ARTHROTEC (diclofenac sodium/misoprostol) is a combination product containing diclofenac sodium, a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin E1 analog. ARTHROTEC oral tablets are white to off-white, round, biconvex and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg (ARTHROTEC 50) or 75 mg (ARTHROTEC 75) diclofenac sodium surrounded by an outer mantle containing 200 mcg misoprostol.

Diclofenac sodium is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium is freely soluble in methanol, soluble in ethanol and practically insoluble in chloroform and in dilute acid. Diclofenac sodium is sparingly soluble in water. Its chemical formula and name are:

C₁₄H₁₀Cl₂NO₂Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt.

Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are:

C₂₂H₃₈O₅ [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate.

Inactive ingredients in ARTHROTEC include: colloidal silicon dioxide; crospovidone; hydrogenated castor oil; hypromellose; lactose; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone (polyvidone) K-30; sodium hydroxide; starch (corn); talc; triethyl citrate.

Last updated on RxList: 10/6/2009

Carefully consider the potential benefits and risks of ARTHROTEC and other treatment options before deciding to use ARTHROTEC. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

ARTHROTEC is indicated for treatment of the signs and symptoms of osteoarthritis or rheumatoid arthritis in patients at high risk of developing NSAID-induced gastric and duodenal ulcers and their complications. See WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding and Perforation for a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications.

Carefully consider the potential benefits and risks of ARTHROTEC and other treatment options before deciding to use ARTHROTEC. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

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 recommended dose 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.

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

Rheumatoid Arthritis: The recommended dosage is ARTHROTEC 50 tid or qid. For patients who experience intolerance, ARTHROTEC 75 bid or ARTHROTEC 50 bid can be used, but are less effective in preventing ulcers. This fixed combination product, ARTHROTEC, is not appropriate for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:

SPECIAL DOSING CONSIDERATIONS: ARTHROTEC contains misoprostol, which provides protection against gastric and duodenal ulcers (see Clinical Studies). For gastric ulcer prevention, the 200 mcg qid and tid regimens are therapeutically equivalent, but more protective than the bid regimen. For duodenal ulcer prevention, the qid regimen is more protective than the tid or bid regimens. However, the qid regimen is less well tolerated than the tid regimen because of usually self-limited diarrhea related to the misoprostol dose (see ADVERSE REACTIONS— Gastrointestinal), and the bid regimen may be better tolerated than tid 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.

For additional information, it may be helpful to refer to the package inserts for Cytotec® tablets and Voltaren® tablets.

ARTHROTEC (diclofenac sodium/misoprostol) is supplied as a film-coated tablet in dosage strengths of either 50 mg diclofenac sodium/200 mcg misoprostol or 75 mg diclofenac sodium/200 mcg misoprostol. The 50 mg/200 mcg dosage strength is a round, biconvex, white to off-white tablet imprinted with four “A's” encircling a “50” in the middle on one side and “SEARLE” and “1411” on the other. The 75 mg/200 mcg dosage strength is a round, biconvex, white to off-white tablet imprinted with four “A's” encircling a “75” in the middle on one side and “SEARLE” and “1421” on the other.

The dosage strengths are supplied in:

Store at or below 25°C (77°F), in a dry area.

Distributed by : G.D.Searle LLC, Division of Pfizer Inc, NY, NY 10017. Revised August 2009

Last updated on RxList: 10/6/2009

Adverse reactions associated with ARTHROTEC

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 Voltaren® Delayed-Release Tablets (diclofenac) and Cytotec® Tablets (misoprostol).

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 - Upper gastrointestinal safety.

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 selflimited (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 CONTRAINDICATIONS AND WARNINGS).

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 or rarely with ARTHROTEC, diclofenac or other NSAIDs, or misoprostol are:

Body as a whole: Asthenia, death, fatigue, fever, infection, malaise, sepsis, chills.

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, dizziness, drowsiness, headache, hyperesthesia, hypertonia, hypoesthesia, insomnia, meningitis, migraine, neuralgia, paresthesia, somnolence, tremor, vertigo.

Digestive: Anorexia, appetite changes, constipation, dry mouth, dysphagia, enteritis, esophageal ulceration, esophagitis, eructation, gastritis, gastroesophageal reflux, GI bleeding, GI neoplasm benign, glossitis, heartburn, hematemesis, hemorrhoids, intestinal perforation, peptic ulcer, stomatitis and ulcerative stomatitis, tenesmus, vomiting.

Female reproductive disorders: Breast pain, dysmenorrhea, intermenstrual bleeding, leukorrhea, menstrual disorder, menorrhagia, vaginal hemorrhage.

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

Hypersensitivity: Angioedema, laryngeal/pharyngeal edema, urticaria.

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

Male reproductive disorders: Impotence, perineal pain.

Metabolic and nutritional: Alkaline phosphatase increased, BUN increased, dehydration, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperuricemia, hypoglycemia, hyponatremia, periorbital edema, porphyria, weight changes.

Musculoskeletal system: Arthralgia, myalgia.

Psychiatric: Anxiety, concentration impaired, confusion, depression, disorientation, dream abnormalities, hallucinations, irritability, nervousness, paranoia, psychotic reaction.

Respiratory system: Asthma, coughing, dyspnea, hyperventilation, pneumonia, respiratory depression.

Skin and appendages: Acne, alopecia, bruising, eczema, erythema multiforme, exfoliative dermatitis, pemphigoid reaction, photosensitivity, pruritus, pruritus ani, rash, skin ulceration, Stevens-Johnson syndrome, sweating increased, toxic epidermal necrolysis.

Special senses: Hearing impairment, taste loss, taste perversion, tinnitus.

Urinary system: Cystitis, dysuria, hematuria, interstitial nephritis, micturition frequency, nocturia, nephrotic syndrome, oliguria/polyuria, papillary necrosis, proteinuria, renal failure, urinary tract infection.

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

ACE-Inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACEinhibitors.

Aspirin

When ARTHROTEC is administered with aspirin, the protein binding of diclofenac is reduced, although the clearance of the free ARTHROTEC is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac sodium and aspirin is not generally recommended because of the potential risk of increased adverse effects.

Digoxin

Elevated digoxin levels have been reported in patients receiving digoxin and diclofenac sodium. Patients receiving digoxin and ARTHROTEC should be monitored for possible digoxin toxicity.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious bleeding greater than users of either drug alone.

Oral hypoglycemics

Diclofenac sodium does not alter glucose metabolism in healthy people nor does it alter the effects of oral hypoglycemic agents. There are rare reports, however, from marketing experience, of changes in effects of insulin or oral hypoglycemic agents in the presence of diclofenac sodium that necessitated change in the doses of such agents. Both hypo- and hyperglycemic effects have been reported. A direct causal relationship has not been established, but physicians should consider the possibility that diclofenac sodium may alter a diabetic patient's response to insulin or oral hypoglycemic agents.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Cyclosporine

ARTHROTEC, like other NSAID containing products, may affect renal prostaglandins and increase the toxicity of certain drugs. Ingestion of ARTHROTEC may increase cyclosporine nephrotoxicity. Patients who begin taking ARTHROTEC or who increase their dose of ARTHROTEC while taking cyclosporine may develop toxicity characteristic for clyclosporine. They should be observed closely, particularly if renal function is impaired.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Antacids

Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac sodium. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea. Thus, it is not recommended that ARTHROTEC be coadministered with magnesium-containing antacids.

Diuretics

Clinical studies, as well as post marketing observations, have shown that ARTHROTEC can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Concomitant therapy with potassium-sparing diuretics may be associated with increased serum potassium levels.

Other drugs

In small groups of patients (7–10 patients/interaction study), the concomitant administration of azathioprine, gold, chloroquine, D-penicillamine, prednisolone, doxycycline or digitoxin did not significantly affect the peak levels and AUC levels of diclofenac sodium. Phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment following the initiation of diclofenac therapy. In vitro, diclofenac interferes minimally with the protein binding of prednisolone (10% decrease in binding). Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence, in vitro, on the protein binding of diclofenac in human serum.

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.

Last updated on RxList: 10/6/2009

Regarding misoprostol

See BOXED CONTRAINDICATIONS AND WARNINGS.

Regarding diclofenac

See BOXED CONTRAINDICATIONS AND WARNINGS.

Cardiovascular Effects

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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding and Perforation).

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 (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including ARTHROTEC, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ARTHROTEC, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. ARTHROTEC should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding and Perforation

NSAIDs, including ARTHROTEC, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the 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 occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

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 a nonsteroidal antiinflammatory drug 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, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

ARTHROTEC contains diclofenac. Diclofenac metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied. Therefore, treatment with ARTHROTEC is not recommended in these patients with advanced renal disease. If ARTHROTEC therapy must be initiated, close monitoring of the patient's renal function is advisable.

Hepatic effects

In clinical trials with ARTHROTEC, meaningful elevation of ALT (SGPT, more than 3 times the 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.

Elevations of one or more liver tests may occur during therapy with diclofenac, a component of ARTHROTEC. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]), or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated 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., more 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 ( > 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.

Physicians should measure transaminases 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.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

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. Caution should be exercised in prescribing ARTHROTEC with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

Anaphylactoid reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ARTHROTEC. ARTHROTEC should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS —Preexisting asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Allergic reactions have been reported by less than 0.1% of patients who received ARTHROTEC in clinical trials, and there have been rare reports of anaphylaxis in the marketed use of ARTHROTEC outside of the United States.

Skin Reactions

NSAIDs, including ARTHROTEC, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, ARTHROTEC should be avoided because it may cause premature closure of the ductus arteriosus.

General

ARTHROTEC cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ARTHROTEC in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

See WARNINGS.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including ARTHROTEC. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ARTHROTEC, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ARTHROTEC who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, ARTHROTEC should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Aseptic meningitis

As with other NSAIDs, aseptic meningitis with fever and coma has been observed on rare occasions in patients on diclofenac therapy. Although it is probably more likely to occur in patients with systemic lupus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on diclofenac, the possibility of its being related to diclofenac should be considered.

