CONTRAINDICATIONS AND WARNINGS.
CONTRAINDICATIONS AND WARNINGS.
Cardiovascular Thrombotic Events
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
NSAIDs, 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 Edema
Fluid 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.
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 these patients with advanced renal disease. If ARTHROTEC therapy must be initiated, close monitoring of the patient's renal function is advisable.
In clinical trials with ARTHROTEC, meaningful elevation of ALT (SGPT, more than 3 times the ULN) 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 [ULN = the upper limit of the normal range]), 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).
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
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.
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.
In late pregnancy, as with other NSAIDs, ARTHROTEC should be avoided because it may cause premature closure of the ductus arteriosus.
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.
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.
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 its being related to diclofenac should be considered.
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 hospitalizations 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 be avoided because it may cause premature closure of the ductus arteriosus.
- Arthrotec should not be taken by nursing mothers.
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.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs of 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 coagulation
Diclofenac 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.
Reports 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.
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.
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.
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.
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.
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.
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 clyclosporine. They should be observed closely, particularly if renal function is impaired.
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 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.
Clinical studies, as well as post marketing 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.
In small groups of patients (7–10 patients/interaction study), the concomitant administration of azathioprine, gold, chloroquine, D-penicillamine, prednisolone, doxycycline or digitoxin did not significantly affect the peak levels and AUC levels of diclofenac sodium. Phenobarbital toxicity has been reported to have occurred in a patient on chronic phenobarbital treatment following the initiation of diclofenac therapy. In vitro, diclofenac interferes minimally with the protein binding of prednisolone (10% decrease in binding). Benzylpenicillin, ampicillin, oxacillin, chlortetracycline, doxycycline, cephalothin, erythromycin, and sulfamethoxazole have no influence, in vitro, on the protein binding of diclofenac in human serum.
A reversible increase in the number of normal surface gastric epithelial cells occurred in the dog, rat, and mouse during long-term toxicology studies with misoprostol. No such increase has been observed in humans administered misoprostol for up to 1 year. An apparent response of the female mouse to misoprostol in long-term studies at 100 to 1000 times the human dose was hyperostosis, mainly of the medulla of sternebrae. Hyperostosis did not occur in long-term studies in the dog and rat and has not been seen in humans treated with misoprostol.
Carcinogenesis, mutagenesis, impairment of fertility
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/m2/day, 24 times the recommended maximum human dose of 0.6 mg/m2/day) was not tumorigenic. In a 21-month mouse carcinogenicity study, oral misoprostol at doses up to 16 mg/kg/day (48 mg/m2/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/m2/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/m2/day) was not tumorigenic. For a 50-kg person of average height (1.46m2 body surface area), this dose represents 0.08 times the recommended maximum human dose (148 mg/m2) 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/m2/day, 0.006 times the recommended maximum human dose based on body surface area) in males and 1 mg/kg/day (3 mg/m2/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/m2/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: See boxed
CONTRAINDICATIONS AND WARNINGS
CONTRAINDICATIONS AND WARNINGS. Misoprostol may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman. Misoprostol may produce uterine contractions, uterine bleeding, and expulsion of the products of conception. Misoprostol has been used to ripen the cervix, to induce labor, and to treat postpartum hemorrhage, outside of its approved indication. A major adverse effect of these uses is hyperstimulation of the uterus. Uterine rupture, amniotic fluid embolism, severe genital bleeding, shock, fetal bradycardia, and fetal and material death have been reported. Higher doses of misoprostol, including the 100 mcg tablet, may increase the risk of complications from uterine hyperstimulation. ARTHROTEC, which contains 200 mcg of misoprostol, is likely to have a greater risk of uterine hyperstimulation than the 100 mcg tablet of misoprostol. Abortions caused by misoprostol may be incomplete. If a woman is or becomes pregnant while taking this drug, the drug should be discontinued and the patient apprised of the potential hazard to the fetus.
Cases of amniotic fluid embolism, which resulted in maternal and fetal death, have been reported with use of misoprostol during pregnancy. Severe vaginal bleeding, retained placenta, shock, fetal bradycardia, and pelvic pain have also been reported. These women were administered misoprostol vaginally and/or orally over a range of doses.
Additionally, because of the known effects of nonsteroidal anti-inflammatory drugs including the diclofenac sodium component of ARTHROTEC, on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
CONTRAINDICATIONS and WARNINGS.
Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated. Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects.
An oral teratology study has been performed in pregnant rabbits at dose combinations (250:1 ratio) up to 10 mg/kg/day diclofenac sodium (120 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area) and 0.04 mg/kg/day misoprostol (0.48 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area) and has revealed no evidence of teratogenic potential for ARTHROTEC.
Oral teratology studies have been performed in pregnant rats at doses up to 1.6 mg/kg/day (9.6 mg/m2/day, 16 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 1.0 mg/kg/day (12 mg/m2/day, 20 times the recommended maximum human dose based on body surface area) and have revealed no evidence of teratogenic potential for misoprostol.
Oral teratology studies have been performed in pregnant mice at doses up to 20 mg/kg/day (60 mg/m2/day, 0.4 times the recommended maximum human dose based on body surface area), pregnant rats at doses up to 10 mg/kg/day (60 mg/m2/day, 0.4 times the recommended maximum human dose based on body surface area) and pregnant rabbits at doses up to 10 mg/kg/day (120 mg/m2/day, 0.8 times the recommended maximum human dose based on body surface area) and have revealed no evidence of teratogenic potential for diclofenac sodium.
However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Diclofenac sodium has been found in the milk of nursing mothers. Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. There are no published reports of adverse effects of misoprostol in breast-feeding infants of mothers taking misoprostol. Caution should be exercised when ARTHROTEC is administered to a nursing woman.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred.
Safety and effectiveness of ARTHROTEC in pediatric patients have not been established.
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
Pharmacokinetics of ARTHROTEC—Special populations), although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging.