Diclofenac Sodium Gel
FDA Label NDC 63187-753

Cardiovascular Risk

• Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)].
• Diclofenac sodium topical gel is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)].

Gastrointestinal Risk

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.2)].

Diclofenac sodium topical gel is indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands.

• Diclofenac sodium topical gel has not been evaluated for use on the spine, hip, or shoulder.

[See the patient Instructions for Use]

The dosing card can be found attached to the inside of the carton.

The proper amount of diclofenac sodium topical gel should be measured using the dosing card supplied in the drug product carton. The dosing card is made of clear polypropylene. The dosing card should be used for each application of drug product. The gel should be applied within the rectangle area of the dosing card up to the 2 gram or 4 gram line (2 g for each elbow, wrist, or hand, and 4 g for each knee, ankle, or foot). The 2 g line is 2.25 inches long. The 4 g line is 4.5 inches long. The dosing card containing diclofenac sodium topical gel can be used to apply the gel. The hands should then be used to gently rub the gel into the skin. After using the dosing card, hold with fingertips, rinse, and dry. If treatment site is the hands, patients should wait at least one (1) hour to wash their hands.

Apply the gel (4 g) to the affected foot or knee or ankle, 4 times daily. Diclofenac sodium topical gel should be gently massaged into the skin ensuring application to the entire affected foot, or knee or ankle. The entire foot includes the sole, top of the foot and the toes. Do not apply more than 16 g daily to any single joint of the lower extremities.

Apply the gel (2 g) to the affected hand or elbow or wrist, 4 times daily. Diclofenac sodium topical gel should be gently massaged into the skin ensuring application to the entire affected hand or elbow or wrist. The entire hand includes the palm, back of the hands, and the fingers. Do not apply more than 8 g daily to any single joint of the upper extremities.
Total dose should not exceed 32 g per day, over all affected joints. 

• Showering/bathing should be avoided for at least 1 hour after the application. Patient should wash his/her hands after use, unless the hands are the treated joint. If diclofenac sodium topical gel is applied to the hand(s) for treatment; patient should not wash the treated hand(s) for at least 1 hour after the application.
• Diclofenac sodium topical gel should not be applied to open wounds.
• Contact of diclofenac sodium topical gel with eyes and mucous membranes should be avoided.
• External heat and/or occlusive dressings should not be applied to treated joints.
• Exposure of the treated joint(s) to sunlight should be avoided.
• Avoid concomitant use of diclofenac sodium topical gel on the treated skin site with other topical products, including sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other topical medications [see Drug Interactions (7.9)].
• Concomitant use of diclofenac sodium topical gel with oral non-steroidal anti-inflammatory drugs (NSAIDs) has not been evaluated, and may increase adverse NSAIDs effects. 
• Wearing of clothing or gloves should be avoided for at least 10 minutes after applying diclofenac sodium topical gel.

1% gel

The use of diclofenac sodium topical gel is contraindicated in patients with a known hypersensitivity to diclofenac.
Diclofenac sodium topical gel should not be administered in patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.1)].
Diclofenac sodium topical gel is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2)].
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 (4)].

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.

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/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.), 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 known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

NSAIDs, including diclofenac sodium topical 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 diclofenac sodium topical gel should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with diclofenac sodium topical gel and throughout the course of therapy.

Fluid retention and edema have been observed in some patients treated with NSAIDs, including diclofenac sodium topical gel. Diclofenac sodium topical gel should be used with caution in patients with fluid retention or heart failure.

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

As with other NSAIDs, anaphylactoid reactions may occur in patients without prior exposure to diclofenac sodium topical gel. Diclofenac sodium topical 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 (4), Warnings and Precautions (5.7)].. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

NSAIDs, including diclofenac sodium topical 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.
Diclofenac sodium topical gel should not be applied to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug. Diclofenac sodium topical gel should not be allowed to come into contact with the eyes or with mucous membranes.
The effect of diclofenac sodium topical gel under occlusive dressings has not been evaluated, and should be avoided.

As with other NSAIDs, diclofenac sodium topical gel should be avoided in late pregnancy, because it may cause premature closure of the ductus arteriosus.

Diclofenac sodium topical gel cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

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.