Porphyria

The use of ARTHROTEC in patients with hepatic porphyria should be avoided. To date, one patient has been described in whom diclofenac sodium probably triggered a clinical attack of porphyria. The postulated mechanism, demonstrated in rats, for causing such attacks by diclofenac sodium, as well as some other NSAIDs, is through stimulation of the porphyrin precursor delta-aminolevulinic acid (ALA).

Information for patients

Women of childbearing potential using ARTHROTEC to treat arthritis should be told that they must not be pregnant when therapy with ARTHROTEC is initiated, and that they must use an effective contraception method while taking ARTHROTEC. See BOXED CONTRAINDICATIONS AND WARNINGS.

THE PATIENT SHOULD NOT GIVE ARTHROTEC TO ANYONE ELSE. ARTHROTEC has been prescribed for the patient's specific condition, may not be the correct treatment for another person, and may be dangerous to the other person if she were to become pregnant.

SPECIAL NOTE FOR WOMEN: ARTHROTEC contains diclofenac sodium and misoprostol. Misoprostol may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women.

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• ARTHROTEC, like other NSAIDs, may cause serious side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
• ARTHROTEC, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalizations and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulceration and bleeding, and should ask for medical advice when observing any indicative sign or symptoms, including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding and Perforation).
• ARTHROTEC, like other NSAIDs, can cause serious skin side effects, such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical attention.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactoid reactions).
• In late pregnancy, as with other NSAIDs, ARTHROTEC should be avoided because it may cause premature closure of the ductus arteriosus.

See PATIENT INFORMATION section for important information to discuss with the patient.

ARTHROTEC is available only as a unit-of-use package that includes a leaflet containing patient information. The patient should read the leaflet before taking ARTHROTEC and each time the prescription is renewed because the leaflet may have been revised. Keep ARTHROTEC out of the reach of children.

Laboratory tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs of symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, ARTHROTEC should be discontinued.

Effect on blood coagulation

Diclofenac sodium impairs platelet aggregation but does not affect bleeding time, plasma thrombin clotting time, plasma fibrinogen, or factors V and VII to XII. Statistically significant changes in prothrombin and partial thromboplastin times have been reported in normal volunteers. The mean changes were observed to be less than 1 second in both instances, however, and are unlikely to be clinically important. Diclofenac sodium is a prostaglandin synthetase inhibitor, however, and all drugs that inhibit prostaglandin synthesis interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed. Misoprostol has not been shown to exacerbate the effects of diclofenac on platelet activity.

Carcinogenesis, mutagenesis, impairment of fertility

Long-term animal studies to evaluate the potential for carcinogenesis and animal studies to evaluate the effects on fertility have been performed with each component of ARTHROTEC given alone. ARTHROTEC itself (diclofenac sodium and misoprostol combinations in 250:1 ratio) was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the rat lymphocyte chromosome aberration test or the mouse micronucleus test.

In a 24-month rat carcinogenicity study, oral misoprostol at doses up to 2.4 mg/kg/day (14.4 mg/m²/day, 24 times the recommended maximum human dose of 0.6 mg/m²/day) was not tumorigenic. In a 21-month mouse carcinogenicity study, oral misoprostol at doses up to 16 mg/kg/day (48 mg/m²/day), 80 times the recommended maximum human dose based on body surface area, was not tumorigenic. Misoprostol, when administered to male and female breeding rats in an oral dose range of 0.1 to 10 mg/kg/day (0.6 to 60 mg/m²/day, 1 to 100 times the recommended maximum human dose based on body surface area) produced dose-related pre- and post-implantation losses and a significant decrease in the number of live pups born at the highest dose. These findings suggest the possibility of a general adverse effect on fertility in males and females.

In a 24-month rat carcinogenicity study, oral diclofenac sodium up to 2 mg/kg/day (12 mg/m²/day) was not tumorigenic. For a 50-kg person of average height (1.46m² body surface area), this dose represents 0.08 times the recommended maximum human dose (148 mg/m²) on a body surface area basis. In a 24-month mouse carcinogenicity study, oral diclofenac sodium at doses up to 0.3 mg/kg/day (0.9 mg/m²/day, 0.006 times the recommended maximum human dose based on body surface area) in males and 1 mg/kg/day (3 mg/m²/day, 0.02 times the recommended maximum human dose based on body surface area) in females was not tumorigenic. Diclofenac sodium at oral doses up to 4 mg/kg/day (24 mg/m²/day, 0.16 times the recommended maximum human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy

Pregnancy category X

See BOXED CONTRAINDICATIONS AND WARNINGS regarding misoprostol.

Non-teratogenic effects

See BOXED CONTRAINDICATIONS AND WARNINGS. Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe genital bleeding, shock, fetal bradycardia, and fetal and material death have been reported. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. ARTHROTEC, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.

Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, fetal bradycardia, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses.

Additionally, because of the known effects of nonsteroidal anti-inflammatory drugs including the diclofenac sodium component of ARTHROTEC, on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

Teratogenic effects

See BOXED CONTRAINDICATIONS AND WARNINGS. 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. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.

