Arthrotec

Concomitant administration of NSAIDs and SSRIs may increase the risk of gastrointestinal ulceration and bleeding (see Warnings and Precautions, Gastrointestinal).

Clinical studies as well as post-marketing observations have shown that NSAIDs can reduce the effect of diuretics. Concomitant treatment of Arthrotec with potassium-sparing diuretics may be associated with increased serum potassium levels, thus making it necessary to monitor the latter. The antihypertensive effect of hydrochlorothiazide and ACE inhibitors may be decreased by diclofenac in patients with essential hypertension. Coadministration of Arthrotec with ACE inhibitors may result in an impairment of renal function.

There is an increased risk of bleeding, via inhibition of platelet function, when anti-platelet agents are combined with NSAIDs, such as Arthrotec (see Warnings and Precautions, Hematologic, Anti-platelet Effects).

Some studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

When diclofenac and ASA are taken simultaneously, the bioavailability of each is reduced. Concomitant administration of Arthrotec and ASA is not recommended because diclofenac is displaced from its binding sites by ASA, resulting in lower plasma concentrations, peak plasma levels and AUC values. Misoprostol does not affect the kinetics of other NSAIDs (e.g., ibuprofen, indomethacin and piroxicam). The use of Arthrotec in addition to any other NSAID, including those over the counter ones (such as ASA and ibuprofen) for analgesic and/or anti-inflammatory effects is not recommended because of the absence of any evidence demonstrating synergistic benefits and the possibility of additive side effects.

The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID therapy is associated with additive adverse reactions.

Some NSAIDs (e.g. ibuprofen) may interfere with the anti-platelet effects of low dose ASA, possibly by competing with ASA for access to the active site of cyclooxygenase-I.

Diclofenac, when administered concomitantly with lithium, increases the lithium plasma concentration through an effect on lithium renal clearance. Lithium toxicity may develop in these patients. Dosage adjustment of lithium may be required with Arthrotec.

Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of GI adverse events such as ulceration and bleeding. Pharmacodynamic studies have shown no potentiation of anticoagulant drugs due to concurrent administration with diclofenac. However, other NSAIDs have been shown to interact with anticoagulant agents. Although clinical investigations would appear to indicate that diclofenac has no influence on the effect of anticoagulants, there are isolated reports of an increased risk of hemorrhage with the combined use of diclofenac and nicoumalone anticoagulant therapy. Special caution is therefore recommended and frequent laboratory tests should be performed to check that the desired response to the anticoagulant is being maintained. Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet function as well, concurrent therapy of Arthrotec with warfarin requires close monitoring to be certain no change in anticoagulant dosage is necessary (see Warnings and Precautions, Hematologic, Anti-coagulants).

NSAIDs may diminish the anti-hypertensive effect of Angiotensin Converting Enzyme (ACE) inhibitors.

Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics with NSAIDs might have an increased risk for acute renal failure and hyperkalemia. Blood pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure.

Diclofenac may increase the plasma concentration of digoxin. Dosage adjustment of the digoxin may be required with Arthrotec. Serum digoxin levels should be monitored for possible digoxin toxicity.

Factors such as excess alcohol intake, smoking, and concomitant NSAID and oral steroid or anticoagulant use have been associated with increased risk of GI adverse events such as ulceration and bleeding. In laboratory studies, misoprostol has shown no significant effect on the cytochrome P450-linked hepatic mixed function oxidase system, and therefore should not affect the metabolism of theophylline, warfarin, benzodiazepines or other drugs normally metabolized by this system.

Interactions with food have not been established.

Diclofenac increases platelet aggregation time but does not affect bleeding time, plasma prothrombin clotting time, plasma fibrinogens, 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, and are unlikely to be clinically important.

Interactions with herbal products have not been established.

Diclofenac does not alter glucose metabolism in normal subjects, and pharmacodynamic studies have shown no potentiation of oral hypoglycemic drugs due to concurrent administration with diclofenac. However, other NSAIDs have been shown to interact with oral hypoglycemic agents. Therefore, Arthrotec should be administered with caution in patients receiving insulin or oral hypoglycemic agents.

Smoking and alcohol intake should be discouraged while taking Arthrotec as they constitute risk factors for increased cardiovascular and gastrointestinal problems respectively.

Misoprostol has been used concomitantly with at least 44 different classes of drugs, including more than 150 drugs. There were no reports of any clinically significant drug interactions.

