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.

KHEDEZLA (NDA-204683)

(DESVENLAFAXINE)

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

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09/20/2021 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Sexual Dysfunction

(Newly added subsection)

Use of SNRIs, including KHEDEZLA, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SNRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of KHEDEZLA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

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

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Sexual problems (dysfunction). Taking serotonin and norepinephrine reuptake inhibitors (SNRIs), including KHEDEZLA, may cause sexual problems.

Symptoms in males may include:

Delayed ejaculation or inability to have an ejaculation
Decreased sex drive
Problems getting or keeping an erection

Symptoms in females may include:

Decreased sex drive

Delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with KHEDEZLA. There may be treatments your healthcare provider can suggest.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Advise patients that use of KHEDEZLA may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.11)].

01/29/2019 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

5.2 Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors (SSRIs), including KHEDEZLA, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs … and with drugs that impair metabolism of serotonin i.e., MAOIs. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms ...

Monitor all patients taking KHEDEZLA for the emergence of serotonin syndrome. Discontinue treatment with KHEDEZLA and any concomitant serotonergic agents immediately if the above symptoms occur and initiate supportive symptomatic treatment. If concomitant use of KHEDEZLA with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including KHEDEZLA, may increase the risk of bleeding events …

Inform patients about the risk of bleeding associated with the concomitant use of KHEDEZLA and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing KHEDEZLA.

5.5 Angle Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including KHEDEZLA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including KHEDEZLA, in patients with untreated anatomically narrow angles.

5.7 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, … tremor …

6 Adverse Reactions

Additions and/or revisions to bulleted line listing are underlined:

Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients
Increased Risk of Bleeding

6.2 Postmarketing Experience

Addition of the following:

Cardiovascular System – Takotsubo cardiomyopathy

7 Drug Interactions

7.1 Drugs Having Clinically Important Interactions with KHEDEZLA

Table 8: Clinically Important Drug Interactions with KHEDEZLA

Table added; please refer to label for complete information.

For the following 3 subsections, additions and/or revisions underlined:

7.2 Drugs Having No Clinically Important Interactions with KHEDEZLA

Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with KHEDEZLA.

7.3 Alcohol

A clinical study has shown …

7.4 Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion; Extensively changed. Please refer to label for complete information.

8.4 Pediatric Use

Extensive changes; please refer to label for complete information.

Additions and/or revisions underlined:

8.6 Renal Impairment

Adjust the maximum recommended dosage in patients with moderate or severe renal impairment (ClCr 15 to 50 mL/min, C-G), or end-stage renal disease (ClCr < 15 mL/min, C-G).

8.7 Hepatic Impairment

Adjust the maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15).

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

MEDICATION GUIDE

Extensive changes; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:
Advise the patient to read the FDA-approved patient labeling …

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down and instruct them to report such symptoms to the healthcare provider.

Increased Risk of Bleeding

Inform patients about the concomitant use of KHEDEZLA with NSAIDs, aspirin, other antiplatelet drugs, warfarin, or other coagulants because the combined use of has been associated with an increased risk of bleeding. Advise patients to inform their healthcare providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding.

Pregnancy

Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to desvenlafaxine during pregnancy.

12/19/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Revised subsection heading; additions and/or revisions are underlined)

Cardiovaslcular System – Takotsubo cardiomyopathy.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of KHEDEZLA with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, amphetamines…

MEDICATION GUIDE KHEDEZLA (key-DEZ-luh) (desvenlafaxine) Extended-release Tablets

(Additions and/or revisions are underlined)

What should I tell my healthcare provider before taking KHEDEZLA?

KHEDEZLA are taken with certain other medicines. Serotonin syndrome can cause serious changes in how your brain, muscles, heart and blood vessels, and digestive system work. Especially tell your healthcare provider if you take the following:

amphetamines

01/04/2017 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

(Additions and/or revisions are underlined)

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including desvenlafaxine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort)…

If concomitant use of KHEDEZLA with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases…

6 Adverse Reactions

6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials

(Revised subsection title)

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Serotonin Syndrome

09/06/2016 (SUPPL-3)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

Gastrointestinal System – Acute Pancreatitis (addition)

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

Medication Guide

General Information about the safe and effective use of KHEDEZLA

For more information, call 800-793-2145 (updated phone number)