An oral teratology study has been performed in pregnant rabbits at dose combinations (250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m²/day, 0.8 times the recommended maximum human dose based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m²/day, 0.8 times the recommended maximum human dose based on body surface area) and has revealed no evidence of teratogenic potential for ARTHROTEC.

Oral teratology studies have been performed in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m²/day, 16 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m²/day, 20 times the recommended maximum human dose based on body surface area) and have revealed no evidence of teratogenic potential for misoprostol.

Oral teratology studies have been performed in pregnant mice at doses up to 20 mg/kg/day (60 mg/m²/day, 0.4 times the recommended maximum human dose based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m²/day, 0.4 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m²/day, 0.8 times the recommended maximum human dose based on body surface area) and have revealed no evidence of teratogenic potential for diclofenac sodium. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.

Nursing mothers

Diclofenac sodium has been found in the milk of nursing mothers. It is unlikely that misoprostol is excreted into milk since the drug is rapidly metabolized throughout the body. Excretion of the active metabolite (misoprostol acid) into milk is possible, but has not been studied. Misoprostol acid could cause significant diarrhea in nursing infants. Because of the potential for serious adverse reactions in nursing infants, ARTHROTEC is not recommended for use by nursing mothers.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred.

Pediatric use

Safety and effectiveness of ARTHROTEC in pediatric patients have not been established.

Geriatric use

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). Of the more than 2,100 subjects in clinical studies with ARTHROTEC, 25% were 65 and over, while 6% were 75 and over. In studies with diclofenac, 31% of subjects were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Diclofenac is known to be substantially excreted by the kidney, and the risk of toxic reactions to ARTHROTEC may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS—Renal effects).

Based on studies in the elderly, no adjustment of the dose of ARTHROTEC is necessary in the elderly for pharmacokinetic reasons (see Pharmacokinetics of ARTHROTEC—Special populations), although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.

Last updated on RxList: 10/6/2009

The toxic dose of ARTHROTEC has not been determined. However, signs of overdosage from the components of the product have been described.

Diclofenac sodium

Clinical signs that may suggest diclofenac sodium overdose include GI complaints, confusion, drowsiness or general hypotonia. Reports of overdosage with diclofenac cover 66 cases. In approximately one-half of these reports of overdosage, concomitant medications were also taken. The highest dose of diclofenac was 5.0 g in a 17-year-old man who suffered loss of consciousness, increased intracranial pressure, and aspiration pneumonitis, and died 2 days after overdose. A 24- year-old woman who took 4.0 g and the 28- and 42-year-old women, each of whom took 3.75 g, did not develop any clinically significant signs or symptoms. However, there was a report of a 17- year-old female who experienced vomiting and drowsiness after an overdose of 2.37 g of diclofenac.

Animal studies show a wide range of susceptibilities to acute overdosage, with primates being more resistant to acute toxicity than rodents (LD₅₀ in mg/kg: rats, 55; dogs, 500; monkeys, 3200).

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. In animals, the acute toxic effects are diarrhea, GI lesions, focal cardiac necrosis, hepatic necrosis, renal tubular necrosis, testicular atrophy, respiratory difficulties, and depression of the central nervous system. Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia.

ARTHROTEC

Symptoms of overdosage with ARTHROTEC should be treated with supportive therapy. In case of acute overdosage, gastric lavage is recommended. 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. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol.

See BOXED CONTRAINDICATIONS AND WARNINGS related to misoprostol.

ARTHROTEC should not be taken by pregnant women.

ARTHROTEC is contraindicated in patients with hypersensitivity to diclofenac or to misoprostol or other prostaglandins. ARTHROTEC should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to diclofenac sodium have been reported in such patients (see WARNINGS- Anaphylactic Reactions, and PRECAUTIONS- Preexisting Asthma).

ARTHROTEC is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see BOXED CONTRAINDICATIONS AND WARNINGS).

Last updated on RxList: 10/6/2009

Pharmacodynamics and pharmacokinetics of diclofenac sodium

Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac sodium has shown anti-inflammatory, analgesic and antipyretic properties. The mechanism of action of diclofenac sodium, like other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Diclofenac sodium is completely absorbed from the GI tract after fasting, oral administration. The diclofenac sodium in ARTHROTEC is in a pharmaceutical formulation that resists dissolution in the low pH of gastric fluid but allows a rapid release of drug in the higher pH environment of the duodenum. Only 50% of the absorbed dose is systemically available due to first pass metabolism. Peak plasma levels are achieved in 2 hours (range 1–4 hours), and the area under the plasma concentration curve (AUC) is dose proportional within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.5 and 2.0 mcg/mL for 50 mg and 75 mg doses, respectively.

Plasma concentrations of diclofenac sodium decline from peak levels in a biexponential fashion, with the terminal phase having a half-life of approximately 2 hours. Clearance and volume of distribution are about 350 mL/min and 550 mL/kg, respectively. More than 99% of diclofenac sodium is reversibly bound to human plasma albumin.

Diclofenac sodium is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Approximately 65% of the dose is excreted in the urine and 35% in the bile.

