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.

LUVOX (NDA-021519)

(FLUVOXAMINE MALEATE)

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

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08/18/2023 (SUPPL-26)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Increased Risk of Bleeding

Subsection title revised

Additions and revisions underlined:

SSRIs and SNRIs, including Fluvoxamine Maleate Tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory 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 use of 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 SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the increased risk of bleeding associated with the concomitant use of Fluvoxamine Maleate Tablets and NSAIDs, aspirin, or other drugs that affect coagulation [see Warnings and Precautions (5.8)].

5.2 Serotonin Syndrome

Additions and revisions underlined:

Selective serotonin reuptake inhibitors (SSRIs), including Fluvoxamine Maleate Tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Fluvoxamine Maleate Tablets with MAOIs is contraindicated. In addition, do not initiate Fluvoxamine Maleate Tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Fluvoxamine Maleate Tablets, discontinue Fluvoxamine Maleate Tablets before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.2)].

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

6 Adverse Reactions

6.9 Postmarketing Reports

Additions and revisions underlined:

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

Voluntary reports of adverse reactions in patients taking Fluvoxamine Maleate Tablets that have been received since market introduction and are of unknown causal relationship to Fluvoxamine Maleate Tablets use include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic reaction, angioedema, anosmia, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, hyposmia, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes).

7 Drug Interactions

7.2 CNS Active Drugs

Newly added information:

Other Serotonergic Drugs: The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with Fluvoxamine Maleate Tablets increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Fluvoxamine Maleate Tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].

8 Use in Specific Populations

8.1 Pregnancy

Newly added information:

Based on data from 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 Warnings and Precautions (5.10) and Clinical Considerations].

Maternal Adverse Reactions

Use of Fluvoxamine Maleate Tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.10)].

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

Medication Guide

Extensive changes; please refer to label

Before starting Fluvoxamine Maleate Tablets, tell your healthcare provider if you:

Are taking certain drugs such as:
. . .
- Tramadol, fentanyl, meperidine, methadone, or other opioids

PATIENT COUNSELING INFORMATION

Additions and revisions underlined:

Patients should be cautioned about the risk of serotonin syndrome particularly with the concomitant use of fluvoxamine with other serotonergic agents (including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John's Wort) [see Warnings and Precautions (5.2)].

09/20/2021 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.16 Sexual Dysfunction

(Newly added subsection)

Use of SSRIs, including Fluvoxamine Maleate Tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.4)]. 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 Fluvoxamine Maleate Tablets 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)

…

10. Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including Fluvoxamine Maleate Tablets, 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 Fluvoxamine Maleate Tablets. There may be treatments your healthcare provider can suggest.
  …

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Advise patients that use of Fluvoxamine Maleate Tablets 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 (5.16)].

…

12/16/2019 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

(Newly added information)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.9 Postmarketing Reports

(Additions and/or revisions underlined)

Voluntary reports of adverse reactions in patients taking Fluvoxamine Maleate Tablets that have been received since market introduction and are of unknown causal relationship to Fluvoxamine Maleate Tablets use include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic reaction, angioedema, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes).

8 Use in Specific Populations

8.1 Pregnancy

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

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; additions and/or revisions underlined)

Data from published literature report the presence of fluvoxamine is in human milk. No adverse effects on the breastfed infant have been reported in most cases of maternal use of fluvoxamine during breastfeeding. However, there are reports of diarrhea, vomiting, decreased sleep, and agitation. There are no data on the effect of fluvoxamine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluvoxamine and any potential adverse effects on the breastfed child from fluvoxamine or from the underlying maternal condition.

Clinical Considerations

Monitor infants exposed to fluvoxamine through breast milk for diarrhea, vomiting, decreased sleep, and agitation.

Data

Milk drug concentrations less than or equal to 425 ng/mL were observed following maternal dosing of fluvoxamine 25 mg/day to 300 mg/day in published case reports and case series.

8.3 Females and Males of Reproductive Potential

(Newly added subsection)

Infertility

Animal findings suggest fertility may be impaired while taking fluvoxamine.

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 pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Fluvoxamine Maleate Tablets.
Advise patients that Fluvoxamine Maleate Tablets use late 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).
Advise women that there is a risk of relapse with discontinuation of antidepressants.

Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Fluvoxamine Maleate Tablets during pregnancy.

Lactation

Advise breastfeeding women using Fluvoxamine Maleate Tablets to monitor infants for diarrhea, vomiting, decreased sleep, and agitation and to seek medical care if they notice these signs.

MEDICATION GUIDE

(Additions and/or revisions underlined)

What should I tell my healthcare provider before taking Fluvoxamine Maleate Tablets? Ask if you are not sure.

are pregnant or plan to become pregnant. Talk to your healthcare provider about the risk to your unborn baby if you take Fluvoxamine Maleate Tablets.
Talk to your healthcare provider about the benefits and risks of treating OCD during pregnancy.
If you become pregnant during treatment with Fluvoxamine Maleate Tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1- 844-405-6185.

01/04/2017 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

Additions and/or revisions underlined:

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and

SSRIs, including Fluvoxamine Maleate Tablets, alone but particularly with concomitant use of serotonergic

drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, busipirone,

amphetamines, and St. John's Wort) and with drugs …

If concomitant use of Fluvoxamine Maleate Tablets with other serotonergic drugs, including triptans,

tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's

Wort is clinically warranted …

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

PATIENT COUNSELING INFORMATION

17.2 Serotonin Syndrome

Additions and/or revisions underlined:

Patients should be cautioned about the risk of serotonin syndrome particularly with the concomitant use of fluvoxamine with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort).