu-like symptoms are very common in patients taking PEGASYS. Symptoms may include tiredness, weakness, fever, chills, muscle aches, joint pain, and headaches. Inform patients that some of these symptoms may be decreased by injecting PEGASYS in the evening. Also inform patients which over-the- counter medicines can be taken to help prevent or decrease some of the symptoms.