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.

ZOLINZA (NDA-021991)

(VORINOSTAT)

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

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12/11/2018 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Thromboembolism

Pulmonary embolism occurred in 5% (4/86) of patients receiving ZOLINZA, and deep vein thrombosis has also been reported. Monitor for signs and symptoms …

5.2 Myelosuppression

Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. Adjust dosage or discontinue treatment with ZOLINZA as clinically appropriate.

5.3 Gastrointestinal Toxicity

…

5.4 Hyperglycemia

Hyperglycemia has been observed in patients receiving ZOLINZA and was severe in 5% (4/86) of patients. Monitor serum glucose every 2 weeks during the first 2 months of therapy and monthly thereafter.

5.5 Clinical Chemistry Abnormalities

Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. Correct hypokalemia and hypomagnesemia prior to administration of ZOLINZA. Monitor potassium and magnesium more frequently in symptomatic patients …

5.6 Severe Thrombocytopenia when Combined with Other Histone Deacetylase (HDAC) Inhibitors

Severe thrombocytopenia leading to gastrointestinal bleeding has been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently.

Addition of the following subsection:

5.7 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, ZOLINZA can cause fetal harm when administered to a pregnant woman. There are insufficient data on ZOLINZA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, vorinostat crossed the placenta and caused adverse developmental outcomes at exposures approximately 0.5 times the human exposure based on AUC0-24 hours. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose.

6 Adverse Reactions

Addition of the following bulleted line listing:

The following serious adverse reactions have been associated with ZOLINZA in clinical trials and are discussed in greater detail in other sections of the label:

Thromboembolism
Myelosuppression
Gastrointestinal Toxicity
Hyperglycemia
Clinical Chemistry Abnormalities
Severe thrombocytopenia when combined with other Histone Deacetylase (HDAC) Inhibitors

6.1 Clinical Trials Experience

Common Adverse Reactions

Additions and/or revisions underlined:

The most common drug-related adverse reactions can be classified into 4 symptom complexes: gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease, vomiting, constipation), constitutional symptoms (fatigue, chills), hematologic abnormalities (thrombocytopenia, anemia), and taste disorders (dysgeusia, dry mouth).

Table 1 summarizes the frequency of CTCL patients with specific adverse reactions, using the National Cancer Institute …

Reactions replaces Events throughout the remainder of the section.

Adverse Reactions in Non-CTCL Patients

… In patients recovering from bowel surgery and treated perioperatively with ZOLINZA, anastomotic healing complications including fistulas, perforations, and abscess formation have occurred.

7 Drug Interactions

7.1 Coumarin-Derivative Anticoagulants

Additions and/or revisions underlined:

… Physicians should monitor PT and INR more frequently in patients concurrently …

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of ZOLINZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience …

8.6 Use in Patients with Hepatic Impairment

Extensively changed; please refer to label for complete information.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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

… Embryo-Fetal Toxicity

Advise patients that ZOLINZA can cause fetal harm when administered during pregnancy.

Contraception

Advise females of reproductive potential to use effective contraception during treatment with ZOLINZA and for at least 6 months 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 ZOLINZA and for at least 3 months after the last dose.

Lactation

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

PATIENT INFORMATION

Newly added section; please refer to label for complete information.