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 diclofenac sodium topical 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 diclofenac sodium topical 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.

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 non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, diclofenac sodium topical gel should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

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 diclofenac sodium topical gel on skin response to ultraviolet damage in humans are not known.

Contact of diclofenac sodium topical 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.

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, diclofenac sodium topical gel should be discontinued.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
During clinical development, 913 patients were exposed to diclofenac sodium topical gel in randomized, double-blind, multicenter, vehicle-controlled, parallel-group studies in osteoarthritis of the superficial joints of the extremities. Of these, 513 patients received diclofenac sodium topical gel for osteoarthritis of the knee and 400 were treated for osteoarthritis of the hand. Additionally, 583 patients were exposed to diclofenac sodium topical gel in an uncontrolled, open-label, long-term safety trial in osteoarthritis of the knee. Of these, 355 patients were treated for osteoarthritis of 1 knee and 228 were treated for osteoarthritis of both knees. Duration of exposure ranged from 8 to 12 weeks for the placebo-controlled studies, and up to 12 months for the open-label safety trial.

Short-Term Placebo-Controlled Trials:
Adverse reactions observed in at least 1% of patients treated with diclofenac sodium topical gel: Non-serious adverse reactions that were reported during the short-term placebo-controlled studies comparing diclofenac sodium topical gel and placebo (vehicle gel) over study periods of 8 to 12 weeks (16 g per day), were application site reactions. These were the only adverse reactions that occurred in >1% of treated patients with a greater frequency in the diclofenac sodium topical gel group (7%) than the placebo group (2%). 
Table 1 lists the types of application site reactions reported. Application site dermatitis was the most frequent type of application site reaction and was reported by 4% of patients treated with diclofenac sodium topical gel, compared to 1% of placebo patients.

^†Preferred Term according to MedDRA 9.1.

In the placebo-controlled trials, the discontinuation rate due to adverse reactions was 5% for patients treated with diclofenac sodium topical gel, and 3% for patients in the placebo group. Application site reactions, including application site dermatitis, were the most frequent reason for treatment discontinuation. 

Long-Term Open-Label Safety Trial:
In the open-label, long-term safety study, distribution of adverse reactions was similar to that in the placebo-controlled studies. In this study, where patients were treated for up to 1 year with diclofenac sodium topical gel up to 32 g per day, application site dermatitis was observed in 11% of patients. Adverse reactions that led to the discontinuation of the study drug were experienced in 12% of patients. The most common adverse reaction that led to discontinuation of the study was application site dermatitis, which was experienced by 6% of patients.

When diclofenac is administered with aspirin, the binding of diclofenac to protein is reduced, although the clearance of free diclofenac is not altered. 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.

The effects of anticoagulants such as 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. 

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. The 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 and Precautions (5.6)], as well as to assure diuretic efficacy.

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, including diclofenac, and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity.

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, including diclofenac, are administered concomitantly with methotrexate.

Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac may increase cyclosporine’s nephrotoxicity. Caution should be used when diclofenac is administered concomitantly with cyclosporine.

Specific interaction studies of diclofenac sodium topical gel and oral NSAIDs were not performed. Also, the clinical trials of diclofenac sodium topical gel prohibited concomitant use of oral NSAIDs. There is systemic exposure to diclofenac following normal use of diclofenac sodium topical gel, up to 6% of the systemic levels of a single oral dose of diclofenac sodium [see Clinical Pharmacology (12.3)].Therefore, concomitant administration of diclofenac sodium topical gel with oral NSAIDs or aspirin may result in increased adverse NSAID effects.

Concomitant use of diclofenac sodium topical gel with other topical products, including topical medications, sunscreens, lotions, moisturizers, and cosmetics, on the same skin site has not been tested and should be avoided because of the potential to alter local tolerability and absorption.

The safety of diclofenac sodium topical 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, diclofenac sodium topical 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 diclofenac sodium topical 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.

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 diclofenac sodium topical gel on labor and delivery in pregnant women are unknown.

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 diclofenac sodium topical 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.

Safety and effectiveness in pediatric patients have not been established.

Of the total number of subjects treated with diclofenac sodium topical 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 diclofenac sodium topical 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 diclofenac sodium topical gel in the elderly, and it may be useful to monitor renal function.

