2.1 Important Dosage Information

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Carefully consider the potential benefits and risks of diclofenac sodium/misoprostol and other treatment options before deciding to use diclofenac sodium/misoprostol. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

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After observing the response to initial therapy with diclofenac sodium/misoprostol, the dose and frequency should be adjusted to suit an individual patient’s needs.

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Diclofenac sodium/misoprostol is not recommended for patients who would not receive the appropriate dosage of both active ingredients.

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Diclofenac sodium/misoprostol, a fixed combination product, is administered as diclofenac sodium/misoprostol 50 (50 mg diclofenac sodium and 200 mcg misoprostol) or as diclofenac sodium/misoprostol 75 (75 mg diclofenac sodium and 200 mcg misoprostol).

2.2 Recommended Dosage in Patients with Osteoarthritis

The recommended dosage for the treatment of osteoarthritis for maximal GI mucosal protection is diclofenac sodium/misoprostol 50 three times a day. For patients who experience intolerance, diclofenac sodium/misoprostol 75 two times a day or diclofenac sodium/misoprostol 50 two times a day can be used, but these dosages are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 150 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows:

2.3 Recommended Dosage in Patients with Rheumatoid Arthritis

The recommended dosage for the treatment of rheumatoid arthritis is diclofenac sodium/misoprostol 50 three or four times a day. For patients who experience intolerance, diclofenac sodium/misoprostol 75 two times a day or diclofenac sodium/misoprostol 50 two times a day can be used, but are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 200 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows:

2.4 Additional Dosage Recommendations

Diclofenac sodium/misoprostol contains misoprostol, which provides protection against gastric and duodenal ulcers [see Clinical Studies (14)]. For gastric ulcer prevention, the 200 mcg four and three times a day regimens are therapeutically equivalent, but more protective than the two times a day regimen. For duodenal ulcer prevention, the four times a day regimen is more protective than the three or two times a day regimens. However, the four times a day regimen is less well tolerated than the three times a day regimen because of usually self-limited diarrhea related to the misoprostol dose [see Adverse Reactions (6.1)], and the two times a day regimen may be better tolerated than three times a day in some patients.

Dosages may be individualized using the separate products (misoprostol and diclofenac sodium), after which the patient may be switched to the appropriate diclofenac sodium/misoprostol dosage. If clinically indicated, misoprostol co-therapy with diclofenac sodium/misoprostol to optimize the misoprostol dose and/or frequency of administration, may be appropriate. Do not exceed a total misoprostol dose of 800 mcg/day and do not administer more than 200 mcg of misoprostol at any one time.

When concomitant use of CYP2C9 inhibitors is necessary, the maximum total daily dose of diclofenac is 100 mg per day. Do not exceed a dosage of diclofenac sodium/misoprostol 50 mg twice daily [see Drug Interactions (7)].

For additional information, refer to the Prescribing Information for the individual products of diclofenac sodium and misoprostol.

5.1 Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs

5.2 Cardiovascular Thrombotic Events

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. 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 diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.3)].

5.3 Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

5.4 Hepatotoxicity

In clinical trials with diclofenac sodium/misoprostol, 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 diclofenac sodium/misoprostol 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 diclofenac sodium/misoprostol. The misoprostol component of diclofenac sodium/misoprostol 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).

In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (i.e., greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.

If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium/misoprostol should be discontinued immediately.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium/misoprostol immediately, and perform a clinical evaluation of the patient.

To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium/misoprostol, the lowest effective dose should be used for the shortest duration possible. Exercise caution when prescribing diclofenac sodium/misoprostol with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

5.5 Hypertension

NSAIDs, including diclofenac, a component of diclofenac sodium/misoprostol, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

5.6 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 diclofenac 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]) [see Drug Interactions (7)].

Avoid the use of diclofenac sodium/misoprostol in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium/misoprostol is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.7 Renal Toxicity and Hyperkalemia

5.8 Anaphylactic Reactions

Diclofenac sodium/misoprostol has been associated with anaphylactic reactions in patients with and without known hypersensitivity to the individual components of diclofenac sodium and misoprostol and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.9)].

Seek emergency help if an anaphylactic reaction occurs.

5.9 Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium/misoprostol is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When diclofenac sodium/misoprostol is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.10 Serious Skin Reactions

NSAIDs, including diclofenac, a component of diclofenac sodium/misoprostol, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium/misoprostol at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium/misoprostol is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

5.11 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium/misoprostol. 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 diclofenac sodium/misoprostol and evaluate the patient immediately.

5.12 Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium/misoprostol has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including diclofenac, a component of diclofenac sodium/misoprostol, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet drugs (e.g., aspirin), and SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

5.13 Masking of Inflammation and Fever

The pharmacological activity of diclofenac, a component of diclofenac sodium/misoprostol, in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.14 Laboratory Monitoring

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 (5.3, 5.7)].

6.1 Clinical Trials Experience

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.

Adverse reaction information for diclofenac sodium/misoprostol is derived from multinational controlled clinical trials in over 2,000 patients receiving diclofenac sodium/misoprostol 50 or diclofenac sodium/misoprostol 75, as well as from blinded, controlled trials of diclofenac sodium delayed-release tablets and misoprostol tablets

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval of diclofenac sodium/misoprostol, 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.

Central and peripheral nervous system: coma, convulsions, hyperesthesia, hypertonia, hypoesthesia, meningitis, migraine, neuralgia, somnolence, stroke, tremor.

Congenital, familial and genetic disorders: birth defects.

Digestive: enteritis, GI bleeding, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, stomatitis and ulcerative stomatitis.