Although this interaction has not been studied with Arthrotec, co-administration of cyclosporin or tacrolimus and any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus due to the NSAID's effect on renal prostaglandins. Renal function should be monitored when Arthrotec and either of these drugs is used in combination

Only aluminum-based antacids should be used with Arthrotec as magnesium-based antacids may increase the potential for diarrhea (see Adverse Reactions). The concomitant administration of aluminum hydroxide or magnesium hydroxide antacids may delay the absorption of diclofenac but does not affect the total amount of the drug absorbed. The total availability of misoprostol acid is reduced by antacids in large doses.

Concurrent administration of methotrexate and diclofenac may result in increased plasma levels of methotrexate and rare cases of fatal renal toxicity have been reported. Thus, caution should be taken when administering Arthrotec and methotrexate.

In elderly patients: the dosage should be reduced to the lowest dose that will provide control of symptoms, adjusted when necessary, and closely supervised.

Renal Insufficiency: In patients with mild to moderate renal insufficiency, the lowest dose of Arthrotec should be considered, and patients should be monitored closely (see Action and Clinical Pharmacology, Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency). Arthrotec is contraindicated in patients with severe renal impairment (estimated creatinine clearance <30 mL/min or 0.5 mL/sec) (see Contraindications).

Use of Arthrotec should be limited to the lowest effective dose in every patient.

Adults: The recommended oral dose of Arthrotec (diclofenac sodium plus misoprostol) for treating the signs and symptoms of rheumatoid arthritis and osteoarthritis is:

Arthrotec 50: one tablet two or three times daily.

Arthrotec 75: one tablet twice daily.

Maximum daily dose: 150 mg of diclofenac (Arthrotec 50 TID or Arthrotec 75 BID).

Arthrotec should be taken immediately after a meal or with food or milk.

In patients with hepatic impairment or in mild to moderate renal failure, the pharmacokinetic parameters for Arthrotec are not altered to any clinically relevant extent. If Arthrotec must be used in patients with severe renal or hepatic impairment, these patients must be closely monitored.

Arthrotec should be swallowed whole.

If a dose of Arthrotec is missed, the next dose should be taken at the regular time. The dose should not be doubled.

dyspnea, hepatitis, interstitial nephritis, pancreatitis, stomatitis.

thrombocytopenia.

Additional reports of serious adverse events temporally associated with Arthrotec during worldwide post-marketing experience are included below. Because these events are reported voluntary from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Arthrotec exposure.

See Drug Interactions, Drug-Laboratory Test Interactions.

abnormal uterine contractions, uterine hemorrhage, uterine rupture/perforation, retained placenta, amniotic fluid embolism, incomplete abortion, premature birth, fetal death, and birth defects.

dysuria and urine abnormal.

blurred vision.

hot flushes, malaise, rigors.

hyperventilation and sputum increased.

BUN increased and glycosuria.

leukopenia and thrombocytopenia.

renal failure.

Reactions including anaphylaxis and angiodema.

The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.

Most fatal gastrointestinal events occur in the elderly or debilitated patients. Gastrointestinal adverse events can develop at any time in the course of the therapy.

The following adverse events were reported by 1% or less of the subjects receiving Arthrotec. Causal relationships between Arthrotec and these events have not been established but cannot be excluded.

cutaneous reactions (including rash, pruritus and bullous eruption), rare cases of mucocutaneous reactions, edema, urticaria.

Abdominal pain and diarrhea were generally transient and mild to moderate in severity, occurring early in the course of therapy and lasting several days. The abdominal pain and diarrhea usually resolved spontaneously while continuing Arthrotec.

changes in mood, nightmares.

palpitation and syncope.

bilirubinemia, abnormal hepatic function, LDH increased, and alkaline phosphatase increased.

Not recommended for pediatric use (see Contraindications).

Evidence from clinical studies and experience suggests that use in geriatric patients is associated with differences in safety or effectiveness (see Warnings and Precautions, Special Populations).

The toxic dose of misoprostol in humans has not been determined. Cumulative total daily doses of 1600 µg have been tolerated with only symptoms of gastrointestinal discomfort being reported.

Clinical signs that may indicate an overdose are sedation, tremor, convulsions, dyspnea, abdominal pain, diarrhea, fever, palpitations, hypotension, or bradycardia. Symptoms should be treated with supportive therapy.

It is not known if misoprostol acid is dialyzable. However, because misoprostol is metabolized like a fatty acid, it is unlikely that dialysis would be appropriate treatment for overdosage.

The use of oral activated charcoal may help to reduce the absorption of diclofenac and misoprostol.

