ARTHROTEC (diclofenac sodium 50 mg misoprostol 200 ug) Dailymed

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

After observing the response to initial therapy with ARTHROTEC, the dose and frequency should be adjusted to suit an individual patient's needs.

For the relief of rheumatoid arthritis and osteoarthritis, the dosage is given below.

ARTHROTEC is administered as ARTHROTEC 50 (50 mg diclofenac sodium/200 mcg misoprostol) or as ARTHROTEC 75 (75 mg diclofenac sodium/200 mcg misoprostol).

Note: See Special Dosing Considerations section below.

For osteoarthritis, the dosage for maximal GI mucosal protection is ARTHROTEC 50 three times a day. For patients who experience intolerance, ARTHROTEC 75 two times a day or ARTHROTEC 50 two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, ARTHROTEC, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

	OA regimen	Diclofenac sodium (mg/day)	Misoprostol (mcg/day)
ARTHROTEC 50	three times a day	150	600
	two times a day	100	400
ARTHROTEC 75	two times a day	150	400

For rheumatoid arthritis , the dosage is ARTHROTEC 50 three or four times a day. For patients who experience intolerance, ARTHROTEC 75 two times a day or ARTHROTEC 50 two times a day can be used, but are less effective in preventing ulcers. This fixed combination product, ARTHROTEC, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

	RA regimen	Diclofenac sodium (mg/day)	Misoprostol (mcg/day)
ARTHROTEC 50	four times a day	200	800
	three times a day	150	600
	two times a day	100	400
ARTHROTEC 75	two times a day	150	400

• Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2)
• OA: 100 to 150 mg diclofenac/400 to 600 mcg misoprostol per day, divided for administration two or three times a day. Dose of diclofenac higher than 150 mg/day is not recommended ( 2)
• RA: 100 to 200 mg diclofenac/400 to 800 mcg misoprostol per day, divided for administration two, three or four times a day. Dose of diclofenac higher than 225 mg/day is not recommended ( 2)

Special Dosing Considerations:

ARTHROTEC 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), after which the patient may be changed to the appropriate dose of ARTHROTEC. If clinically indicated, misoprostol co-therapy with ARTHROTEC, or use of the individual components to optimize the misoprostol dose and/or frequency of administration, may be appropriate. The total dose of misoprostol should not exceed 800 mcg/day, and no more than 200 mcg of misoprostol should be administered at any one time. Doses of diclofenac higher than 150 mg/day in osteoarthritis or higher than 225 mg/day in rheumatoid arthritis are not recommended.

When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of ARTHROTEC 50 two times a day.

For additional information, it may be helpful to refer to the package inserts for misoprostol and diclofenac.

ARTHROTEC is contraindicated in the following patients:

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium/misoprostol, other prostaglandins, or any components of the drug product [see Warnings and Precautions (5.7, 5.9)] Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium/misoprostol, other prostaglandins, or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)] History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]
• In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)] In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]
• Pregnancy. Use of ARTHROTEC during pregnancy can result in maternal and fetal harm, including abortion, premature birth, birth defects, and uterine rupture [see Use in Specific Populations (8.1)] Pregnancy. Use of ARTHROTEC during pregnancy can result in maternal and fetal harm, including abortion, premature birth, birth defects, and uterine rupture [see Use in Specific Populations (8.1)]
• Active gastrointestinal bleeding [see Warnings and Precautions (5.2)] Active gastrointestinal bleeding [see Warnings and Precautions (5.2)]

• Known hypersensitivity to diclofenac, misoprostol or any components of the drug product ( 4)
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4)
• In the setting of CABG surgery ( 4)
• Pregnancy ( 4)
• Active gastrointestinal bleeding ( 4)

5 Warnings And Precautions

• Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3)
• Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4, 7)
• Heart Failure and Edema: Avoid use of ARTHROTEC in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5)
• Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of ARTHROTEC in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6)
• Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs ( 5.7)
• Exacerbation of Asthma Related to Aspirin Sensitivity: ARTHROTEC is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8)
• Serious Skin Reactions: Discontinue ARTHROTEC at first appearance of skin rash or other signs of hypersensitivity ( 5.9)
• Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnancy. Diclofenac may cause premature closure of the fetal ductus arteriosus. ( 5.10, 8.1)
• Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.11, 7)

5.1Cardiovascular 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 diclofenac, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)] .

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 [see Contraindications (4)] .

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 ARTHROTEC in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ARTHROTEC is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2Gastrointestinal 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 3–6 months, and in about 2%–4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

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, 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.

Strategies to Minimize the GI Risks in NSAID-treated patients:

• Use the lowest effective dosage for the shortest possible duration.Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time. Avoid administration of more than one NSAID at a time.
• Avoid use in patients at high risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.Avoid use in patients at high risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ARTHROTEC until a serious GI adverse event is ruled out.If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue ARTHROTEC until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)] . In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)] .

5.3Hepatotoxicity

In clinical trials with ARTHROTEC, meaningful elevation of ALT (SGPT, more than 3 times the ULN [ULN = the upper limit of the normal range]) 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 AST (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 2–6 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 (3–8 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.), ARTHROTEC 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 ARTHROTEC immediately, and perform a clinical evaluation of the patient.