Conjugates of unchanged diclofenac account for 5–10% of the dose excreted in the urine and for less than 5% excreted in the bile. Little or no unchanged unconjugated drug is excreted. Conjugates of the principal metabolite account for 20–30% of the dose excreted in the urine and for 10–20% of the dose excreted in the bile.

Conjugates of three other metabolites together account for 10–20% of the dose excreted in the urine and for small amounts excreted in the bile. The elimination half-life values for these metabolites are shorter than those for the parent drug. Urinary excretion of an additional metabolite (half-life = 80 hours) accounts for only 1.4% of the oral dose. The degree of accumulation of diclofenac metabolites is unknown. Some of the metabolites may have activity.

Pharmacodynamics and pharmacokinetics of misoprostol

Misoprostol is a synthetic prostaglandin E₁ analog with gastric antisecretory and (in animals) mucosal protective properties. NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within the gastric and duodenal mucosa may lead to diminishing bicarbonate and mucus secretion and may contribute to the mucosal damage caused by NSAIDs.

Misoprostol can increase bicarbonate and mucus production, but in humans this has been shown at doses 200 mcg and above that are also antisecretory. It is therefore not possible to tell whether the ability of misoprostol to reduce the risk of gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both.

In vitro studies on canine parietal cells using titrated misoprostol acid as the ligand have led to the identification and characterization of specific prostaglandin receptors. Receptor binding is saturable, reversible, and stereo-specific. The sites have a high affinity for misoprostol, for its acid metabolite, and for other E type prostaglandins, but not for F or I prostaglandins and other unrelated compounds, such as histamine or cimetidine. Receptor-site affinity for misoprostol correlates well with an indirect index of antisecretory activity. It is likely that these specific receptors allow misoprostol taken with food to be effective topically, despite the lower serum concentrations attained.

Misoprostol produces a moderate decrease in pepsin concentration during basal conditions, but not during histamine stimulation. It has no significant effect on fasting or postprandial gastrin nor intrinsic factor output.

Effects on gastric acid secretion

Misoprostol, over the range of 50–200 mcg, inhibits basal and nocturnal gastric acid secretion, and acid secretion in response to a variety of stimuli, including meals, histamine, pentagastrin, and coffee. Activity is apparent 30 minutes after oral administration and persists for at least 3 hours. In general, the effects of 50 mcg were modest and shorter-lived, and only the 200 mcg dose had substantial effects on nocturnal secretion or on histamine- and meal-stimulated secretion.

Orally administered misoprostol is rapidly and extensively absorbed, and it undergoes rapid metabolism to its biologically active metabolite, misoprostol acid. Misoprostol acid in ARTHROTEC reaches a maximum plasma concentration in about 20 minutes and is, thereafter, quickly eliminated with an elimination t½ of about 30 minutes. There is high variability in plasma levels of misoprostol acid between and within studies, but mean values after single doses show a linear relationship with dose of misoprostol over the range of 200 to 400 mcg. No accumulation of misoprostol acid was found in multiple-dose studies, and plasma steady state was achieved within 2 days. The serum protein binding of misoprostol acid is less than 90% and is concentrationindependent in the therapeutic range.

After oral administration of radio-labeled misoprostol, about 70% of detected radioactivity appears in the urine. Maximum plasma concentrations of misoprostol acid are diminished when the dose is taken with food, and total availability of misoprostol acid is reduced by use of concomitant antacid. Clinical trials were conducted with concomitant antacid; this effect does not appear to be clinically important.

Pharmacokinetic studies also showed a lack of drug interaction with antipyrine or propranolol given with misoprostol. Misoprostol given for 1 week had no effect on the steady state pharmacokinetics of diazepam when the two drugs were administered 2 hours apart.

Pharmacokinetics of ARTHROTEC

The pharmacokinetics following oral administration of a single dose (see Table 1) or multiple doses of ARTHROTEC (diclofenac sodium/misoprostol) to healthy subjects under fasted conditions are similar to the pharmacokinetics of the two individual components.

Table 1

The rate and extent of absorption of both diclofenac sodium and misoprostol acid from ARTHROTEC 50 and ARTHROTEC 75 are similar to those from diclofenac sodium and misoprostol formulations each administered alone.

Neither diclofenac sodium nor misoprostol acid accumulated in plasma following repeated doses of ARTHROTEC given every 12 hours under fasted conditions. Food decreases the multiple-dose bioavailability profile of ARTHROTEC 50 and ARTHROTEC 75.

Special populations

A 4-week study, comparing plasma level profiles of diclofenac (50 mg bid) in younger (26–46 years) versus older (66–81 years) adults, did not show differences between age groups (10 patients per age group). In a multiple-dose (bid) crossover study of 24 people aged 65 years or older, the misoprostol contained in ARTHROTEC did not affect the pharmacokinetics of diclofenac sodium. Differences in the pharmacokinetics of diclofenac have not been detected in studies of patients with renal (50 mg intravenously) or hepatic impairment (100 mg oral solution). In patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min), AUC values and elimination rates were comparable to those in healthy people. In patients with biopsy-confirmed cirrhosis or chronic active hepatitis (variably elevated transaminases and mildly elevated bilirubins, N=10), diclofenac concentrations and urinary elimination values were comparable to those in healthy people.

