Arthrotec Information
Arthrotec () 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 (see also ). Arthrotec () SHOULD NOT BE TAKEN BY PREGNANT WOMEN (see and ).
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 (see ). In such patients, Arthrotec () may be prescribed if the patient:
Arthrotec () Description
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 E 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:
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 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.
Arthrotec () Clinical Pharmacology
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.
Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac.
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.
Misoprostol is a synthetic prostaglandin E 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
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.
The pharmacokinetics following oral administration of a single dose (see ) 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.
Arthrotec () Clinical Studies
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 ).
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 ).
Arthrotec () Indications And Usage
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 ).
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 for a list of factors that may increase the risk of NSAID-induced gastric and duodenal ulcers and their complications.
Arthrotec () Contraindications
See boxed related to misoprostol.
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 , and ).
Arthrotec () is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see boxed ).
Arthrotec () Warnings
Regarding misoprostol:
See boxed .
Regarding diclofenac:
See boxed .
Arthrotec () Precautions
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.
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.
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 .
THE PATIENT SHOULD NOT GIVE Arthrotec () TO ANYONE ELSE.
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.
See at the end of this labeling 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.
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/m/day, 24 times the recommended maximum human dose of 0.6 mg/m/day) was not tumorigenic. In a 21-month mouse carcinogenicity study, oral misoprostol at doses up to 16 mg/kg/day (48 mg/m/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/m/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/m/day) was not tumorigenic. For a 50-kg person of average height (1.46m body surface area), this dose represents 0.08 times the recommended maximum human dose (148 mg/m) 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/m/day, 0.006 times the recommended maximum human dose based on body surface area) in males and 1 mg/kg/day (3 mg/m/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/m/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 category X:
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 ).
Based on studies in the elderly, no adjustment of the dose of Arthrotec () is necessary in the elderly for pharmacokinetic reasons (see ), although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.
Arthrotec () Adverse Reactions
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 .
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.
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:
Cardiovascular system:
Central and peripheral nervous system:
Digestive:
Female reproductive disorders:
Hemic and lymphatic system:
Hypersensitivity:
Liver and biliary system:
Male reproductive disorders:
Metabolic and nutritional:
Musculoskeletal system:
Psychiatric:
Respiratory system:
Skin and appendages:
Special senses:
Urinary system:
Vision:
Arthrotec () Overdosage
The toxic dose of Arthrotec () has not been determined. However, signs of overdosage from the components of the product have been described.
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 woman 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 (LD in mg/kg: rats, 55; dogs, 500; monkeys, 3200).
Arthrotec () Dosage And Administration
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 ).
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 section below.
Arthrotec () Patient Information
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 ).
Do not take Arthrotec () if you are pregnant (see boxed ). 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 ). Arthrotec () should never be used for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see boxed ).
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 ).
Arthrotec () , like other NSAIDs, may cause GI discomfort and, rarely, serious GI effects such as ulcers and bleeding, which may result in hospitalization 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 ). 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 .)
Arthrotec () , like other NSAIDs, may cause serious skin side effects, such as 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 signs 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.
Arthrotec () Medication Guide For Non-steroidal Anti-inflammatory Drugs (nsaids)
. This chance increases:
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
Arthrotec () Arthrotec Mg (mg/.mg) Tablet
