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.

YONSA (NDA-210308)

(ABIRATERONE ACETATE)

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

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03/24/2022 (SUPPL-3)

Approved Drug Label (PDF)

7 Drug Interactions

Additions and/or revisions underlined:

7.1 ‘Effect of Other Drugs on Yonsa’ replaces ‘Drugs that Inhibit or Induce CYP3A4 Enzymes’

7.2 Effects of YONSA on Other Drugs

CYP2D6 Substrates

Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. The co-administration of YONSA with CYP2D6 substrates increases the concentration of the CYP2D6 substrate, which may increase the frequency and/or severity of adverse reactions of these substrates.

Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug in accordance with its Prescribing Information [see Clinical Pharmacology (12.3)].

CYP2C8

Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. The co-administration of YONSA with CYP2C8 substrates increases the concentration of the CYP2C8 substrate, which may increase the frequency and/or severity of adverse reactions of these substrates. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

Additions and/or revisions underlined:

8.6 Hepatic Impairment

No dosage modification is recommended for patients with baseline mild hepatic impairment (Child-Pugh Class A). In patients with baseline moderate hepatic impairment (Child-Pugh Class B) …

8.7 Renal Impairment

No dosage modification is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].

01/28/2022 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Hepatotoxicity

Additions and/or revisions underlined:

In postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2)].

In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received abiraterone acetate, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to ALT and AST increases occurred in 1% of patients taking abiraterone acetate. In these clinical trials, no deaths clearly related to abiraterone acetate were reported due to hepatotoxicity events.

5.5 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

The safety and efficacy of YONSA have not been established in females. Based on animal reproductive studies and mechanism of action, YONSA can cause fetal harm and loss of pregnancy when administered to a pregnant female. In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ? 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with YONSA and for 3 weeks after the final dose of YONSA [see Use in Specific Populations (8.1, 8.3)].

YONSA should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)].

5.6 Hypoglycemia

Newly added subsection:

Severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2)]. Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with abiraterone acetate.

Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Immune System Disorders – Hypersensitivity: anaphylactic reactions (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).

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

17 PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Hypoglycemia

Inform patients that severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes who were receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide – antidiabetic drugs. Advise patients with diabetes to monitor blood glucose levels during and after treatment with abiraterone acetate [see Warnings and Precautions (5.6) and Drug Interactions (7.2)].

PATIENT INFORMATION

Additions and/or revisions underlined:

What is YONSA?

YONSA is a prescription medicine that is used along with methylprednisolone. YONSA is used to treat men with prostate cancer that has spread to other parts of the body and no longer responds to medical or surgical treatment that lowers testosterone.

Before taking YONSA, tell your healthcare provider about all of your medical conditions, including if you:

have heart problems
have liver problems
have diabetes

Severe low blood sugar (hypoglycemia). Severe low blood sugar with abiraterone acetate can happen in people who have diabetes and take certain antidiabetic medicines. You and/or your healthcare provider should check your blood sugar levels regularly during treatment with abiraterone acetate and after you stop treatment. Your healthcare provider may also need to change the dose of your antidiabetic medicines. Signs and symptoms of low blood sugar may include:

headache o irritability
drowsiness o hunger
weakness o fast heart beat
dizziness o sweating
confusion o feeling jittery

09/17/2020 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess

(Additions underlined)

…

… In postmarketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate.

…

5.4 Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride

(New subsection added)

YONSA plus methylprednisolone is not recommended for use in combination with radium 223 dichloride outside of clinical trials.

The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus a corticosteroid and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.

At the primary analysis, increased incidences of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received abiraterone acetate plus a corticosteroid in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus a corticosteroid.

5.5 Embryo-Fetal Toxicity

(New subsection added)

Females who are pregnant or females who may be pregnant should not handle YONSA tablets if broken, crushed, or damaged without protection, e.g., gloves [see How Supplied/Storage and Handling (16)].

6 Adverse Reactions

(Additions underlined)

…

Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride [see Warnings and Precautions (5.4)].