Pharmacokinetic studies with misoprostol in patients with varying degrees of renal impairment showed an approximate doubling of t1/2, Cmax and AUC compared to healthy people. In people over 64 years of age, the AUC for misoprostol acid is increased. In a study of people with mild to moderate hepatic impairment, mean misoprostol acid AUC and Cmax showed approximately double the mean values obtained in healthy people. Three people who had the lowest antipyrine and lowest indocyanine green clearance values had the highest misoprostol acid AUC and Cmax values.

After a single oral dose of misoprostol to nursing mothers, misoprostol acid was excreted in breast milk. The maximum concentration of misoprostol acid in expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/mL (CV 37%) and 20.9 pg/mL (CV 77%) after single 200 μg and 600 μg misoprostol administration, respectively. The misoprostol acid concentrations in breast milk declined to < 1 pg/mL at 5 hours post-dose.

Clinical Studies

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 qid, tid or bid, was significantly more effective than placebo in reducing the incidence of gastric ulcer in OA and RA patients using a variety of NSAIDs. The tid regimen was therapeutically equivalent to misoprostol 200 mcg qid with respect to the prevention of gastric ulcers. Misoprostol 200 mcg given bid was less effective than 200 mcg given tid or qid. The incidence of NSAID-induced duodenal ulcer was also significantly reduced with all three regimens of misoprostol compared to placebo (see Table 2).

Table 2

Results of a study in 572 patients with osteoarthritis demonstrate that patients receiving ARTHROTEC have a lower incidence of endoscopically defined gastric ulcers compared to patients receiving diclofenac sodium (see Table 3).

Table 3

Last updated on RxList: 10/6/2009

Read this leaflet before taking ARTHROTEC (diclofenac sodium 50 or 75 mg/misoprostol 200 mcg) and each time your prescription is renewed, because the leaflet may be changed. ARTHROTEC is being prescribed by your doctor for treatment of your arthritis symptoms while at the same time providing protection from the development of stomach and intestinal ulcers due to the arthritis medication. ARTHROTEC contains diclofenac, an arthritis medication. ARTHROTEC also contains misoprostol to decrease the chance of getting stomach and intestinal ulcers that sometimes develop with NSAID medications. Serious side effects are still possible, however, and you should report to your doctor any signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, weight gain or swelling. If signs of liver toxicity occur (nausea, fatigue, lethargy, itching, jaundice, right upper quadrant tenderness, and “flu-like” symptoms) you should stop therapy and seek immediate medical attention.

If signs of an anaphylactic reaction occur (e.g. difficulty breathing, swelling of the face or throat) you should stop therapy and seek immediate medical attention (see WARNINGS).

Do not take ARTHROTEC if you are pregnant (see BOXED CONTRAINDICATIONS AND WARNINGS). ARTHROTEC contains diclofenac sodium and misoprostol. Misoprostol can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects. It is also important to avoid pregnancy while taking this medication and for at least one month or through one menstrual cycle after you stop taking it. Misoprostol has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death.

If you become pregnant during therapy with ARTHROTEC, stop taking ARTHROTEC and contact your doctor immediately. Remember that even if you are using a means of birth control, it is still possible to become pregnant. Should this occur, stop taking ARTHROTEC and consult your doctor immediately.

ARTHROTEC is not recommended for nursing mothers.

ARTHROTEC, like other NSAIDs, may cause an increased risk of heart attack, or stroke, which can lead to death. This risk may increase with duration of use. If you have heart disease or risk factors for heart disease, you may be at greater risk (see BOXED CONTRAINDICATIONS AND WARNINGS).

ARTHROTEC should never be used for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see BOXED CONTRAINDICATIONS AND WARNINGS).

Although serious CV events can occur without warning symptoms, ask for medical advice when observing signs and symptoms of chest pain, shortness of breath, weakness, or slurring of speech (see BOXED CONTRAINDICATIONS AND WARNINGS).

ARTHROTEC, like other NSAIDs, may cause GI discomfort and, rarely, serious GI effects such as ulcers and bleeding, which may result in hospitalizations and even death.

ARTHROTEC may cause diarrhea, abdominal pain, upset stomach and/or nausea in some people. In most cases these problems develop during the first few weeks of therapy and stop after about a week with continued treatment. You can minimize possible diarrhea by making sure you take ARTHROTEC with meals and by avoiding the use of antacids containing magnesium (if needed, use one containing aluminum or calcium instead). ARTHROTEC tablets should be swallowed whole, and not chewed, crushed or dissolved.

Because these side effects are usually mild to moderate and usually go away in a matter of days, most patients can continue to take ARTHROTEC. If you have prolonged difficulty (more than 7 days), or if you have severe diarrhea, cramping and/or nausea, call your doctor.

ARTHROTEC may also cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can lead to death. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see BOXED CONTRAINDICATIONS AND WARNINGS). This risk may increase with duration of use.

Although serious GI tract ulcerations and bleeding can occur without warning symptoms, ask for medical advice when observing signs and symptoms of ulceration and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis.

(See BOXED CONTRAINDICATIONS AND WARNINGS.)