Worldwide reports on overdosage with diclofenac cover 27 cases. In 10 of these 27 cases, diclofenac was the only drug taken; all of these patients recovered. The highest dose of diclofenac was 2.5 g in a 20-year-old male who suffered acute renal failure as a consequence, and who was treated with dialysis sessions and recovered in 2 days. The next highest dose was 2.35 g in a 17-year-old female who experienced vomiting and drowsiness. A dose of 2.0 g of diclofenac was taken by a woman of unspecified age who remained asymptomatic.

There is no specific antidote for diclofenac. In cases of overdosage, absorption should be prevented as soon as possible by means of induction of vomiting, gastric lavage or treatment with activated charcoal.

Supportive and symptomatic treatment should be given for complications such as drowsiness, confusion, general hypotonia, hypotension, renal failure, convulsions, gastrointestinal irritation and respiratory depression. Measures to accelerate elimination (forced diuresis, hemoperfusion, dialysis) may be considered, but may be of limited use because of the high protein-binding and extensive metabolism (diclofenac 99% protein bound and misoprostol acid less than 90% protein bound).

Each white to off-white, round and biconvex tablet, engraved “SEARLE” over “1411” on one side, 4דA” around the circumference of the reverse side with “50” in the middle, contains: an enteric-coated core of diclofenac sodium 50 mg, surrounded by an outer mantle containing misoprostol 200 µg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, crospovidone, hydrogenated castor oil, hypromellose, lactose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone K-30, sodium hydroxide, talc and triethyl citrate. Bottles of 250.

Each white to off-white, round and biconvex tablet, engraved “SEARLE” over “1421” on one side, 4דA” around the circumference of the reverse side with a “75” in the middle, contains: an enteric-coated core of diclofenac sodium 75 mg, surrounded by an outer mantle containing misoprostol 200 µg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, crospovidone, hydrogenated castor oil, hypromellose, lactose, magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, povidone K-30, sodium hydroxide, talc and triethyl citrate. Bottles of 250.

Pharmacist: Dispense with Patient Insert.

Renal function should be monitored in high-risk populations, such as the elderly, patients with advanced renal disease, patients with cardiovascular disease and diabetes mellitus, as well as in the setting of concomitant use of diuretics and ACE inhibitors (see Contraindications). If abnormal renal tests persist or worsen, Arthrotec should be discontinued.

Laboratory abnormalities included increased alkaline phosphatase, decreased hematocrit and elevated ALT.

Persistently abnormal or worsening renal, hepatic or hematological test values should be followed up carefully since they may be related to therapy.

See Contraindications, Coronary Artery Bypass Graft Surgery).

Numerous studies have shown that the concomitant use of NSAIDs and anti-coagulants increases the risk of bleeding. Concurrent therapy of Arthrotec with warfarin requires close monitoring of the international normalized ratio (INR).

Even with therapeutic INR monitoring, increased bleeding may occur.

Arthrotec (diclofenac sodium plus misoprostol) is not a substitute for corticosteroids. It does not treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroidresponsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids (see Drug Interactions, Drug-Drug Interactions, Glucocorticoids).

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Blurred, diminished vision, and/or sensitivity to light have been reported with the use of NSAIDs. If such symptoms develop this drug should be discontinued and an ophthalmologic examination performed; ophthalmologic examination should be carried out at periodic intervals in any patient receiving Arthrotec for an extended period of time.

Arthrotec is contraindicated for use in women who are pregnant, or in whom pregnancy has not been excluded (see Contraindications, Boxed Serious Warnings and Precautions, Adverse Reactions and Post-Market Adverse Drug Reactions). Misoprostol administration to pregnant women induces uterine contractions and is associated with abortion, premature birth, birth defects and fetal death. Misoprostol can cause uterine tetany and uterine rupture if administered to pregnant women beyond the eighth week of pregnancy. (See Contraindications and Adverse Reactions, Post-Market Adverse Drug Reactions.)

As with other NSAIDs, borderline elevations of one or more liver function tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. In clinical trials of 4 to 12 weeks duration, clinically significant (>3 times the upper limit of normal) elevations of ALT and/or AST, were observed in 2.5% or less of patients who received diclofenac/misoprostol or diclofenac/placebo.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic failure have been reported with nonsteroidal anti-inflammatory drugs.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from NSAIDs. The incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding (see Action and Clinical Pharmacology). For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision.

As with any NSAID, the elderly are likely to tolerate adverse events less well than younger patients.