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

5.4Hypertension

NSAIDs, including ARTHROTEC, 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.

5.5Heart Failure and Edema

The Coxib and traditional NSAID Triauls' 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 ARTHROTEC in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ARTHROTEC is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6Renal Toxicity and Hyperkalemia

Renal Toxicity

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of ARTHROTEC in patients with advanced renal disease. The renal effects of ARTHROTEC may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating ARTHROTEC. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of ARTHROTEC [see Drug Interactions (7)] . Avoid the use of ARTHROTEC in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If ARTHROTEC is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

5.7Anaphylactic Reactions

Diclofenac/misoprostol has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac/misoprostol and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)] .

Seek emergency help if an anaphylactic reaction occurs.

5.8Exacerbation 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, ARTHROTEC is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)] . When ARTHROTEC is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.9Serious Skin Reactions

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. 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)] .

5.10 Premature Closure of Fetal Ductus Arteriosus

Diclofenac may cause premature closure of the fetal ductus arteriosus. 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 ARTHOTEC. Advise females of reproductive potential to use effective contraception during treatment with ARTHROTEC [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)] .

5.11 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 ARTHROTEC has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

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

5.12Masking of Inflammation and Fever

The pharmacological activity of ARTHROTEC in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.13Laboratory 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 CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.6)] .

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
• GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Heart Failure and Edema [see Warnings and Precautions (5.5)]
• Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
• Anaphylactic Reactions [see Warnings and Precautions (5.7)]
• Serious Skin Reactions [see Warnings and Precautions (5.9)]
• Hematologic Toxicity [see Warnings and Precautions (5.11)]

Most common adverse reactions (incidence > 2% from clinical trials) are: abdominal pain, diarrhea, dyspepsia, nausea, flatulence, gastritis, vomiting, constipation, headache, dizziness, alanine aminotransferase increased, hematocrit decreased ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 ARTHROTEC is derived from Phase III multinational controlled clinical trials in over 2,000 patients receiving ARTHROTEC 50 or ARTHROTEC 75, as well as from blinded, controlled trials of diclofenac delayed-release tablets and misoprostol tablets.

Gastrointestinal

GI disorders had the highest reported incidence of adverse events for patients receiving ARTHROTEC. These events were generally minor, but led to discontinuation of therapy in 9% of patients on ARTHROTEC and 5% of patients on diclofenac. For GI ulcer rates, [see Clinical Studies (14)] .

GI disorder	ARTHROTEC	Diclofenac
Abdominal pain	21%	15%
Diarrhea	19%	11%
Dyspepsia	14%	11%
Nausea	11%	6%
Flatulence	9%	4%

ARTHROTEC can cause more abdominal pain, diarrhea, and other GI symptoms than diclofenac alone.

Diarrhea and abdominal pain developed early in the course of therapy, and were usually self-limited (resolved after 2 to 7 days). Rare instances of profound diarrhea leading to severe dehydration have been reported in patients receiving misoprostol. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if ARTHROTEC is prescribed. The incidence of diarrhea can be minimized by administering ARTHROTEC with food and by avoiding coadministration with magnesium-containing antacids.

Gynecological

Gynecological disorders previously reported with misoprostol use have also been reported for women receiving ARTHROTEC (see below). Postmenopausal vaginal bleeding may be related to administration of ARTHROTEC. If it occurs, diagnostic workup should be undertaken to rule out gynecological pathology [see Boxed Warnings, Contraindications (4) and Warnings and Precautions (5)] .

Elderly

Overall, there were no significant differences in the safety profile of ARTHROTEC in over 500 patients 65 years of age or older compared with younger patients.

Other adverse experiences reported occasionally with ARTHROTEC, diclofenac or other NSAIDs, or misoprostol are:

Body as a whole: asthenia, fatigue, malaise.

Central and peripheral nervous system: dizziness, drowsiness, headache, insomnia, paresthesia, vertigo.

Digestive: anorexia, appetite changes, constipation, dry mouth, dysphagia, esophageal ulceration, oesophagitis, eructation, gastritis, gastroesophageal reflux, GI neoplasm benign, peptic ulcer, tenesmus, vomiting.

Female reproductive disorders: breast pain, dysmenorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.

Hemic and lymphatic system: epistaxis, leukopenia, melena, purpura, decreased hematocrit.

Metabolic and nutritional: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, dehydration, hyponatremia.

Musculoskeletal system: arthralgia, myalgia.

Psychiatric: anxiety, concentration impaired, depression, irritability.

Respiratory system: asthma, coughing, hyperventilation.

Skin and appendages: alopecia,eczema, pemphigoid reaction, photosensitivity, sweating increased, pruritus.

Special senses: taste perversion, tinnitus.

Renal and urinary disorders: dysuria, nocturia, polyuria, proteinuria, urinary tract infection.

Vision: diplopia.

6.2Postmarketing Experience

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 CPK, increased 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: 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, glomerulohephritis.

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