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Side Effects & Adverse Reactions
Regarding misoprostol:
See boxed CONTRAINDICATIONS AND WARNINGS.
Regarding diclofenac:
See boxed CONTRAINDICATIONS AND WARNINGS.
The use of diclofenac sodium/misoprostol tablets with concomitant NSAIDs including COX-2 inhibitors should be avoided.
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
NSAIDs, including diclofenac sodium/misoprostol tablets, 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 diclofenac sodium/misoprostol tablets, 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.
Fluid retention and edema have been observed in some patients taking NSAIDs. Diclofenac sodium/misoprostol tablets should be used with caution in patients with fluid retention or heart failure.
NSAIDs, including diclofenac sodium/misoprostol tablets, 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.
Diclofenac sodium/misoprostol tablets are contraindicated in patients with active GI bleeding.
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.
Diclofenac sodium/misoprostol tablets contain 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 diclofenac sodium/misoprostol tablets are not recommended in patients with advanced renal disease. If diclofenac sodium/misoprostol therapy must be initiated, close monitoring of the patient's renal function is advisable.
In clinical trials with diclofenac sodium/misoprostol tablets, 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 diclofenac sodium/misoprostol tablets 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 diclofenac sodium/misoprostol tablets. The misoprostol component of diclofenac sodium/misoprostol tablets 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 diclofenac sodium/misoprostol tablets. 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. In another clinical trial where over 17,000 patients received diclofenac for a mean of 18 months, hepatitis was rarely observed.
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 usually occur within 1-6 months, 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.), diclofenac sodium/misoprostol tablets 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 diclofenac sodium/misoprostol tablets, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing diclofenac sodium/misoprostol tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).
As with other NSAIDs, anaphylactic reactions may occur in patients without known prior exposure to diclofenac sodium/misoprostol tablets. Diclofenac sodium/misoprostol tablets 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 diclofenac sodium/misoprostol tablets. 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 diclofenac sodium/misoprostol tablets in clinical trials, and there have been rare reports of anaphylaxis in the marketed use of diclofenac sodium/misoprostol tablets outside of the United States.
NSAIDs, including diclofenac sodium/misoprostol tablets, 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 appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. 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.
In late pregnancy, as with other NSAIDs, diclofenac sodium/misoprostol tablets should be avoided because it may cause premature closure of the ductus arteriosus.
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FDA Safety Alerts
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Manufacturer Warnings
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FDA Labeling Changes
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Uses
Carefully consider the potential benefits and risks of diclofenac sodium/misoprostol tablets and other treatment options before deciding to use diclofenac sodium/misoprostol tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
Diclofenac sodium/misoprostol tablets are 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.
History
There is currently no drug history available for this drug.
Other Information
Diclofenac sodium/misoprostol tablet 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. Diclofenac sodium/misoprostol 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 or 75 mg of 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 diclofenac sodium/misoprostol tablets 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.
Sources
Colgate Great Regular Flavor Manufacturers
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Mission Hills S.a De C.v
Colgate Great Regular Flavor | Greenstone Llc
Carefully consider the potential benefits and risks of diclofenac sodium/misoprostol tablets and other treatment options before deciding to use diclofenac sodium/misoprostol tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with diclofenac sodium/misoprostol tablets, 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.
Diclofenac sodium/misoprostol tablets are administered as diclofenac sodium/misoprostol 50 (50 mg diclofenac sodium/200 mcg misoprostol) or as diclofenac sodium/misoprostol 75 (75 mg diclofenac sodium/200 mcg misoprostol).
Note: See SPECIAL DOSING CONSIDERATIONS section below.
OsteoarthritisThe recommended dosage for maximal GI mucosal protection is diclofenac sodium/misoprostol 50 tid. For patients who experience intolerance, diclofenac sodium/misoprostol 75 bid or diclofenac sodium/misoprostol 50 bid can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium/misoprostol tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:
OA regimen Diclofenac sodium
(mg/day) Misoprostol
(mcg/day) Diclofenac sodium/misoprostol 50 tid
bid 150
100 600
400 Diclofenac sodium/misoprostol 75 bid 150 400 Rheumatoid ArthritisThe recommended dosage is diclofenac sodium/misoprostol 50 tid or qid. For patients who experience intolerance, diclofenac sodium/misoprostol 75 bid or diclofenac sodium/misoprostol 50 bid can be used, but are less effective in preventing ulcers. This fixed combination product, diclofenac sodium/misoprostol tablets, is not recommended for patients who would not receive the appropriate dose of both ingredients. Doses of the components delivered with these regimens are as follows:
RA regimen Diclofenac sodium
(mg/day) Misoprostol
(mcg/day) Diclofenac sodium/misoprostol 50 qid
tid
bid 200
150
100 800
600
400 Diclofenac sodium/misoprostol 75 bid 150 400 SPECIAL DOSING CONSIDERATIONSDiclofenac sodium/misoprostol tablets contain misoprostol, which provides protection against gastric and duodenal ulcers (see CLINICAL STUDIES). For gastric ulcer prevention, the 200 mcg qid and tid regimens are therapeutically equivalent, but more protective than the bid regimen. For duodenal ulcer prevention, the qid regimen is more protective than the tid or bid regimens. However, the qid regimen is less well tolerated than the tid regimen because of usually self-limited diarrhea related to the misoprostol dose (see ADVERSE REACTIONS —Gastrointestinal), and the bid regimen may be better tolerated than tid in some patients.
Dosages may be individualized using the separate products (misoprostol and diclofenac), after which the patient may be changed to the appropriate dose of diclofenac sodium/misoprostol tablets. If clinically indicated, misoprostol co-therapy with diclofenac sodium/misoprostol tablets, 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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