There has been no experience of overdose with diclofenac sodium topical gel.
No events of accidental ingestion have been reported with diclofenac sodium topical gel. Effects similar to those observed after an overdose of diclofenac tablets can be expected if substantial amounts of diclofenac sodium topical gel are ingested. Symptoms following acute oral NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur after an overdose.
In the event of oral ingestion resulting in significant systemic side effects, it is recommended that the stomach be emptied by vomiting or lavage. Forced diuresis may theoretically be beneficial because the drug is excreted in the urine. The effect of dialysis or hemoperfusion in the elimination of diclofenac (99% protein-bound) remains unproven. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of diclofenac. Supportive and symptomatic treatment should be given for complications such as renal failure, convulsions, gastrointestinal irritation, and respiratory depression.
For additional information about overdose treatment, call a Poison Control Center (1-800-222-1222).

Diclofenac sodium topical gel is a non-steroidal anti-inflammatory drug (NSAID) for topical use only. It contains the active ingredient, diclofenac sodium, in an opaque, white gel base. Diclofenac sodium is a white to slightly yellow crystalline powder. Diclofenac sodium is a benzeneacetic acid derivative. The chemical name is 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C₁₄H₁₀Cl₂NNaO₂. It has the following structural formula:

Formula (Image 01)

Diclofenac sodium topical gel also contains carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution.

The mechanism of action of diclofenac is similar to that of other non-steroidal anti-inflammatory drugs. Diclofenac inhibits the enzyme, cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.

Diclofenac, the active component of diclofenac sodium topical gel has anti-inflammatory, anti-nociception, and anti-pyretic effects.

The pharmacokinetics of diclofenac sodium topical gel were assessed in healthy volunteers following repeated applications during 7 days of diclofenac sodium topical gel to 1 knee (4 x 4 g per day) or to 2 knees and 2 hands (4 x 12 g per day) versus the recommended oral dose of diclofenac sodium for the treatment of osteoarthritis (3 x 50 mg per day). A summary of the pharmacokinetic parameters is presented in Table 2.

      C_max = maximum plasma concentration; T_max = time of C_max; AUC_0-24 = area

      under the concentration time curve; SD = standard deviation; CI = confidence interval.

Systemic exposure (area under the concentration-time curve) and maximum plasma concentrations of diclofenac are significantly lower with diclofenac sodium topical gel than with comparable oral treatment of diclofenac sodium.
Systemic exposure with recommended use of diclofenac sodium topical gel (4 x 4 g per day applied to 1 knee) is on average 17 times lower than with oral treatment. (Basis: treatment with diclofenac sodium topical gel of 1 knee, 4 times a day versus 50 mg, 3 times a day of oral diclofenac tablets.) The amount of diclofenac sodium that is systemically absorbed from diclofenac sodium topical gel is on average 6% of the systemic exposure from an oral form of diclofenac sodium.
The average peak plasma concentration with recommended use of diclofenac sodium topical gel (4 x 4 g per day applied to 1 knee) is 158 times lower than with the oral treatment. 
The pharmacokinetics of diclofenac sodium topical gel has been tested under conditions of moderate heat (application of a heat patch for 15 minutes prior to gel application) and of moderate exercise (first gel application followed by a 20-minute treadmill exercise). No clinically relevant differences of systemic absorption and of tolerability were found between applications of diclofenac sodium topical gel (4 x 4 g per day on 1 knee) with and under the conditions tested. However, the pharmacokinetics of diclofenac sodium topical gel were not tested under the condition of heat application following gel application. Therefore, concurrent use of diclofenac sodium topical gel and heat is not recommended.

Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years at doses 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 diclofenac sodium topical 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 diclofenac sodium topical 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 diclofenac sodium topical 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 diclofenac sodium topical gel (based on bioavailability and body surface area comparison). 

