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.
Arthrotec - Clinical Pharmacology
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.
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.
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 secretionMisoprostol, 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 t1/2 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 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.
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
| SD: Standard deviation of the mean |
| AUC: Area under the curve |
| Cmax: Peak concentration |
| tmax: Time to peak concentration |
| MISOPROSTOL ACID Mean (SD) |
| Treatment (n=36) |
Cmax (pg/mL) |
tmax (hr) |
AUC (0–4h)
(pg∙hr/mL) |
| Arthrotec 50 |
441 (137) |
0.30 (0.13) |
266 (95) |
| Cytotec® |
478 (201) |
0.30 (0.10) |
295 (143) |
| Arthrotec 75 |
304 (110) |
0.26 (0.09) |
177 (49) |
| Cytotec |
290 (130) |
0.35 (0.12) |
176 (58) |
| DICLOFENAC Mean (SD) |
| Treatment (n=36) |
Cmax (ng/mL) |
tmax (hr) |
AUC (0–12h)
(ng∙hr/mL) |
| Arthrotec 50 |
1207 (364) |
2.4 (1.0) |
1380 (272) |
| Voltaren® |
1298 (441) |
2.4 (1.0) |
1357 (290) |
| Arthrotec 75 |
2025 (2005) |
2.0 (1.4) |
2773 (1347) |
| Voltaren |
2367 (1318) |
1.9 (0.7) |
2609 (1185) |
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.
Specific populationsA 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
| Misoprostol 200 mcg Dosage Regimen |
|---|
|
Placebo |
bid |
tid |
qid |
|---|
| N=1623; 12 weeks |
|
| Gastric ulcer |
11% |
6% |
3%* |
3%* |
| Duodenal ulcer |
6% |
2%* |
3%* |
1%* |
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
| Osteoarthritis patients with history of ulcer or erosive disease (N=572), 6 weeks |
Incidence of ulcers |
|---|
| Gastric |
Duodenal |
|---|
|
| Arthrotec 50 tid |
3% |
6% |
| Arthrotec 75 bid |
4%* |
3% |
| diclofenac sodium 75 mg bid |
11% |
7% |
| placebo |
3% |
1% |
Indications and Usage for Arthrotec
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.
Contraindications
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).
Warnings
Regarding misoprostol:
See boxed CONTRAINDICATIONS AND WARNINGS.
Regarding diclofenac:
See boxed CONTRAINDICATIONS AND WARNINGS.
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic EventsClinical 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).
HypertensionNSAIDs, 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 EdemaFluid 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 anti-inflammatory 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 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 [ULN = the upper limit of the normal range]) occurred in 1.6% of 2,184 patients treated with Arthrotec and in 1.4% of 1,691 patients treated with diclofenac sodium. These increases were generally transient, and enzyme levels returned to within the normal range upon discontinuation of therapy with Arthrotec. The misoprostol component of Arthrotec does not appear to exacerbate the hepatic effects caused by the diclofenac sodium component.
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), 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).
Anaphylactic Reactions
As with other NSAIDs, anaphylactic 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). Anaphylactic reactions may also occur to the misoprostol component of Arthrotec. Emergency help should be sought in cases where an anaphylactic 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.
Precautions
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 it 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 hospitalization 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 anaphylactic 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, Anaphylactic Reactions).
- In late pregnancy, as with other NSAIDs, Arthrotec should not be taken because it may cause premature closure of the ductus arteriosus.
- Arthrotec should not be taken by nursing mothers.
- Concomitant use of voriconazole increases the systemic exposure to diclofenac. When concomitant voriconazole use is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of Arthrotec 50 twice daily (see Drug Interactions and Dosage and Administration).
See PATIENT INFORMATION 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.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or 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 coagulationDiclofenac 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.
Drug Interactions
ACE-InhibitorsReports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
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 cyclosporine. 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 postmarketing 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.