Female reproductive disorders: intermenstrual bleeding, leukorrhea, vaginitis, uterine cramping, uterine hemorrhage.

Hemic and lymphatic system: agranulocytosis, anemia, aplastic anemia, coagulation time increased, ecchymosis, eosinophilia, hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, pulmonary embolism, rectal bleeding, thrombocythemia, thrombocytopenia.

Hypersensitivity: angioedema, laryngeal/pharyngeal edema, urticaria.

Liver and biliary system: abnormal hepatic function, bilirubinemia, liver failure, pancreatitis, hepatitis, jaundice.

Male reproductive disorders: impotence, perineal pain.

Metabolic and nutritional: blood urea nitrogen (BUN) increased, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, periorbital edema, porphyria, weight changes, fluid retention.

Pregnancy, puerperium and perinatal conditions: abnormal uterine contractions, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death.

Psychiatric: confusion, disorientation, dream abnormalities, hallucinations, nervousness, paranoia, psychotic reaction.

Reproductive system and breast disorders: female fertility decreased.

Respiratory system: dyspnea, pneumonia, respiratory depression.

Skin and appendages: acne, bruising, erythema multiforme, exfoliative dermatitis, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous reactions (bullous eruption).

Special senses: hearing impairment, taste loss.

Renal and urinary disorders: cystitis, hematuria, interstitial nephritis, micturition frequency, nephrotic syndrome, oliguria, papillary necrosis, renal failure, glomerulonephritis membranous, glomerulonephritis minimal lesion, glomerulonephritis.

Vision: amblyopia, blurred vision, conjunctivitis, glaucoma, iritis, lacrimation abnormal, night blindness, vision abnormal.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Diclofenac sodium/misoprostol is not recommended in women of childbearing potential [see Warnings and Precautions (5.1)]. If diclofenac sodium/misoprostol is prescribed, patients must be advised of the abortifacient property and warned not to give the drug to others.

8.4 Pediatric Use

Safety and effectiveness of diclofenac sodium/misoprostol in pediatric patients have not been established.

8.5 Geriatric Use

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 diclofenac sodium/misoprostol 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 diclofenac sodium/misoprostol, especially in patients with concomitant use of ACE inhibitors or ARBs.

Of the 2,184 patients in clinical studies with diclofenac sodium/misoprostol, 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)].

8.6 Renal Impairment

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 diclofenac sodium/misoprostol. 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 diclofenac sodium/misoprostol 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)].

Diclofenac

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.2, 5.3, 5.5, 5.7)].

Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness, or general hypotonia.

If gastric decontamination may be potentially beneficial to the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

Misoprostol

The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 mcg have been tolerated, with only symptoms of GI discomfort being reported. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia.

Diclofenac sodium/misoprostol

Symptoms of acute overdosage with diclofenac sodium/misoprostol should be treated with supportive and symptomatic therapy. There are no specific antidotes. In case of acute overdosage, emesisis and/or gastric lavage may be considered dependent upon amount ingested and time since ingestion. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol. Induced diuresis may be beneficial because diclofenac sodium and misoprostol metabolites are excreted in the urine. The effect of dialysis or hemoperfusion on the elimination of diclofenac sodium (99% protein bound) and misoprostol acid remains unproven.

12.1 Mechanism of Action

Diclofenac sodium/misoprostol is a combination product containing diclofenac sodium, an NSAID with analgesic, anti-inflammatory and antipyretic properties, and misoprostol, a GI mucosal protective prostaglandin-1 (PGE1) analog.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology

A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.

Osteoarthritis

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of osteoarthritis.

Rheumatoid Arthritis

Diclofenac sodium, as a single ingredient or in combination with misoprostol, has been shown to be effective in the management of the signs and symptoms of rheumatoid arthritis.

Upper Gastrointestinal Safety

Diclofenac, and other NSAIDs, have caused serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation of the stomach, small intestine or large intestine. Misoprostol has been shown to reduce the incidence of endoscopically diagnosed NSAID-induced gastric and duodenal ulcers. In a 12-week, randomized, double-blind, dose-response study, misoprostol 200 mcg administered four, three or two times a day, was significantly more effective than placebo in reducing the incidence of gastric ulcer in osteoarthritis and rheumatoid arthritis patients using a variety of NSAIDs. The three times a day regimen was therapeutically equivalent to misoprostol 200 mcg four times a day with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given two times a day was less effective than 200 mcg given three or four times a day. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 3).

Table 3

N=1623; 12 weeks

Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving diclofenac sodium/misoprostol have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 4).

Table 4

Store at 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

Uterine Rupture, Abortion, Premature Birth, or Birth Defects with Misoprostol and Embryo-Fetal Toxicity with NSAIDs

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Advise females that diclofenac sodium/misoprostol is contraindicated in pregnant women. Use of misoprostol, a component of diclofenac sodium/misoprostol 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.

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Advise patients not to give diclofenac sodium/misoprostol to others.

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Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with diclofenac sodium/misoprostol. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].

Infertility

Advise females of reproductive potential that diclofenac sodium/misoprostol may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Use in Specific Populations (8.3)].

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 health care provider immediately [see Warnings and Precautions (5.2)].

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.3)].

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop diclofenac sodium/misoprostol and seek immediate medical therapy [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.6)].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.8)].

Serious Skin Reactions, including DRESS

Advise patients to stop taking diclofenac sodium/misoprostol immediately if they develop any type of rash or fever and contact their healthcare provider as soon as possible [see Warnings and Precautions (5.10), (5.11)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of diclofenac sodium/misoprostol with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.3) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia.

Use of NSAIDS and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium/misoprostol until they talk to their healthcare provider [see Drug Interactions (7)].