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 and Precautions, Renal).

Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with Arthrotec (diclofenac sodium plus misoprostol) must be stopped to ascertain if symptoms disappear. This should be done before any urological investigations or treatments are carried out.

Post-menopausal vaginal bleeding may be related to Arthrotec administration. If this occurs, diagnostic workup should be undertaken to rule out gynecological pathology (see Adverse Reactions).

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs such as Arthrotec. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Frail or debilitated patients may tolerate side effects less well and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Arthrotec is not recommended for use with other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions (see Drug Interactions, Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or other NSAID's).

In common with other anti-inflammatory drugs, Arthrotec may mask the usual signs of infection, such as fever.

With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with beta-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike acetylsalicyclic acid (ASA), their effect on platelet function is quantitatively less, or of shorter duration, and is reversible. Misoprostol does not exacerbate the effects of diclofenac on platelet activity.

In clinical trials, there has been no evidence that Arthrotec affects hemostasis.

Arthrotec and other NSAIDs have no proven efficacy as anti-platelet agents and should not be used as a substitute for ASA or other anti-platelet agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g. ASA) should not be discontinued. There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA (see Drug Interactions, Drug-Drug Interactions, Acetylsalicylic Acid (ASA) or other NSAID's).

Concomitant administration of Arthrotec with low dose ASA increases the risk of GI ulceration and associated complications.

(See Contraindications.)

The use of Arthrotec, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of Arthrotec should be considered.

Use of NSAIDs, such as Arthrotec, can promote sodium retention in a dose-dependent manner, which can lead to fluid retention and edema, and consequences of increased blood pressure and exacerbation of congestive heart failure. Thus, caution should be exercised in prescribing Arthrotec in patients with a history of congestive heart failure, compromised cardiac function, hypertension, increased age or other conditions predisposing to fluid retention (see Warnings and Precautions, Cardiovascular).

Use of NSAIDs, such as Arthrotec, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics.

Electrolytes should be monitored periodically (see Contraindications).

The presence of misoprostol in the product may protect against the mucosal damaging effects of the other component, diclofenac.

However, serious GI toxicity, such as peptic/duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) including Arthrotec (diclofenac sodium plus misoprostol). NSAIDs, including Arthrotec, should be used with caution in patients with a history of, or active, GI disease, such as ulceration, bleeding, or inflammatory conditions. 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, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered (see Warnings and Precautions, Special Populations, Geriatrics (>65 years of age)).

Minor upper GI problems, such as dyspepsia, commonly occur at any time. Physicians should remain alert for ulceration and bleeding in patients treated with nonsteroidal anti-inflammatory drugs, even in the absence of previous GI tract symptoms.

Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and instruct them to discontinue using Arthrotec and seek emergency medical attention if they experience any such symptoms.

Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Most patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to 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, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even short-term therapy has its risks.

Caution should be taken if prescribing Arthrotec to patients with a prior history of peptic/duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a GI bleed when taking a NSAID than patients with neither of these risk factors. Other risk factor for GI ulceration and bleeding include the following: H. pylori infection, increased age, prolonged use of NSAID therapy, excess alcohol intake, smoking, female gender, poor general health status or concomitant therapy with any of the following:

• Anti-coagulants (e.g. warfarin)

  
  

• Anti-platelet agents (e.g. ASA, clopidogrel)

  
  

• Oral corticosteroids (e.g. prednisone)

  
  

• Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluoxetine, paroxetine, sertraline)

  
  

If ulceration is suspected or confirmed, or if GI bleeding occurs, Arthrotec should be discontinued immediately, appropriate treatment instituted and the patient monitored closely. No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. Studies to date show that all NSAIDs can cause GI tract adverse events. Although existing data do not clearly identify differences in risk between various NSAIDs, this may be shown in the future.

Arthrotec should not be given to patients with complete or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction (see Contraindications).

Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs as well.

Arthrotec, in common with other NSAIDs, may mask signs and symptoms of an underlying infections disease.

Some patients may experience depression with the use of diclofenac. (See Warnings and Precautions, Neurologic.)

As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to Arthrotec. In post-marketing experience, rare cases of anaphylactic/anaphylactoid reactions and angioedema have been reported in patients receiving Arthrotec. Arthrotec should not be given to patients with the ASA-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 ASA or other NSAIDs (see Contraindications).

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 or blood loss. Concurrent therapy of Arthrotec with warfarin requires close monitoring of the international normalized ratio (INR).

(See Contraindications.)

