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.

PEXEVA (NDA-021299)

(PAROXETINE MESYLATE)

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

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08/18/2023 (SUPPL-35)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; please refer to label for complete information)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; please refer to label for complete information)

8.3 Females and Males of Reproductive Potential

(Newly added subsection)

Infertility

Male

Based on findings from clinical studies, paroxetine may affect sperm quality which may impair fertility; it is not known if this effect is reversible [see Nonclinical Toxicology (13.1)].

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

…

Pregnancy

Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with PEXEVA. Advise women of risks associated with first trimester use of PEXEVA and that use later in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Warnings and Precautions

(5.4), Use in Specific Populations (8.1)]. Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

Lactation

Advise breastfeeding women using PEXEVA to monitor infants for agitation, irritability, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].

Females and Males of Reproductive Potential

Advise men that PEXEVA may affect sperm quality, which may impair fertility; it is unknown if this effect is reversible [see Use in Specific Populations (8.3)].

08/18/2023 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Embryofetal Toxicity

(Additions and/or revisions underlined)

Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants. For women who intend to become pregnant or who are in their first trimester of pregnancy, PEXEVA, should be initiated only after consideration of the other available treatment options [see Use in Specific Populations (8.1)].

5.5 Increased Risk of Bleeding

(Additions and/or revisions underlined)

Drugs that interfere with serotonin reuptake inhibition, including PEXEVA, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants, may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following reactions have been identified during post approval use of paroxetine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), priapism, syndrome of inappropriate ADH secretion (SIADH), prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura) and premature births in pregnant women. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

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

MEDICATION GUIDE

(Extensive changes; please refer to label for complete information)

09/20/2021 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.13 Sexual Dysfunction

(Newly added subsection)

Use of SSRIs, including PEXEVA, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI 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 PEXEVA 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 selective serotonin reuptake inhibitors (SSRIs), including PEXEVA, 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 PEXEVA. There may be treatments your healthcare provider can suggest.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Advise patients that use of PEXEVA may cause symptoms of sexual dysfunction in 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 (5.13)].

12/31/2020 (SUPPL-31)

Approved Drug Label (PDF)

Boxed Warning

Section revised, additions underlined

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all anti-depressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. PEXEVA is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

4 Contraindications

Additions underlined)

PEXEVA is contraindicated in patients:

Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2), Drug Interaction (7)].
Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interaction (7)].
Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interaction (7)].
With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in PEXEVA [see Adverse Reactions (6.2, 6.3)]

5 Warnings and Precautions

The following subsections were created to comply with the Physician Labeling Rule (PLR). Please refer to label for complete information.

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

5.2 Serotonin Syndrome

5.3 Drug Interactions Leading to QT Prolongation

5.4 Embryofetal and Neonatal Toxicity

5.5 Increased Risk of Bleeding

5.6 Activation of Mania or Hypomania

5.7 Discontinuation Syndrome

5.8 Seizures

5.9 Angle-Closure Glaucoma

5.10 Hyponatremia

5.11 Reduction of Efficacy of Tamoxifen

5.12 Bone Fracture

6 Adverse Reactions

Addition of the following bulleted line listing:

The following adverse reactions are included in more detail in other sections of the prescribing information:

Hypersensitivity reactions to paroxetine [see Contraindications (4)]
Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)]
Serotonin syndrome [see Warnings and Precautions (5.2)]
Embryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)]
Increased Risk of Bleeding [see Warnings and Precautions (5.5)]
Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]
Discontinuation Syndrome [see Warnings and Precautions (5.7)]
Seizure [see Warnings and Precautions (5.7)]
Angle-closure Glaucoma [see Warnings and Precautions (5.9)]
Hyponatremia [see Warnings and Precautions (5.10)]
Bone Fracture [see Warnings and Precautions (5.12)]

7 Drug Interactions

7.1 Clinically Significant Drug Interactions

New subsection created to comply with the Physician Labeling Rule (PLR). Please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Extensive additions, please refer to label for complete information.

8.3 Nursing Mothers

Additions underlined

Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from PEXEVA, a decision should be made whether to discontinue nursing infants or to discontinue the drug, taking into account the importance of the drug to the mother.

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

PATIENT COUNSELING INFORMATION

New section created to comply with the Physician Labeling Rule (PLR), please refer to label for complete information.

MEDICATION GUIDE

Section reformatted and revised to comply the Physician Labeling Rule (PLR), please refer to label for complete information.

Other

PLR conversion.

01/04/2017 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

Serotonin Syndrome:

Additions and/or revisions underlined:

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PEXEVA®, 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 PEXEVA® with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines and St. John’s Wort is clinically warranted …

7 Drug Interactions

Additions and/or revisions underlined:

Serotonergic Drugs: Based on the mechanism of action of paroxetine and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, fentanyl, tramadol, amphetamines, or St. John’s Wort.

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

MEDICATION GUIDE

Before starting PEXEVA®, tell your healthcare provider if you:

are taking certain drugs such as:
- drugs that affect serotonin such as lithium, tramadol, tryptophan, amphetamines, St. John’s wort …
  General information about PEXEVA®

For more information about PEXEVA® call (1- 844-732-3521) or …