Study 1 evaluated the efficacy of diclofenac sodium topical gel for the treatment of osteoarthritis of the knee in a 12-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial. Diclofenac sodium topical gel was administered at a dose of 4 g, 4 times daily, on 1 knee (16 g per day). Pain as assessed by the patients at Week 12 using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) Pain Subindex was lower in the diclofenac sodium topical gel group than the placebo group.
Study 2 evaluated the efficacy of diclofenac sodium topical gel for the treatment of osteoarthritis in subjects with osteoarthritis of the hand in an 8-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group study. Diclofenac sodium topical gel was administered at a dose of 2 g per hand, 4 times daily, on both hands (16 g per day). Pain in the target hand as assessed by the patients at Weeks 4 and 6 on a visual analog scale from 0 to 100 was lower in the diclofenac sodium topical gel group than the placebo group.

* WOMAC = Western Ontario McMaster Osteoarthritis Index.

# Scale from 0 (best) to 100 (worst).

† Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment and center and baseline covariate.

‡ Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment, center, indicator for pain in the CMC-1 joint, and baseline as a covariate, and the treatment-by-CMC-1 indicator interaction. Difference is weighted by size of CMC-1 strata.

Diclofenac sodium topical gel is available in tubes containing 100 g of the topical gel in each tube. Each tube contains diclofenac sodium in a gel base (10 mg of diclofenac sodium per gram of gel or 1%).

100 g tube……………………………………NDC 63187-753-00  

Storage
Store at 20°C to 25°C (68°F to 77°F). Keep from freezing. Store the dosing card with your diclofenac sodium topical gel.

Advise the patient to read the FDA-approved patient labeling (NSAIDs Medication Guide and Instructions for Use) prior to using diclofenac sodium topical gel.

Inform patients of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.

Cardiovascular Effects

Diclofenac sodium topical 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. Advise patients of the importance of this follow-up [see Warnings and Precautions (5.1)].

Gastrointestinal Effects

Diclofenac sodium topical 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. Instruct patients to 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 (5.2)].

Hepatotoxicity

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). If these occur, patients should be instructed to stop therapy with diclofenac sodium topical gel and seek immediate medical therapy [see Warnings and Precautions (5.3)].

Adverse Skin Reactions

Diclofenac sodium topical gel, 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. Instruct patients to ask for medical advice when observing any indicative signs or symptoms [see Warnings and Precautions (5.8)].
Advise patients to stop diclofenac sodium topical gel immediately if they develop any type of rash and contact their physicians as soon as possible.
Instruct patients not to apply diclofenac sodium topical gel to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug.
Instruct patients to avoid concomitant use of diclofenac sodium topical gel with other topical products, including sunscreens, cosmetics, lotions, moisturizers, and insect repellants. Concomitant use may result in skin reactions or change the absorption of diclofenac sodium topical gel.
Instruct patients to minimize or avoid exposure of treated areas to natural or artificial sunlight.

Weight Gain and Edema

Instruct patients to report to their physicians signs or symptoms of unexplained weight gain or edema following treatment with diclofenac sodium topical gel [see Warnings and Precautions (5.5)].

Anaphylactoid Reactions

Inform patients 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 (5.7)].

Effects During Pregnancy

In late pregnancy, as with other NSAIDs, diclofenac sodium topical gel should be avoided because it will cause premature closure of the ductus arteriosus [see Warnings and Precautions (5.9)].

Eye Exposure

Instruct patients to avoid contact of diclofenac sodium topical 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.                       

Proper Application

Instruct patients how to use the dosing card to measure the proper dose of diclofenac sodium topical gel to apply.
If the patient loses their dosing card, instruct them that they can call 1-800-398-5876 to request a replacement dosing card or ask their pharmacist for a new dosing card. Instruct patients how to correctly measure the 2.25 inches (2 g) dose or 4.5 inches (4 g) dose while waiting for a replacement dosing card.

Comments or Questions?
Call toll-free 1-800-398-5876

Marketed by:

Par Pharmaceutical
Chestnut Ridge, NY 10977

Manufactured by:

Novartis Pharma Produktions GmbH
Wehr, Germany

Revised: February 2016

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called “corticosteroids” and “anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breast-feeding. Talk to your healthcare provider.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include: heart attack stroke high blood pressure heart failure from body swelling (fluid retention) kidney problems including kidney failure bleeding and ulcers in the stomach and intestine low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions liver problems including liver failure asthma attacks in people who have asthma

Other side effects include: stomach pain constipation diarrhea gas heartburn nausea vomiting dizziness