Blood dyscrasias (such as neutropenia, leucopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.

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

(See Warnings and Precautions, Skin).

(See Warnings and Precautions, Infection, Aseptic Meningitis).

Rarely, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health care provider must be vigilant to the development of this complication.

In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is not clear. These reactions are potentially life-threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

Arthrotec may cause sensitivity to sunlight. Any exposure to sunlight or sunlamps may cause sunburn, skin blisters, skin rash, redness, itching or discoloration. Patients should be advised that if they experience any of these symptoms, they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

Fluid retention and edema have been observed in patients treated with Arthrotec. Therefore, as with many other nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Arthrotec should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention. (See Warnings and Precautions, Renal, Fluid and Electrolyte Balance.)

(See Contraindications.)

Patient with symptoms and/or signs of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Arthrotec. If abnormal liver tests persist or worsen, Arthrotec should be discontinued.

(Hypertension): Blood pressure should be monitored regularly during therapy with Arthrotec.

The kinetics and metabolism of diclofenac do not appear to be affected by hepatic impairment.

Misoprostol does not affect the hepatic mixed function oxidase (cytochrome P-450) enzyme system in animals. In a study of people with mild to moderate hepatic impairment, mean misoprostol acid AUC and C_max 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 C_max values.

The kinetics and metabolism of diclofenac do not appear to be affected by age. In the elderly, the AUC of misoprostol acid is increased by roughly 40%.

Diclofenac is highly but reversibly bound in the plasma. Following administration of enteric-coated tablets there is high between- and within-subject variability in the plasma concentrations of diclofenac, particularly if the tablets are taken with food. However, the plasma concentrations show a linear relationship to the amount of drug administered and no accumulation occurs provided that the recommended dosage intervals are observed.

There is high variability in plasma levels of misoprostol acid, but mean values after single doses show a linear relationship with dose over the range of 200 to 400 µg. No accumulation has been found in multiple dose studies and plasma steady state was achieved within two days.

Orally administered diclofenac is rapidly and almost completely absorbed.

Orally administered misoprostol is also rapidly and extensively absorbed.

With Arthrotec the effect of food on the bioavailability of the diclofenac and misoprostol components is similar to that reported for the individual drugs. The times of peak concentration (T_max) for diclofenac and misoprostol are prolonged by approximately 50% and 100% respectively, while the peak concentrations (C_max) are decreased by about 25% for diclofenac and 50% for misoprostol: the AUC for diclofenac is decreased by approximately 60%, while that of misoprostol is increased by about 25%.

Arthrotec (diclofenac sodium plus misoprostol) is a combination of a nonsteroidal anti-inflammatory drug (NSAID) with a mucosal protective synthetic analog of prostaglandin E₁.

Diclofenac inhibits prostaglandin synthesis by interfering with the action of prostaglandin synthetase. This inhibitory effect may partially explain its actions, both therapeutic and adverse.

Misoprostol has been shown to inhibit both basal and stimulated gastric acid secretion. In addition, increases in gastric mucosal blood flow, duodenal bicarbonate secretion and gastric mucus secretion have all been observed following treatment with misoprostol. It is not known whether the ability of misoprostol to prevent gastric and duodenal ulcers is the result of its antisecretory effect, its mucosal protective effect, or both.

The half-life of diclofenac is 1 to 2 hours. Forty to 60% of the drug and its metabolites are eliminated in the urine and the balance in the bile.

Misoprostol acid is quickly eliminated (elimination half-life of approximately 30 minutes). Approximately 70% of the dose of misoprostol is excreted in the urine, mainly as biologically inactive metabolites.

Differences in the pharmacokinetics of diclofenac (50 mg intravenously) have not been detected in studies of patients with renal impairment (N=5, creatinine clearance 3 to 42 mL/min). In these patients, AUC values and elimination rates were comparable to those in healthy people.

Following oral administration of misoprostol in patients with mild-to-moderate renal impairment, there was no significant effect on the pharmacokinetic profile compared to normal subjects. However, in anuric patients, an approximate doubling of C_max, AUC and t_½ of misoprostol acid has been observed compared to normal subjects.

Diclofenac undergoes single and multiple hydroxylation and methoxylation, producing 3'-, 4'-, 5-hydroxy, 4'-5-hydroxy and 3'-hydroxy-4'-methoxy derivatives of diclofenac. These phenolic metabolites are largely inactive, and (along with the parent compound) are mostly converted to glucuronide conjugates.

Misoprostol undergoes rapid metabolism to misoprostol acid.