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.

SYNRIBO (NDA-203585)

(OMACETAXINE MEPESUCCINATE)

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

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11/26/2019 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

Based on findings from animal reproduction studies and the drug’s mechanism of action, SYNRIBO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with SYNRIBO and for 6 months after the final dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with SYNRIBO and for 3 months after the final dose.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions have been associated with SYNRIBO in clinical trials and are discussed in greater detail in other sections of the label.

Myelosuppression
Bleeding
Hyperglycemia

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on its mechanism of action and findings from animal studies, SYNRIBO can cause fetal harm when administered to pregnant women. In animal reproduction studies, subcutaneous administration of omacetaxine mepesuccinate to pregnant mice during organogenesis at doses approximately 0.25-0.5 times the maximum recommended human doses (MRHD) resulted in embryo-fetal mortality, structural abnormalities, and alterations to growth. There are no available data on SYNRIBO use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryo-fetal development study, pregnant mice were administered omacetaxine mepesuccinate subcutaneously during the period of organogenesis at doses of 0.63 or 1.23 mg/m^2/day (approximately 0.25-0.5 times the MRHD on a body surface area basis). Drug-related adverse effects included embryonic death, an increase in unossified bones/reduced bone ossification, and decreased fetal body weights. Fetal toxicity occurred at doses of 1.23 mg/m^2/day, which is approximately half the recommended daily human dose.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of omacetaxine mepesuccinate in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with SYNRIBO, and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to initiating SYNRIBO. Contraception

Females

SYNRIBO can cause embryo-fetal harm when administered to pregnant women. Advise female patients of reproductive potential to use effective contraception during treatment with SYNRIBO and for 6 months after the final dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with SYNRIBO and for 3 months after the final dose.

Infertility

Males

Based on findings from animal studies, SYNRIBO may impair male fertility. Studies in mice demonstrated adverse effects on male reproductive organs where bilateral degeneration of the seminiferous tubular epithelium in testes and hypospermia/aspermia were observed. The long-term effects of SYNRIBO on male fertility, including the reversibility of adverse effects, have not been studied.

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

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Before using SYNRIBO, tell your healthcare provider about all of your medical conditions, including if you:

have diabetes or a family history of diabetes
have bleeding problems
plan to have any dental or surgical procedures

are pregnant or plan to become pregnant. SYNRIBO can harm your unborn baby. You should not become pregnant during treatment with SYNRIBO. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with SYNRIBO.

Females who are able to become pregnant:

Your healthcare provider may give you a pregnancy test before you start treatment with SYNRIBO.

You should use effective birth control (contraception) during treatment with SYNRIBO and for 6 months after the final dose.

Males with female partners who are able to become pregnant should use effective birth control during treatment with SYNRIBO and for 3 months after the final dose.

are breastfeeding or plan to breastfeed. It is not known if SYNRIBO passes into your breast milk. Do not breastfeed during treatment with SYNRIBO and for 2 weeks after the final dose.

…

What are the possible side effects of SYNRIBO? SYNRIBO may cause serious side effects, including:

See “What is the most important information I should know about SYNRIBO?”

High blood sugar levels (hyperglycemia). If you have diabetes or are at risk for diabetes, your healthcare provider will check your blood sugar levels often during treatment with SYNRIBO. If you have diabetes or if your blood sugar is not well controlled, your healthcare provider may decide not to start treatment with SYNRIBO until your diabetes is under control first.

The most common side effects of SYNRIBO include:

infections. See the information about low blood cell counts in the section “What is the most important information I should know about SYNRIBO?”
diarrhea
weakness
nausea
redness, swelling, or pain at injection site
tiredness

fever

Tell your healthcare provider or get medical help right away if you get nausea, diarrhea, stomach (abdominal) pain, severe or worsening skin rash, or itching that does not go away.

You may have hair loss during treatment with SYNRIBO.

SYNRIBO may cause fertility problems in males, which may affect your ability to have children. Talk to your healthcare provider if this is a concern for you.

These are not all of the side effects of SYNRIBO.

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise female patients of reproductive potential to use effective contraception during treatment with SYNRIBO and for 6 months after the final dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with SYNRIBO and for 3 months after the final dose.

Lactation

Advise females not to breastfeed during treatment with SYNRIBO and for 2 weeks after the final dose.

Infertility

Advise males of reproductive potential that SYNRIBO may impair fertility.

01/23/2019 (SUPPL-6)

Approved Drug Label (PDF)

Other

INSTRUCTIONS FOR USE

(Additions and/or revisions are underlined)

….

Put on a pair of gloves and your protective eyewear before you handle the syringe containing SYNRIBO. Wearing gloves and protective eyewear
(even if you wear glasses) protects you from splashes or spills. See Figure A.

Look at the date printed on the syringe label to make sure that the expiration date has not passed. Do not use if the expiration date has passed and contact your doctor or pharmacy immediately.

Gather the rest of your supplies and place them on your work surface.….

...

How should I throw away (dispose of) used SYNRIBO syringes, needles, and other supplies?

Throw away (dispose of) used SYNRIBO syringes, needles, gloves, and other used supplies in an appropriate biohazard container.

…

06/21/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 2: Adverse Reactions Occurringa in at Least 10% of Patients (Chronic Myeloid Leukemia – Chronic Phase)

Table 3: Adverse Reactions Occurringa in at Least 10% of Patients (Chronic Myeloid Leukemia – Accelerated Phase)

Data in tables have changed; please refer to label for complete information.