
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.
ARTHROTEC (NDA-020607)
(DICLOFENAC SODIUM; MISOPROSTOL)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
11/21/2024 (SUPPL-43)
5 Warnings and Precautions
5.10 Serious Skin ReactionsAdditions and/or revisions underlined:
NSAIDs, including diclofenac, a component of ARTHROTEC, 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 ARTHROTEC at the first appearance of skin rash or any other sign of hypersensitivity. ARTHROTEC is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].
6 Adverse Reactions
6.2 Postmarketing ExperienceAdditions and/or revisions underlined:
…
Skin and appendages: acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE), cutaneous reactions (bullous eruption).
…
08/26/2022 (SUPPL-40)
Boxed Warning
Additions and/or revisions underlined:
WARNING: RISK OF UTERINE RUPTURE, ABORTION, PREMATURE BIRTH, BIRTH DEFECTS; SERIOUS CARDIOVASCULAR EVENTS; AND SERIOUS GASTROINTESTINAL EVENTS
Uterine Rupture, Abortion, Premature Birth, and Birth Defects
Administration of misoprostol, a component of ARTHROTEC, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered in pregnant women to induce labor or an abortion [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
ARTHROTEC is contraindicated in pregnancy [see Contraindications (4)] and not recommended in women of childbearing potential. Patients must be advised of the abortifacient property and warned not to give the drug to others [see Warnings and Precautions (5.1)].
If ARTHROTEC is prescribed, verify the pregnancy status of females of reproductive potential prior to initiation of treatment and advise them to use effective contraception during treatment [see Use in Specific Populations (8.3)].
Cardiovascular Thrombotic Events
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 [see Warnings and Precautions (5.2)].
ARTHROTEC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.2)].
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 [see Warnings and Precautions (5.3)].
4 Contraindications
Additions and or revisions underlined
ARTHROTEC is contraindicated in the following patients:
Pregnancy. Use of misoprostol, a component of ARTHROTEC, during pregnancy can result in maternal and fetal harm, including uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]
In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.2)]
Active gastrointestinal bleeding [see Warnings and Precautions (5.3)]
…
5 Warnings and Precautions
Subsection title and content revised; additions and/or revisions underlined
5.1 Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs
Misoprostol
Administration of misoprostol, a component of ARTHROTEC, to pregnant women can cause uterine rupture, abortion, premature birth, or birth defects. Uterine rupture has occurred when misoprostol was administered to pregnant women to induce labor or an abortion.
ARTHROTEC is contraindicated in pregnant women. ARTHROTEC is not recommended in women of childbearing potential. Patients must be advised of the abortifacient property and warned not to give the drug to others [see Use in Specific Populations (8.1)].
If ARTHROTEC is prescribed, verify the pregnancy status of females of reproductive potential prior to initiation of treatment and advise the use effective contraception during treatment with ARTHROTEC [see Use in Specific Populations (8.3)].
Diclofenac
Premature Closure of Fetal Ductus Arteriosus
NSAIDs, including diclofenac, a component of ARTHROTEC, increase the risk of premature closure of the fetal ductus arteriosus at about 30 weeks of gestation and later.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac, 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 [see Use in Specific Populations (8.1)].
8 Use in Specific Populations
8.1 PregnancyAdditions and/or revisions underlined
…
Adverse Reactions Misoprostol
Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Use of misoprostol for the induction of labor in the third trimester was associated with uterine hyperstimulation with resulting changes in the fetal heart rate (fetal bradycardia) and fetal death (misoprostol is not approved for this use). ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)].
…
Additions and/or revisions underlined
ARTHROTEC is not recommended in women of childbearing potential [see Warnings and Precautions (5.1)]. If ARTHROTEC is prescribed, patients must be advised of the abortifacient property and warned not to give the drug to others.
…
Advise females to inform their healthcare provider of a known or suspected pregnancy.
…
Additions and/or revisions underlined
Geriatric patients (those 65 years of age and older), compared to younger adult patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions [see Warnings and Precautions (5.2, 5.3, 5.7)]. In addition, the risk of diclofenac-associated adverse reactions may be greater in geriatric patients with renal impairment or those taking concomitant ACE inhibitors or ARBs [see Drug Interactions (7) and Use in Specific Populations (8.6)].
