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.

FLECTOR (NDA-021234)

(DICLOFENAC EPOLAMINE)

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

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11/21/2024 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Serious Skin Reactions

Additions and/or revisions underlined:

NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of FLECTOR at the first appearance of skin rash or any other sign of hypersensitivity. FLECTOR is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added subsection:

The following adverse reactions have been identified during post-approval use of diclofenac. 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.

Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

04/28/2021 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

New subsection added

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as FLECTOR. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue FLECTOR and evaluate the patient immediately.

5.11 Fetal Toxicity

Additions underlined

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including FLECTOR, in pregnant women at about 30 weeks gestation and later. NSAIDs, including FLECTOR, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including FLECTOR, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit FLECTOR use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if FLECTOR treatment extends beyond 48 hours. Discontinue FLECTOR if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

8 Use in Specific Populations

8.1 Pregnancy

Extensive additions and revisions, please refer to label for complete information

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Serious Skin Reactions including DRESS

Advise patients to stop using FLECTOR immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.10, 5.9)].

…

Fetal Toxicity

Inform pregnant women to avoid use of FLECTOR and other NSAIDs starting at 30 weeks of gestation because of the risk of the premature closure of the fetal ductus arteriosus. If treatment with FLECTOR is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

…

MEDICATION GUIDE

Additions underlined

Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you:

have liver or kidney problems
have high blood pressure
have asthma
are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy.
…

03/01/2019 (SUPPL-16)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Adult Clinical Trials Experience

In controlled trials during the premarketing development …

Newly added information:

Pediatric Clinical Trials Experience

In one open-label trial, 104 male and female pediatric patients 6 years and older presenting with minor strains, sprains, and contusions received FLECTOR twice a day for as many as 16 days. The most commonly reported adverse events (incidence ? 2%) were headache (9%), application site pruritus (7%), nausea (3%), and dyspepsia (3%). No adverse events led to discontinuation of treatment.

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

The safety and effectiveness of FLECTOR have been established in pediatric patients 6 years and older based on evidence from adequate and well-controlled studies with FLECTOR in adults, as well as an open-label study in pediatric patients 6 years and older. The pediatric study enrolled 104 patients, 6 years of age and older with minor soft tissue injuries. One FLECTOR was applied to the injury site twice daily for a maximum of 14 days or until treatment was no longer required for pain management, whichever occurred first. Based on the available data from the pediatric study, the safety profile of FLECTOR topical system in pediatric patients is similar to that in adults. The safety and effectiveness of FLECTOR has not been investigated in pediatric patients less than 6 years old.

03/01/2019 (SUPPL-17)

Approved Drug Label (PDF)

Other

“Topical System” replaces “patch” throughout label.

08/30/2018 (SUPPL-15)

Approved Drug Label (PDF)

7 Drug Interactions

Table 2: Clinically Significant Drug Interactions with Diclofenac

Addition of ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers with Clinical Impact and Interventions; please see label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Published literature reports that use of NSAIDs, including FLECTOR PATCH, after 30 weeks’ gestation increases the risk of premature closure of the fetal ductus arteriosus. Data from observational studies regarding potential embryofetal risks of NSAID use, including diclofenac, in women in the first or second trimester of pregnancy are inconclusive. Avoid use of NSAIDs, including FLECTOR PATCH, in pregnant women starting at 30 weeks of gestation (third trimester) …

… In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of 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 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Avoid use of NSAIDS in pregnant women after 30 weeks’ gestation because NSAIDS, including FLECTOR PATCH, can cause premature closure of the fetal ductus arteriosus.

Data

Human Data

Published literature reports that use of NSAIDS, including diclofenac, after 30 weeks’ gestation may cause constriction of the patent ductus arteriosus and premature closure of the fetal ductus arteriosus …

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Data from published literature reports with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk (see Data). There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits …

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including FLECTOR PATCH, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.

Premature Closure of the Fetal Ductus Arteriosus

Advise pregnant women to avoid use of FLECTOR PATCH and other NSAIDs starting at 30 weeks’ gestation because of the risk of the premature closure of the fetal ductus arteriosus.

Advise females of reproductive potential to contact their healthcare provider with a known or suspected pregnancy.

05/09/2016 (SUPPL-13)

Approved Drug Label (PDF)

Boxed Warning

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

Cardiovascular Thrombotic Events

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
{Product} is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

5 Warnings and Precautions

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of {Product} in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If {Product} is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Heart Failure and Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of {Product} may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).
Avoid the use of {Product} in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If {Product} is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

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

Includes new safety information pertaining to the risks of Cardiovascular Thrombotic Events, Heart Failure and Edema.

PCI - Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately.

PCI - Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.