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.

ISTODAX (NDA-022393)

(ROMIDEPSIN)

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

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07/30/2021 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

The data in the WARNINGS AND PRECAUTIONS reflect exposure to ISTODAX in four clinical trials involving 363 patients with T-cell lymphoma, including 185 patients with CTCL. ISTODAX was administered as a single agent at a dosage of 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Among 363 patients who received ISTODAX, 21% were exposed for 6 months or longer and 13% were exposed for greater than one year.

Cutaneous T-Cell Lymphoma

The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a dosage of 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Treatment continued as long as the patient benefitted from and tolerated the drug. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

…

Other Clinical Trials Experience

The following common adverse reactions have been reported following administration of ISTODAX a single agent in 178 patients with peripheral T-cell lymphoma, for which ISTODAX is not indicated or recommended. The most common adverse reactions (greater than or equal to30%) included nausea (63%), fatigue (61%), thrombocytopenia (49%), vomiting (39%), neutropenia (39%), pyrexia (38%), diarrhea (36%) and anemia (35%). Other common (greater than or equal to 10%) clinically significant adverse reactions included dysgeusia (22%), headache (20%), cough (19%), dyspnea (15%), abdominal pain (13%) and stomatitis (10%). Grade 3 and higher adverse reactions in greater than or equal to 10% were hematologic toxicities (including thrombocytopenia, neutropenia, leukopenia and anemia) and fatigue.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined

…

Of the 186 patients with CTCL who received ISTODAX in clinical studies, 51 (28%) were 65 years of age and older, while 16 (9%) were 75 years of age. No overall differences in safety or effectiveness were observed between patients 65 years or age and over and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

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

PATIENT INFORMATION

Additions underlined

…

Before receiving ISTODAX, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. ISTODAX may harm your unborn baby.
- Females who are able to become pregnant:
  - Your healthcare provider will perform a pregnancy test within 7 days before you start treatment with ISTODAX.
    …
- ISTODAX may cause fertility problems in males and females. Talk to your healthcare provider if this is a concern for you.
are breastfeeding or plan to breastfeed. It is not known if ISTODAX passes into your breast milk. You should not breastfeed during treatment with ISTODAX and for 1 week after the last dose. Talk to your healthcare provider about the best way to feed your baby while you are being treated with ISTODAX.

…
What are the possible side effects of ISTODAX?
ISTODAX may cause serious side effects, including:
…
The most common side effects of ISTODAX include:

nausea, tiredness, vomiting, loss of appetite, changes in sense of taste, constipation, and itching.
These are not all the possible side effects of ISTODAX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

…

11/27/2018 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, ISTODAX can cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and caused adverse developmental outcomes at exposures below those in patients at the recommended dose of 14 mg/m2. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 1 is now Table 2 Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) no data changes

Serious Adverse Reactions

Additions and/or revisions to the 2nd paragraph underlined under this title:

There were eight deaths not due to disease progression. In Study 1, there were two deaths: one due to cardiopulmonary failure and one due to acute renal failure. There were six deaths in Study 2: four due to infection and one each due to myocardial ischemia and acute respiratory distress syndrome.

7 Drug Interactions

7.3 Drugs That Induce CYP3A4 Enzymes

Additions and/or revisions underlined:

Rifampin (a potent CYP3A4 inducer) increased the concentrations of romidepsin. Avoid co-administration of ISTODAX with rifampin … The use of other potent CYP3A4 inducers …

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; extensive changes. Please refer to label for complete information.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

There are no data on the presence of ISTODAX or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with ISTODAX and for at least 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Newly added subsection:

ISTODAX can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Perform pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with ISTODAX.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with ISTODAX and for at least 1 month after the last dose. ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. Therefore, alternative methods of non-estrogen containing contraception (e.g., condoms, intrauterine devices) should be used in patients receiving ISTODAX.

Males

Advise males with female partners of reproductive potential to use effective contraception and to avoid fathering a child during treatment with ISTODAX and for at least 1 month after the last dose.

Infertility

Based on findings in animals, romidepsin has the potential to affect male and female fertility.

8.6 Hepatic Impairment

Additions and/or revisions underlined:

In a hepatic impairment study, ISTODAX was evaluated in 19 patients with advanced cancer and mild (8), moderate (5), or severe (6) hepatic impairment. There were 4 deaths during the first cycle of treatment: 1 patient with mild hepatic impairment, 1 patient with moderate hepatic impairment, and 2 patients with severe hepatic impairment. [see No dose adjustments are recommended for patients with mild hepatic impairment. Reduce the ISTODAX starting dose for patients with moderate and severe hepatic impairment)]. Monitor patients with hepatic impairment more frequently for toxicity, especially during the first cycle of therapy.

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Embryo-Fetal Toxicity

Advise patients that ISTODAX can cause fetal harm when administered during pregnancy

Contraception

Advise females of reproductive potential to use effective contraception during treatment with ISTODAX and for at least 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception and to avoid fathering a child during treatment with ISTODAX and for at least 1 month after the last dose.

Lactation

Advise lactating women not to breastfeed during treatment with ISTODAX and for at least 1 week after the last dose.

Infertility

Advise females and males of reproductive potential that ISTODAX may cause infertility.

PATIENT INFORMATION

Section reformatted; please refer to label for complete information.