Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1457
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Arthrotec (Tablet, Film Coated)
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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 . 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.<br/>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:<br/>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:<br/>SPECIAL DOSING CONSIDERATIONS: ARTHROTEC contains misoprostol, which provides protection against gastric and duodenal ulcers . 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 , 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.
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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 Eanalog. 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: CHClNONa [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: CHO[M.W. = 382.54] (��) methyl 11��,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.
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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.<br/>Pharmacodynamics and pharmacokinetics of misoprostol: Misoprostol is a synthetic prostaglandin Eanalog 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.<br/>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 tof 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 concentration-independent 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.<br/>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. 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.<br/>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 t, Cand AUC compared to healthy people. In people over 64 years of age, the AUC for misoprostol acid is increased. 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 Cshowed 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 Cvalues.
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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.
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CONTRAINDICATIONS AND WARNINGS: ARTHROTEC CONTAINS DICLOFENAC SODIUM AND MISOPROSTOL. ADMINISTRATION OF MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, OR BIRTH DEFECTS. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION BEYOND THE EIGHTH WEEK OF PREGNANCY . ARTHROTEC SHOULD NOT BE TAKEN BY PREGNANT WOMEN . PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. ARTHROTEC should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID . In such patients, ARTHROTEC may be prescribed if the patient:<br/>Cardiovascular Risk:<br/>Gastrointestinal Risk:
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dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:crospovidone,
dailymed-ingredient:hydrogenated_castor_oil,
dailymed-ingredient:hypromellose,
dailymed-ingredient:lactose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:methacrylic_acid_copolymer,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:povidone_(polyvidone)_K-30,
dailymed-ingredient:sodium_hydroxide,
dailymed-ingredient:starch_(corn),
dailymed-ingredient:talc,
dailymed-ingredient:triethyl_citrate
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The toxic dose of ARTHROTEC has not been determined. However, signs of overdosage from the components of the product have been described.<br/>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 (LDin mg/kg: rats, 55; dogs, 500; monkeys, 3200).<br/>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.<br/>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 misoprostolacid remains unproven. The use of oral activated charcoal may help to reduce the absorption of diclofenac sodium and misoprostol.
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diclofenac sodium and misoprostol
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Arthrotec (Tablet, Film Coated)
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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).<br/>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 self-limited (resolved after 2 to 7 days). Rare instances of profound diarrhea leading to severe dehydration have been reported in patients receiving misoprostol. Patients with an underlying condition such as inflammatory bowel disease, or those in whom dehydration, were it to occur, would be dangerous, should be monitored carefully if ARTHROTEC is prescribed. The incidence of diarrhea can be minimized by administering ARTHROTEC with food and by avoiding coadministration with magnesium-containing antacids.<br/>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 .<br/>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. 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, stomatitisand 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.
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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 . 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.
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Arthrotec
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