GASTROINTESTINAL (GI) EFFECTS - RISK OF GI ULCERATION, BLEEDING, AND PERFORATION:
Serious gastrointestinal toxicity such as inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and the steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to 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 thus, 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. 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, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmacoepidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Voltaren® -XR (diclofenac sodium extended-release tablets). Voltaren-XR 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.) Emergency help should be sought in cases where an anaphylactoid reaction occurs.
ADVANCED RENAL DISEASE
In cases with advanced kidney disease, treatment with Voltaren-XR is not recommended. If NSAID therapy, however, must be initiated, close monitoring of the patient's kidney function is advisable (see PRECAUTIONS - Renal Effects).
In late pregnancy, as with other NSAIDs, Voltaren-XR should be avoided because it may cause premature closure of the ductus arteriosus.
Voltaren® -XR (diclofenac sodium extended-release tablets) 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 Voltaren-XR in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Voltaren-XR. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Based on this experience, in patients on chronic treatment with Voltaren-XR, periodic monitoring of transaminases is recommended (See PRECAUTIONS - Laboratory Tests). Notable elevations of ALT or AST (three or more times the upper limit of normal) have been reported in approximately 2%-4% of patients, including marked elevations (eight or more times the upper limit of normal) in about 1% of patients in clinical trials with diclofenac. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Voltaren-XR. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Voltaren-XR should be discontinued.
Caution should be used when initiating treatment with Voltaren-XR in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Voltaren-XR. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS - Advanced Renal Disease).
As with other NSAIDs, long-term administration of diclofenac has resulted in renal papillary necrosis and other renal medullary changes. Renal toxicity has also been seen in patients in which 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 non-steroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state.
Voltaren-XR metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied. As with other NSAIDs, metabolites of which are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored.
Anemia is sometimes seen in patients receiving NSAIDs, including Voltaren-XR. This may be due to fluid retention, GI loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Voltaren-XR, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding.
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. Voltaren-XR does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving Voltaren-XR who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
FLUID RETENTION AND EDEMA
Fluid retention and edema have been observed in some patients taking NSAIDs. Therefore, as with other NSAIDs, Voltaren-XR should be used with caution in patients with fluid retention, hypertension, or heart failure.
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, Voltaren-XR should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma.
INFORMATION FOR PATIENTS
Voltaren-XR, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, 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 - Risk of Gastrointestinal Ulceration, Bleeding and Perforation).
Patients should report to their physicians' signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, weight gain, or edema.
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 therapy.
Patients should also be instructed to seek immediate emergency help in the case of an anaphylactoid reaction (see WARNINGS).
In late pregnancy, as with other NSAIDs, Voltaren-XR should be avoided because it will cause premature closure of the ductus arteriosus.
Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile (including transaminases) 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, Voltaren-XR should be discontinued.
Aspirin: When Voltaren-XR is administered with aspirin, its protein binding is reduced. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.
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: Voltaren-XR, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with Voltaren-XR may increase cyclosporine's nephrotoxicity. Caution should be used when Voltaren-XR is administered concomitantly with cyclosporine.
ACE-inhibitors: 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.
Furosemide: Clinical studies, as well as post marketing observations, have shown that Voltaren-XR 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 PRE-CAUTIONS - Renal Effects), as well as to assure diuretic efficacy.
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.
Warfarin: The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
TERATOGENIC EFFECTS: PREGNANCY CATEGORY C
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
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. The effects of Voltaren-XR on labor and delivery in pregnant women are unknown.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Voltaren-XR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).