6.2 Postmarketing Experience

(Additions underlined)

…

Cardiac Disorders: QT prolongation and Torsades de Pointes (observed in patients who developed hypokalemia or had underlying cardiovascular conditions).

8 Use in Specific Populations

8.1 Pregnancy

(Addition/revisions underlined; updates made to comply with PLLR)

Risk Summary

The safety and efficacy of YONSA have not been established in females. Based on findings from animal studies and the mechanism of action, YONSA can cause fetal harm and potential loss of pregnancy.

…

8.2 Lactation

(Additions/revisions underlined; updates made to comply with PLLR)

Risk Summary

The safety and efficacy of YONSA have not been established in females. There is no information available on the presence of abiraterone acetate in human milk, or on the effects on the breastfed child or milk production.

8.3 Females and Males of Reproductive Potential

(Additions/revisions underlined; Updates made to comply with PLLR)

Contraception

Males

Based on findings in animal reproduction studies and its mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of YONSA [see Use in Specific Populations (8.1)].

Infertility

Based on animal studies, abiraterone acetate may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].

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

PATIENT COUNSELING INFORMATION

(Additions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions

Inform patients that YONSA is associated with hypertension, hypokalemia, and peripheral edema that may lead to QT prolongation and Torsades de Pointes in patients who develop hypokalemia while taking YONSA. Advise patients that their blood pressure, serum potassium and signs and symptoms of fluid retention will be monitored clinically at least monthly. Advise patients to adhere to corticosteroids and to report symptoms of hypertension, hypokalemia, or edema to their healthcare provider [see Warnings and Precautions (5.1)].

…

Use in Combination with Radium Ra 223 Dichloride

Advise patients that radium Ra 223 dichloride showed an increase in mortality and an increased rate of fracture when used in combination with abiraterone acetate plus a corticosteroid. Inform patients to speak with their healthcare provider about any other medications or treatment they are currently taking for prostate cancer [see Warnings and Precautions (5.4)].

…

Embryo-Fetal Toxicity

Inform patients that YONSA may harm a developing fetus and can cause loss of pregnancy.
Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of YONSA [see Use in Specific Populations (8.1)].
Advise females who are pregnant or women who may be pregnant not to handle YONSA tablets if broken, crushed, or damaged without protection, e.g., gloves [see Use in Specific Populations (8.1) and How Supplied/Storage and Handling (16)].

PATIENT INFORMATION

(Additions underlined)

…

Before taking YONSA, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. YONSA can cause harm to your unborn baby and loss of pregnancy (miscarriage). Females who are or may become pregnant should not handle YONSA tablets if broken, crushed, or damaged without protection, such as gloves.
have a partner who is pregnant or may become pregnant.
o Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with YONSA and for 3 weeks after the final dose of YONSA.
are breastfeeding or plan to breastfeed. It is not known if YONSA passes into your breastmilk.
…
What are the possible side effects of YONSA? YONSA may cause serious side effects, including:

High blood pressure (hypertension), low blood potassium levels (hypokalemia), fluid retention
(edema), and irregular heartbeats can happen during treatment with YONSA. This can be life threatening. To decrease the chance of this happening, you must take methylprednisolone with YONSA exactly as your healthcare provider tells you. Your healthcare provider will check your blood pressure, do blood tests to check your potassium levels, and check for any signs and symptoms of fluid retention every month during treatment with YONSA.
Tell your healthcare provider if you get any of the following symptoms:
…

fast or irregular heartbeats

…

Severe liver problems. You may develop changes in liver function blood tests. Your healthcare provider will do blood tests to check your liver before treatment with YONSA and during treatment with YONSA. Liver failure may occur, which can lead to death. Tell your healthcare provider right away if you notice any of the following changes:

yellowing of the skin or eyes
darkening of the urine
severe nausea or vomiting

Increased risk of bone fracture and death when YONSA and methylprednisolone, is used in combination with a type of radiation called radium Ra 223 dichloride. Tell your healthcare provider about any other treatments you are taking for prostate cancer.

…