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Voltaren Gel

"Jan. 12, 2011 -- A new study weighs in on the debate over the relative safety of nonsteroidal anti-inflammatory medications (NSAIDs), commonly used to treat joint and muscle aches and pain.

The study, published online in the BMJ,"...

Voltaren Gel

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 NSAIDs, 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 toxicity 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 NSAIDs use. The concurrent use of aspirin and NSAIDs such as diclofenac, does increase the risk of serious GI events.

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 1014 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see CONTRAINDICATIONS].

Gastrointestinal Effects – Risk of GI Ulceration, Bleeding, and Perforation

NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) events including 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 patients 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 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 NSAIDs 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, the lowest effective dose should be used for the shortest possible duration. Physicians and patients should remain alert for signs and symptoms of GI ulceration and bleeding during diclofenac therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Hepatic Effects

Elevations of one or more liver tests may occur during therapy with diclofenac sodium. 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 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 (GOT) (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/orAST 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, fulfillment 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 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, diarrhea, 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, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing diclofenac sodium with concomitant drugs that are know to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

Hypertension

NSAIDs, including Voltaren® Gel (diclofenac sodium gel) , can lead to the onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Voltaren® Gel (diclofenac sodium gel) should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with Voltaren® Gel (diclofenac sodium gel) and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients treated with NSAIDs, including Voltaren® Gel (diclofenac sodium gel) . Voltaren® Gel (diclofenac sodium gel) should be used with caution in patients with fluid retention or heart failure.

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 an NSAID may cause a dosedependent 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.

No information is available from controlled clinical studies regarding the use of Voltaren® Gel (diclofenac sodium gel) in patients with advanced renal disease. Therefore, treatment with Voltaren® Gel (diclofenac sodium gel) is not recommended in patients with advanced renal disease. If Voltaren® Gel (diclofenac sodium gel) therapy is initiated, close monitoring of the patient's renal function is advisable.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to Voltaren® Gel (diclofenac sodium gel) . Voltaren® Gel (diclofenac sodium gel) 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, WARNINGS AND PRECAUTIONS]. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Voltaren® Gel (diclofenac sodium gel) , 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 the use of the drug should be discontinued at the first appearance of skin rash or any other signs of hypersensitivity.

Voltaren® Gel (diclofenac sodium gel) should not be applied to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug. Voltaren® Gel should not be allowed to come into contact with the eyes or with mucous membranes.

The effect of Voltaren® Gel (diclofenac sodium gel) under occlusive dressings has not been evaluated, and should be avoided.

Pregnancy

As with other NSAIDs, Voltaren® Gel should be avoided in late pregnancy, because it may cause premature closure of the ductus arteriosus.

Corticosteroid treatment

Voltaren® Gel (diclofenac sodium gel) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroidresponsive illness.

Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

Inflammation

The pharmacological activity of diclofenac in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoeisis. Patients on long-term treatment with NSAIDs, including Voltaren® Gel (diclofenac sodium gel) , should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

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 treated with Voltaren® Gel (diclofenac sodium gel) who may be adversely affected by alteration 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 aspirinsensitive 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® Gel (diclofenac sodium gel) should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Sun Exposure

Patients should minimize or avoid exposure to natural or artificial sunlight on treated areas because studies in animals indicated topical diclofenac treatment resulted in an earlier onset of ultraviolet light induced skin tumors. The potential effects of Voltaren® Gel (diclofenac sodium gel) on skin response to ultraviolet damage in humans are not known.

Eye Exposure

Contact of Voltaren® Gel (diclofenac sodium gel) with eyes and mucosa, although not studied, should be avoided. Patients should be advised that if eye contact occurs, they should immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

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 a CBC and a chemistry profile checked periodically. If abnormal liver tests or renal tests persist or worsen, Voltaren® Gel (diclofenac sodium gel) should be discontinued.

Patient Counseling Information

See Medication Guide.

Medication Guide

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should be informed of the availability of a Medication Guide for Non-Steroidal Anti-inflammatory Drugs (NSAIDs), and they should be instructed to read the Medication Guide prior to using Voltaren® Gel (diclofenac sodium gel) .

Cardiovascular effects

Voltaren® Gel (diclofenac sodium gel) , like other NSAIDs, may cause serious CV 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 AND PRECAUTIONS].

Gastrointestinal effects

Voltaren® Gel (diclofenac sodium gel) , like other NSAIDs, can cause GI discomfort and, rarely, more 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 ulcerations 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 AND PRECAUTIONS].

Hepatotoxicity

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 with Voltaren® Gel (diclofenac sodium gel) and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS].

Adverse Skin Reactions

Voltaren® Gel (diclofenac sodium gel) , like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations 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 signs or symptoms [see WARNINGS AND PRECAUTIONS].