ARTHROTEC, like other NSAIDs, may cause serious skin side effects, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis, which may result in hospitalization and even death.

Although serious skin reactions may occur without warning, ask for medical advice when observing sign or symptoms, such as skin rash and blisters, fever, or other signs of hypersensitivity such as itching. Stop the drug immediately at the first appearance of skin rash or any other signs of hypersensitivity and contact your physician as soon as possible.

Take ARTHROTEC only according to the directions given by your doctor. Changes in dose should be made only with your doctor's approval.

Do not give ARTHROTEC to anyone else. It has been prescribed for your specific condition, may not be the correct treatment for another person, and could be dangerous for another person, especially a woman who may be, or could become, pregnant.

This information sheet does not cover all possible side effects of ARTHROTEC. See your doctor if you have questions.

Keep out of reach of children.

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death.

This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Get emergency help right away if you have any of the following symptoms:

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.

Some of these NSAID medicines are sold in lower doses without a prescription (over –the –counter). Talk to your healthcare provider before using over –the –counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

* Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last updated on RxList: 10/6/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DICLOFENAC/MISOPROSTOL - ORAL

(dye-KLO-fen-ack/my-so-PROSS-tull)

COMMON BRAND NAME(S): Arthrotec

WARNING: This medication is a combination of 2 drugs, diclofenac and misoprostol. Do not take this medication if you are pregnant or think that you may be pregnant. Misoprostol may cause loss of pregnancy, premature birth, or birth defects. In rare cases, serious complications (e.g., uterine rupture) have occurred when misoprostol was used to start labor or used in combination with another drug to end pregnancy after the eighth week. These complications have resulted in harm to the unborn baby and mother.

Avoid pregnancy while taking this medication and for at least one month or one complete menstrual cycle after you have stopped treatment. If you become pregnant while taking this medication, contact your doctor immediately.

If you are of a woman of childbearing age, do not use this medication unless you require a nonsteroidal anti-inflammatory drug (NSAID) such as diclofenac and you are at high risk of having an ulcer or ulcer complications from NSAID treatment.

Female patients must meet the following four requirements in order to use this drug: 1) test negative for pregnancy within 2 weeks before starting treatment; 2) use effective birth control to prevent pregnancy; 3) receive oral and written warnings on the dangers of using misoprostol while of childbearing age and the risks of possible birth control failure; 4) start taking this medication only on the second or third day of the next normal menstrual period.

This medication must not be shared with others.

Diclofenac may infrequently cause serious (rarely fatal) bleeding from the stomach or intestines. This side effect can occur without warning at any time during treatment with diclofenac. The elderly are at increased risk for serious stomach/intestinal bleeding.

Drugs related to diclofenac have rarely caused blood clots to form, resulting in serious (possibly fatal) heart attacks and strokes. This medication might also rarely cause similar problems. The risk of these serious side effects may increase if you have heart disease and with longer use of this medication. Talk to your doctor or pharmacist about the benefits and risks of treatment, as well as other possible medication choices.

Stop taking this medication and seek immediate medical attention if you notice any of the following rare but very serious side effects: black stools, persistent stomach/abdominal pain, vomit that looks like coffee grounds, chest pain, shortness of breath, weakness on one side of the body, sudden vision changes, slurred speech.

This medication should not be used right before or after heart bypass surgery.

USES: Diclofenac is used to relieve pain, swelling (inflammation), and joint stiffness caused by arthritis. Reducing these symptoms helps you do more of your normal daily activities. Diclofenac is known as a nonsteroidal anti-inflammatory drug (NSAID). Misoprostol protects the stomach from diclofenac's irritating effects. This combination medication is used to treat arthritis in people at high risk of developing stomach ulcers and serious complications such as bleeding.

HOW TO USE: Read the Patient Information Leaflet and the Medication Guide provided by your pharmacist before you start using this medication and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth with a full glass of water (8 ounces or 240 milliliters) unless your doctor directs you otherwise. Do not lie down for at least 30 minutes after taking this drug.

Swallow this medication whole. Do not crush, chew, or dissolve the tablets. Doing so may increase side effects.

Take this medication with food to prevent stomach upset and to reduce the chances of diarrhea. Avoid taking antacids that contain magnesium while using this medication because they may worsen diarrhea. If you need an antacid, consult your doctor or pharmacist to help you choose a product.

Dosage is based on your medical condition and response to therapy. To minimize side effect risks (e.g., stomach bleeding), use this medication at the lowest effective dose for the shortest possible length of time. Do not increase your dose or take it more often than prescribed. For ongoing conditions such as arthritis, continue taking it as directed by your doctor. Discuss the risks and benefits with your doctor or pharmacist.

Take this medication regularly in order to get the most benefit from it. Remember to take it at the same times each day. It may take up to 2 weeks of regular use before the full benefits of this medication take effect.

Inform your doctor if your condition worsens.

Diarrhea and upset stomach may occur within a few weeks after you start taking this medication, and usually last for about 1 week. See How to Use for ways to reduce diarrhea.

