Drug Safety-related Labeling Changes (SrLC)

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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.

RETACRIT (BLA-125545)

(EPOETIN ALFA-EPBX)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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06/04/2024 (SUPPL-32)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

Chronic Kidney Disease:

In controlled trials, patients with chronic kidney disease (CKD) experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered…

5 Warnings and Precautions

5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer

Extensive changes to table 2; please refer to label for complete information

6 Adverse Reactions

6.3 Immunogenicity

Additions and/or revisions underlined:

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of epoetin alfa or of other epoetin alfa products.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

Use of RETACRIT in pediatric patients with CKD not requiring dialysis is supported by efficacy of epoetin alfa in pediatric patients requiring dialysis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

General information about the safe and effective use of RETACRIT.

06/30/2020 (SUPPL-5)

Approved Drug Label (PDF)

4 Contraindications

Newly added information:

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in:

Neonates, infants, pregnant women, and lactating women [see Warnings and Precautions (5.9), Use in Specific Populations (8.1, 8.2 and 8.4)].

5 Warnings and Precautions

Newly added subsection:

5.9 Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated for use in neonates, infants, pregnant women, and lactating women [see Contraindications (4)]. In addition, do not mix RETACRIT with bacteriostatic saline (which also contains benzyl alcohol) when administering RETACRIT to these patient populations [see Dosage and Administration (2)].

Serious and fatal reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including RETACRIT multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. There is a potential for similar risks to fetuses and infants exposed to benzyl alcohol in utero or in breast-fed milk, respectively. RETACRIT multiple-dose vials contain 8.5 mg of benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.1, 8.2, and 8.4)].

6 Adverse Reactions

6.3 Immunogenicity

Additions and/or revisions underlined:

… For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies to other epoetin alfa products may be misleading …

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in pregnant women [see Contraindications (4)]. When therapy with RETACRIT is needed during pregnancy, use a benzyl alcohol-free formulation (i.e., single-dose vial). Do not mix RETACRIT with bacteriostatic saline when administering to pregnant women because it contains benzyl alcohol (see Clinical Considerations) [see Dosage and Administration (2.1)].

The limited available data on epoetin alfa use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes …

… Clinic al Considerations

Fetal/Neonatal Adverse Reactions

The multiple-dose vials of RETACRIT contain benzyl alcohol. The preservative benzyl alcohol has been associated with serious adverse reactions and death when administered intravenously to neonates and infants [see Warnings and Precautions (5.9), Use in Specific Populations (8.4)]. There is a potential for similar risks to fetuses exposed to benzyl alcohol in utero.

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in lactating women [see Contraindications (4), Warnings and Precautions (5.9)]. Advise a lactating woman not to breastfeed for at least 2 weeks after the last dose. The preservative benzyl alcohol has been associated with serious adverse reactions and death when administered intravenously to neonates and infants [see Use in Specific Populations (8.4)]. There is a potential for similar risks to infants exposed to benzyl alcohol through human milk.

Do not mix RETACRIT with bacteriostatic saline containing benzyl alcohol, if administering RETACRIT to a lactating woman [see Dosage and Administration (2.1)].

There is no information regarding the presence of epoetin alfa products in human milk, the effects on the breastfed infant, or the effects on milk production …

8.4 Pediatric Use

Newly added information:

The multiple-dose vials are formulated with benzyl alcohol and are contraindicated for use in neonates and infants [see Contraindications (4), Warnings and Precautions (5.9)]. When therapy with RETACRIT is needed in neonates and infants, use the single-dose vial, which is a benzyl alcohol-free formulation. Do not mix the single-dose vials with bacteriostatic saline when administering RETACRIT to neonates or infants because it contains benzyl alcohol [see Dosage and Administration (2.6)].

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to

1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.9)].

Pediatric Patients with CKD

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Who should not take RETACRIT?

Do not take RETACRIT if you:

Have had a serious allergic reaction to RETACRIT or other epoetin alfa products.

Do not give RETACRIT from multiple-dose vials to:

Pregnant or breastfeeding women
Babies

What are the possible side effects of RETACRIT?

Newly added information:

Dangers of using RETACRIT from multiple-dose vials in newborns, infants, and pregnant or breastfeeding women. Do not use RETACRIT from multiple-dose vials in newborns, infants,

pregnant or breastfeeding women because the RETACRIT in these vials contains benzyl alcohol.

Benzyl alcohol has been shown to cause brain damage, other serious side effects, and death in

newborn and premature babies. If you use RETACRIT from multiple-dose vials you should not

breastfeed for at least 2 weeks after the last dose. RETACRIT that comes in single-dose vials does not contain benzyl alcohol. See “Who should not take RETACRIT?”

How should I store RETACRIT?

Additions and/or revisions underlined:

Do not freeze RETACRIT. Do not use the carton of RETACRIT multi-dose vials if it that has been frozen or if the green area on the freeze strip indicator inside the RETACRIT carton looks white or cloudy.
Throw away multiple-dose vials of RETACRIT no later than 21 days from the first day that you put a needle into the vial.
Single-dose vials of RETACRIT should be used only one time. Throw the vial away after use even if there is medicine left in the vial.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and lactating women [see Use in Specific Populations (8.1, 8.2, 8.4)].

… This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

01/18/2019 (SUPPL-3)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer

(Additions and/or revisions are underlined)

Decreased Progression-free Survival and Overall Survival

Study 1 was a randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non-inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, the median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%). At the final analysis, 1653 deaths were reported (79.8% subjects in the epoetin alfa plus SOC group and 77.8% subjects in the SOC group. Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18).