Avoid use of ARTHROTEC in geriatric patients with cardiovascular and/or renal risk factors. If use cannot be avoided, use the lowest recommended dosage for the shortest duration and monitor for cardiac and renal adverse reactions [see Dosage and Administration (2.1)]. Monitor renal function in geriatric patients during treatment with ARTHROTEC, especially in patients with concomitant use of ACE inhibitors or ARBs.
Of the 2,184 patients in clinical studies with ARTHROTEC, 557 (25.5%) were 65 years of age and over. No overall differences in effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in effectiveness between geriatric patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.
No clinically meaningful differences in the pharmacokinetics of diclofenac and misoprostol were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)].
New subsection added
Diclofenac and misoprostol are primarily excreted by the kidney. Long-term administration of NSAIDs has resulted in renal toxicity. Correct volume status in dehydrated or hypovolemic patients prior to initiating ARTHROTEC. Monitor renal function, especially during concomitant use of ACE inhibitors or ARBs. Also, monitor renal function in patients with hepatic impairment. Avoid the use of ARTHROTEC in patients with advanced renal disease. If use cannot be avoided in patients with advanced renal disease, use the lowest dosage for the shortest duration, monitor the patient’s renal function and monitor for clinical signs of worsening renal function [see Warnings and Precautions (5.7), Drug Interactions (7) and Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined
…
Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs
Advise females that ARTHROTEC is contraindicated in pregnant women. Use of misoprostol, a component of ARTHROTEC during pregnancy can result in maternal and fetal harm, including uterine rupture, abortion, premature birth, or birth defects. Use of diclofenac may cause oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus.
…
MEDICATION GUIDE
Medication Guide has undergone extensive changes; please refer to label.
08/02/2021 (SUPPL-39)
5 Warnings and Precautions
5.1 Cardiovascular Thrombotic Events
(Additions and/or revisions underlined)
Clinical trials of several cyclooxygenase-2 (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.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
(Additions and/or revisions underlined)
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding…
5.3 Hepatotoxicity
(Additions and/or revisions underlined)
In clinical trials with ARTHROTEC, meaningful elevation of alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT], more than 3 times the upper limit of the normal range [ULN]) occurred in 1.6% of 2,184 patients treated with ARTHROTEC and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with ARTHROTEC. The misoprostol component of ARTHROTEC does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component.
In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).
5.14 Laboratory Monitoring
(Additions and/or revisions underlined)
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.6)].
6 Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions underlined)
The following adverse reactions have been identified during post approval of ARTHROTEC, diclofenac or misoprostol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliable estimate their frequency or establish a causal relationship to drug exposure.
Body as a whole: death, fever, infection, sepsis, chills, edema.
Cardiovascular system: arrhythmia, atrial fibrillation, congestive heart failure, hypertension, hypotension, increased creatine phosphokinase (CPK), increased lactate dehydrogenase (LDH), myocardial infarction, palpitations, phlebitis, premature ventricular contractions, syncope, tachycardia, vasculitis.
Metabolic and nutritional: blood urea nitrogen (BUN) increased, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, periorbital edema, porphyria, weight changes, fluid retention.
04/28/2021 (SUPPL-38)
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 ARTHROTEC. 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 ARTHROTEC and evaluate the patient immediately.
Additions underlined
ARTHROTEC is contraindicated in pregnant women. Advise pregnant women of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiation of ARTHROTEC. Advise females of reproductive potential to use effective contraception during treatment with ARTHROTEC [see Contraindications (4), Use in Specific Populations (8.1, 8.3)].
Misoprostol
Misoprostol during pregnancy can result in maternal and fetal harm.
Diclofenac
Premature Closure of Fetal Ductus Arteriosus
NSAIDs, including diclofenac, increase the risk of premature closure of the fetal ductus arteriosus at about 30 weeks of gestation and later.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including diclofenac, 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 [see Use in Specific Populations (8.1)].