Patients should be advised to stop Voltaren® Gel (diclofenac sodium gel) immediately if they develop any type of rash and contact their physicians as soon as possible.

Patients should be instructed not to apply Voltaren® Gel (diclofenac sodium gel) to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.

Patients should be instructed to avoid concomitant use of Voltaren® Gel (diclofenac sodium gel) with other topical products, including sunscreens, cosmetics lotions, moisturizers, insect repellants, on the treated skin site. Concomitant use may result in skin reactions or change the absorption of Voltaren® Gel (diclofenac sodium gel) .

Patients should be instructed to minimize or avoid exposure of treated areas to natural or artificial sunlight.

Weight gain and edema

Patients should promptly report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with Voltaren® Gel (diclofenac sodium gel) [see WARNINGS AND PRECAUTIONS].

Anaphylactoid reactions

Patients should be informed of the signs of an anaphylactoid 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 AND PRECAUTIONS].

Effects during pregnancy

In late pregnancy, as with other NSAIDs, Voltaren® Gel (diclofenac sodium gel) should be avoided because it will cause premature closure of the ductus arteriosus [see WARNINGS AND PRECAUTIONS].

Eye Exposure

Patients should be instructed to avoid contact of Voltaren® Gel (diclofenac sodium gel) with the eyes and mucosa, although not studied, should be avoided. Patients should be advised that if eye contact occurs, they should immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour.

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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years at does up to 2 mg/kg/day resulted in no significant increases in tumor incidence corresponding to a human equivalent dose approximately 0.5- and 1-fold (mouse and rat, respectively) of the maximum human topical dose of Voltaren® Gel (diclofenac sodium gel) (based on bioavailability and body surface area comparison).

In a dermal carcinogenicity study conducted in albino mice, daily topical applications of a diclofenac sodium gel product for two years at concentrations up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in Voltaren® Gel (diclofenac sodium gel) ) did not increase neoplasm incidence.

In a photococarcinogenicity study conducted in hairless mice, topical application of a diclofenac sodium gel product at doses up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in Voltaren® Gel (diclofenac sodium gel) ) resulted in an earlier median time of onset of tumors.

Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal aberration assay of bone marrow cells.

Diclofenac did not affect male or female fertility in rats at doses up to 4 mg/kg/day which induced toxicity, corresponding to a human equivalent dose approximately 2-fold greater than the maximum human topical dose of Voltaren® Gel (diclofenac sodium gel) (based on bioavailability and body surface area comparison).

Use In Specific Populations

Pregnancy

The safety of Voltaren® Gel (diclofenac sodium gel) has not been established during pregnancy. There are no well-controlled studies of diclofenac in pregnant women. Human and animal studies indicate that diclofenac crosses the placenta. In late pregnancy, as with other NSAIDs, Voltaren® Gel (diclofenac sodium gel) should be avoided because it may cause premature closure of the ductus arteriosus.

Teratogenic effects

Pregnancy Category C: Studies in mice, rats, and rabbits in which diclofenac was administered orally throughout gestation revealed no evidence of teratogenicity despite the induction of maternal toxicity and fetal toxicity corresponding to a human equivalent dose approximately 4.5-, 2-, and 9-fold (mouse, rat, rabbit, respectively) of the maximum human topical dose of Voltaren® Gel (diclofenac sodium gel) (based on bioavailability and body surface area comparison).

Nonteratogenic effects

The use of diclofenac, as with other NSAIDs, is associated with the adverse fetal cardiovascular effect of premature closure of the ductus arteriosus.

Labor and Delivery

In rat studies with oral NSAIDs, including diclofenac, as with other drugs known to inhibit prostaglandin synthesis, there is an increased incidence of dystocia and delayed parturition corresponding to a human equivalent dose approximately similar to the maximum recommended clinical dose (based on bioavailability and body surface area comparison). The effects of Voltaren® Gel (diclofenac sodium gel) on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known whether diclofenac is excreted in human milk; however, studies in animals detected diclofenac in the milk after oral administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Voltaren® Gel (diclofenac sodium gel) 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects treated with Voltaren® Gel (diclofenac sodium gel) in clinical studies, 498 were 65 years of age and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity to the effect of NSAIDs in some older individuals cannot be ruled out.

Diclofenac, as with any NSAID, is known to be substantially excreted by the kidney, and the risk of toxic reactions to Voltaren® Gel (diclofenac sodium gel) may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when using Voltaren® Gel (diclofenac sodium gel) in the elderly, and it may be useful to monitor renal function.

Last reviewed on RxList: 10/15/2009
This monograph has been modified to include the generic and brand name in many instances.

Warnings
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