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.

SINEQUAN (NDA-017516)

(DOXEPIN HYDROCHLORIDE)

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

Download Data

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07/03/2025 (SUPPL-26)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

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

4 Contraindications

Additions and/or revisions underlined:

SINEQUAN is contraindicated in patients:

With hypersensitivity to doxepin (hypersensitivity reactions have included tongue edema and urticaria). The possibility of cross sensitivity with other dibenzoxepines should be kept in mind.
With glaucoma [see Warnings and Precautions (5.3)].
With current or past urinary retention [see Adverse Reactions (6.1)].
Taking MAOIs, or within 14 days of stopping MAOIs (including the MAOIs linezolid or intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7)].

5 Warnings and Precautions

The following subsections created to comply with 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 Angle-Closure Glaucoma

Additions and/or revisions underlined:

The pupillary dilation that occurs following use of many antidepressant drugs including SINEQUAN may trigger an angle closure glaucoma attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

SINEQUAN is contraindicated in patients with glaucoma. Avoid use of SINEQUAN in patients with untreated anatomically narrow angles.

The following subsections created to comply with PLR; please refer to label for complete information.

5.4 Sedation and Driving Risks

5.5 Activation of Mania or Hypomania

5.6 Risk of Seizures

5.7 Psychosis

Additions and/or revisions underlined:

In patients with schizophrenia, treatment with SINEQUAN for MDD may activate psychosis. If this occurs, stop SINEQUAN and consider alternative treatment options.

6 Adverse Reactions

The following subsections created to comply with PLR; please refer to label for complete information.

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 Drug Interactions

PLR conversion; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion:

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including SINEQUAN, during pregnancy. Health care providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants

1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/antidepressants.

Risk Summary

Available data from published epidemiological studies and postmarketing reports have not established an increased risk for major birth defects or miscarriage with SINEQUAN use (see Data). There are risks (see Clinical Considerations):

To the mother associated with untreated depression in pregnancy.
Poor neonate adaptation from exposure to tricyclic antidepressants (TCAs), including SINEQUAN, during the third trimester of pregnancy.

Animal reproduction toxicity of doxepin has not been fully characterized.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major 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 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryofetal Risk

Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of MDD than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of MDD who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated MDD when considering discontinuation of SINEQUAN drugs during pregnancy and the postpartum period.

Fetal/Neonatal Adverse Reactions

Neonates previously exposed to TCAs, including SINEQUAN, late in the third trimester during pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either direct toxic effects of TCAs or possibly a drug discontinuation syndrome. Monitor neonates who were exposed to SINEQUAN in the third trimester of pregnancy for poor neonatal adaptation syndrome.

Data

Human Data: Published epidemiological studies of pregnant women exposed to TCAs, including SINEQUAN, have not established an association with major birth defects, miscarriage, or adverse maternal outcomes. Methodological limitations of these observational studies include small sample size and lack of adequate controls.

8.2 Lactation

PLLR conversion:

Risk Summary

Data from published literature report the presence of doxepin and nordoxepin in human milk. There are reports of excessive sedation, respiratory depression, poor suckling and swallowing and hypotonia in breastfed infants exposed to doxepin at doses used to treat MDD. There are no data on the effects of doxepin on milk production.

Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during SINEQUAN treatment.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of SINEQUAN in pediatric patients have not been established.

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

Additions and/or revisions underlined:

Clinical studies of SINEQUAN did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Sedating drugs, including SINEQUAN, may cause confusion and oversedation in geriatric patients. The recommended starting SINEQUAN dosage in geriatric patients is generally lower than those of younger adult patients.

8.6 Hepatic Impairment

New subsection added to comply with PLR; please refer to label for complete information.

8.7 Use in Genomic Subgroups

New subsection added to comply with PLR; please refer to label for complete information.

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

MEDICATION GUIDE

Medication Guide has undergone extensive changes to comply with PLR; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

New section added to comply with PLR; please refer to label for complete information.

Other

Physician Labeling Rule (PLR) conversion.