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.

TORISEL (NDA-022088)

(TEMSIROLIMUS)

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

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03/23/2018 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.15 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on findings in animal studies and its mechanism of action, TORISEL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, daily oral administration of temsirolimus to pregnant animals during organogenesis caused adverse embryo-fetal effects in rats and rabbits at approximately 0.04 and 0.12 times the AUC in patients at the recommended human dose, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose.

6 Adverse Reactions

In this general section, all instances of (greater than or equal to 30%) were changed to (2:30%)

6.1 Clinical Trials Experience

Table 1 - Adverse Reactions Reported in at Least 10% of Patients Who Received 25 mg IV TORISEL or IFN- a in the Randomized Trial Data has been added to the table, please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions underlined:

Based on findings in animal studies and its mechanism of action, temsirolimus can cause fetal harm when administered to a pregnant woman Although there are no data on the use of TORISEL in pregnant women, there are limited data on the use of sirolimus, the active metabolite of temsirolimus, during pregnancy; however, these data are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproductive studies, oral daily administration of temsirolimus to pregnant rats and rabbits during organogenesis caused adverse embryo-fetal effects at approximately

0.04 and 0.12 times the AUC in patients at the recommended dose, respectively. Advise pregnant women of the potential hazard 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

Temsirolimus administered daily as an oral formulation throughout organogenesis caused adverse embryo-fetal effects in rats …

In rats, the adverse embryo-fetal effects were observed at the oral dose of 2.7 mg/m2/day (approximately 0.04-fold the AUC in patients with cancer at the human recommended dose). In rabbits, the adverse embryo-fetal effects were observed at the oral dose of 2:7.2 mg/m2/day …

8.2 Lactation

PLLR conversion; newly added information:

Risk Summary

There is no information regarding the presence of TORISEL or its metabolites in human milk, or their effects on the breastfed child or milk production. Trace amounts of sirolimus, the active metabolite of temsirolimus, were present in milk from lactating rats administered sirolimus. Because of the potential for serious adverse reactions in a breastfed child from TORISEL, advise a lactating woman not to breastfeed during treatment with TORISEL and for 3 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

PLLR conversion; newly added information:

Contraception

Females

TORISEL can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose.

Males

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

Infertility

Based on the findings in animal fertility studies, male and female fertility may be compromised by the treatment with Torisel. It is not known if the effects on fertility in animal studies were reversible.

8.4 Pediatric Use

(greater than or equal to 20%) changed to (2:20%)

8.7 Hepatic Impairment

Table 3 - Adverse Reactions in Patients with Advanced Malignancies Plus Normal or Impaired Hepatic Function heading changed in table; please refer to label for complete information.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Proteinuria and Nephrotic Syndrome

Advise patients that treatment with TORISEL may require monitoring for proteinuria and nephrotic syndrome and to contact their health care provider for signs and symptoms of nephrotic syndrome.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential that TORISEL can cause fetal harm. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after receiving the last dose.

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

Lactation

Advise lactating women not to breastfeed during treatment with TORISEL and for 3 weeks after the last dose.

Infertility

Advise patients that male and female fertility may be compromised by treatment with TORISEL.

03/23/2018 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Proteinuria and Nephrotic Syndrome

Newly added subsections:

Proteinuria (including cases of nephrotic syndrome) has occurred in patients treated with TORISEL. Monitor urine protein prior to the start of TORISEL therapy and periodically thereafter. Discontinue TORISEL in patients who develop nephrotic syndrome.

05/22/2017 (SUPPL-20)

Approved Drug Label (PDF)

7 Drug Interactions

Addition of the following subsection:

7.3 Angioedema with ACE inhibitors and Calcium Channel Blockers

Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with ramipril and/or amlodipine. Monitor patients for signs and symptoms of angioedema when temsirolimus is given concomitantly with an angiotensin converting enzyme (ACE) inhibitors (e.g., ramipril) or calcium channel blockers (CCB) (e.g., amlodipine).