Nausea, heartburn, gas, stomach pain, constipation, headache, tiredness, drowsiness, and dizziness may also occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Rarely, diarrhea can become so severe and persistent that it may lead to a large loss of your body's water and minerals (dehydration). Be sure to drink plenty of fluids and get enough minerals/electrolytes to prevent dehydration. Tell your doctor immediately if you develop any of the following signs: severe/persistent diarrhea, stomach cramps, severe dizziness, decreased amount of urine, muscle weakness.

Tell your doctor immediately if any of these unlikely but serious side effects occur: difficult/painful swallowing, swelling of the hands/feet, sudden/unexplained weight gain, vision changes, hearing changes (e.g., ringing in the ears), mental/mood changes (e.g., depression), fast/pounding heartbeat, persistent/severe headache, fainting, unusual/heavy vaginal bleeding, menstrual problems/irregular periods.

Tell your doctor immediately if any of these rare but very serious side effects occur: change in the amount of urine, easy bruising/bleeding, signs of infection (e.g., fever, persistent sore throat), unexplained stiff neck, seizures.

This drug may rarely cause serious (possibly fatal) liver disease. If you notice any of the following rare but very serious side effects, stop taking diclofenac/misoprostol and tell your doctor immediately: yellowing eyes/skin, dark urine, unusual/extreme tiredness, severe stomach/abdominal pain, persistent nausea/vomiting.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking diclofenac/misoprostol, tell your doctor or pharmacist if you are allergic to either of these drugs; or to aspirin or other NSAIDs (e.g., ibuprofen, naproxen, celecoxib); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: aspirin-sensitive asthma (a history of worsening breathing with runny/stuffy nose after taking aspirin or other NSAIDs), recent heart bypass surgery (CABG), certain liver problem (hepatic porphyria).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, poorly controlled diabetes, stomach/intestine/esophagus problems (e.g., bleeding, ulcers, inflammatory bowel disease), heart disease (e.g., congestive heart failure, history of heart attack), high blood pressure, stroke, swelling (edema, fluid retention), a severe loss of body water (dehydration), blood disorders (e.g., anemia), bleeding or clotting problems, asthma, growths in the nose (nasal polyps).

Before having surgery, tell your doctor or dentist that you are using this medication.

This drug may make you dizzy or drowsy; use caution while engaging in activities requiring alertness such as driving or using machinery.

Diclofenac may cause stomach bleeding. Daily use of alcohol and tobacco may increase your risk for stomach bleeding, especially when combined with this medicine. Limit alcohol and stop smoking. Consult your doctor or pharmacist for more information.

This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.

The elderly may be more sensitive to the side effects of this drug, especially stomach/intestinal bleeding and kidney effects.

This medication must not be used during pregnancy. It can harm the unborn baby and mother. Use reliable forms of birth control to prevent pregnancy while taking this medication. If you become pregnant or think you may be pregnant, inform your doctor immediately. See Warning section.

It is not known if this medication passes into breast milk. Breast-feeding while using this medication is not recommended because it may have undesirable effects on a nursing infant. Consult your doctor before breast-feeding.

Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: high doses of aspirin and related drugs (salicylates), cidofovir, other NSAIDs (e.g., ketorolac).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting diclofenac/misoprostol.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: anti-platelet drugs (e.g., cilostazol, clopidogrel), oral bisphosphonates (e.g., alendronate), "blood thinners" (e.g., enoxaparin, heparin, warfarin), corticosteroids (e.g., prednisone), cyclosporine, desmopressin, digoxin, high blood pressure drugs (including ACE inhibitors such as captopril, angiotensin receptor blockers such as losartan, and beta-blockers such as metoprolol), lithium, methotrexate, pemetrexed, probenecid, SSRI antidepressants (e.g., fluoxetine, sertraline), "water pills" (diuretics such as furosemide, hydrochlorothiazide, triamterene).

Check all prescription and nonprescription medicine labels carefully for other pain/fever drugs (NSAIDs such as aspirin, celecoxib, ibuprofen). These drugs are similar to this medication, so taking one of these drugs while also taking this medication may increase your risk of side effects. However, if your doctor has prescribed low doses of aspirin to prevent heart attack or stroke (usually at dosages of 81-325 milligrams a day), you should continue to take the aspirin. Daily use of NSAIDs (e.g., ibuprofen) may decrease aspirin's ability to prevent heart attack/stroke. Consult your doctor or pharmacist for more details and to discuss other possible treatments (e.g., acetaminophen) for your pain/fever.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: severe stomach pain, vomit that looks like coffee grounds, persistent diarrhea, extreme drowsiness, slow/shallow breathing, slow/irregular heartbeat, seizures.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count, liver and kidney function tests) may be performed periodically to check for side effects. Consult your doctor for more details.

Non-drug treatment for arthritis that is approved by your doctor (e.g., weight loss if needed, strengthening and conditioning exercises) may help improve your flexibility, range of motion, and joint function. Consult your doctor for specific instructions.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store the U.S. product at room temperature at or below 77 degrees F (25 degrees C) away from light and moisture.

Store the Canadian product at room temperature at 59-77 degrees F (15-25 degrees C) away from light and moisture.

Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.