8 Use in Specific Populations
8.1 PregnancyExtensive additions and revisions, please refer to label for complete information.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions underlined
…
Embryo-Fetal Toxicity
Advise females that ARTHROTEC is contraindicated in pregnant women. Use of misoprostol, a component of ARTHROTEC during pregnancy can result in maternal and fetal harm, including abortion, premature birth, birth defects and uterine rupture. Use of diclofenac may cause oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].
…
Serious Skin Reactions, including DRESS
Advise patients to stop taking ARTHROTEC immediately if they develop any type of rash or fever and contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].
…
07/28/2020 (SUPPL-33)
Boxed Warning
(Box Warning in supplement 33 has been revised; see underlined text)ARTHROTEC CONTAINS DICLOFENAC SODIUM AND MISOPROSTOL. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, BIRTH DEFECTS, OR UTERINE RUPTURE. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION. THE RISK OF UTERINE RUPTURE INCREASES WITH ADVANCING GESTATIONAL AGES AND WITH PRIOR UTERINE SURGERY, INCLUDING CESAREAN DELIVERY. ARTHROTEC SHOULD NOT BE TAKEN BY PREGNANT WOMEN (4, 5.10, 8.1).
PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO
OTHERS. ARTHROTEC should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, ARTHROTEC may be prescribed if the patient:
has had a negative serum pregnancy test within 2 weeks prior to beginning therapy (8.3).
is capable of complying with effective contraceptive measures.
has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.
- will begin ARTHROTEC only on the second or third day of the next normal menstrual period.
Cardiovascular Thrombotic Events Risk
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 (5.1).
- ARTHROTEC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1).
Gastrointestinal Bleeding, Ulceration, and Perforation Risk
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 (5.2).
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions underlined)
Risk Summary
ARTHROTEC is contraindicated in pregnant women [see Contraindications (4)].
There are no adequate and well-controlled studies of ARTHROTEC in pregnant women; however, there is information available about the active drug components of ARTHROTEC, misoprostol and diclofenac sodium. Administration of misoprostol to pregnant women can cause abortion, premature birth, birth defects or uterine rupture. Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug’s teratogenic mechanism has not been demonstrated. Use of NSAIDS, including diclofenac, during the third trimester of pregnancy increases the risk of premature closure of fetal ductus arteriosus [see Data]. There are clinical considerations when misoprostol and diclofenac are used in pregnant women [see Clinical Considerations]. In reproduction studies with pregnant rabbits, there were no skeletal or visceral malformations when the combination of diclofenac sodium and misoprostol was administered during organogenesis at doses less than the maximum recommended human doses (MRHD); however, embryotoxicity was observed at this exposure [see Data]. Based
on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. If a woman becomes pregnant while taking ARTHROTEC, discontinue the drug and advise the woman of the potential risks to her and to a fetus.
…
Labor or Delivery
There are no studies on the effects of ARTHROTEC or diclofenac during labor or delivery. In animal studies, NSAIDS, including diclofenac, are known to inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. In humans, some case reports and studies have associated misoprostol with risk of stillbirth, uterine hyperstimulation, perineal tear, amniotic fluid embolism, severe bleeding, shock, uterine rupture and death. The risk of uterine rupture associated with misoprostol use in pregnancy may occur at any gestational age, and increases with advancing gestational ages and with prior uterine surgery, including cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions and/or revisions underlined)
What is the most important information I should know about Arthrotec?
Arthrotec contains diclofenac (a nonsteroidal anti-inflammatory drug (NSAID)) and misoprostol, and can cause abortion, premature birth, birth defects, and the uterus to tear (uterine rupture). The risk of uterine rupture increases as your pregnancy advances, if you have given birth to 5 or more children, and if you have had surgery on the uterus, such as a cesarean delivery. Do not take Arthrotec if you are pregnant.
…
05/09/2016 (SUPPL-31)
Boxed Warning
WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTSCardiovascular 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.
- 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)
MG - Includes new safety information pertaining to the risks of Cardiovascular Thrombotic Events, Heart Failure and Edema.
- 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.
- 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.