Get emergency help right away if you have any of the following symptoms:

shortness of breath or trouble breathing chest pain weakness in one part or side of your body

slurred speech swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

nausea more tired or weaker than usual itching your skin or eyes look yellow stomach pain flu-like symptoms vomit blood

there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs):

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic Name	Tradename
Celecoxib	Celebrex®
Diclofenac	Flector®, Cataflam®, Cambia®, Voltaren®, VOLTAREN® GEL, Arthrotec® (combined with misoprostol), Pennsaid®, Zipsor®, Zorvolex™
Diflunisal	Dolobid®
Etodolac	Lodine®, Lodine® XL
Fenoprofen	Nalfon®, Nalfon® 200
Flurbirofen	Ansaid®
Ibuprofen	Motrin®, Tab-Profen®, Vicoprofen®* (combined with hydrocodone), Combunox™ (combined with oxycodone), Duexis® (combined with famotidine)
Indomethacin	Indocin®, Indocin® SR, Indo-Lemmon™, Indomethagan™
Ketoprofen	Oruvail®, Nexcede™
Ketorolac	Toradol®, Sprix®
Mefenamic Acid	Ponstel®
Meloxicam	Mobic®
Nabumetone	Relafen®
Naproxen	Naprosyn®, Anaprox®, Anaprox® DS, EC-Naprosyn®, Naprelan®, Naprapac® (co-packaged with lansoprazole), Treximet® (combined with sumatriptan succinate), Vimovo® (combined with esomeprazole magnesium)
Oxaprozin	Daypro®
Piroxicam	Feldene®
Sulindac	Clinoril®
Tolmetin	Tolectin®, Tolectin® DS, Tolectin® 600
*Vicoprofen® contains the same dose of ibuprofen as over-the-counter (OTC) NSAID, and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long-term continuous use may increase the risk of heart attack or stroke.

Diclofenac Sodium

Important: Use the dosing card that is inside the diclofenac sodium topical gel carton to correctly measure each dose. The dosing card is re-usable. Do not throw the dosing card away. Before you use diclofenac sodium topical gel for the first time, your healthcare provider or pharmacist should show you how to correctly measure your dose using the dosing card.

Read this Instructions for Use before you start using diclofenac sodium topical gel and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Your healthcare provider has prescribed diclofenac sodium topical gel to help relieve arthritis pain in some of your joints. Diclofenac sodium topical gel may be used to treat arthritis pain in the arms (hands, wrists, and elbows) and in the legs (feet, ankles, and knees). It is not known if diclofenac sodium topical gel is safe and effective if used on your spine, hips, or shoulders.

• Use diclofenac sodium topical gel exactly how your healthcare provider prescribes it for you. Do not apply diclofenac sodium topical gel anywhere other than where your healthcare provider tells you to.
• Do not use more than a total of 32 grams of diclofenac sodium topical gel each day. If you add up the amount of diclofenac sodium topical gel as directed by your healthcare provider, it should not be more than 32 grams in one day.

The dose for your hands, wrists, or elbows is 2 grams of diclofenac sodium topical gel each time you apply it.

• Apply diclofenac sodium topical gel 4 times a day (a total of 8 grams each day). Do not apply more than 8 grams each day to any one of your affected hands, wrists, or elbows.

The dose for your feet, ankles, or knees is 4 grams of diclofenac sodium topical gel each time you apply it.

• Apply diclofenac sodium topical gel 4 times a day (a total of 16 grams each day). Do not apply more than 16 grams each day to any one of your affected feet, ankles, or knees.

Some examples of diclofenac sodium topical gel application include:

• If you use 2 grams of diclofenac sodium topical gel on one hand, 4 times a day, your total dose for one day is 8 grams.
• If you use 4 grams of diclofenac sodium topical gel on one knee, 4 times a day, your total dose for one day is 16 grams.
• Your total dose for one day, treating one hand and one knee, is 8 grams plus 16 grams, which equals 24 grams of diclofenac sodium topical gel.


Dosing Card (Image 02)

Figure A

• Before you use a new tube of diclofenac sodium topical gel for the first time, open the foil seal that covers the tube opening by using the spiked top of the cap. Remember to remove the dosing card from the carton to measure your dose (see Figure A).
• Apply diclofenac sodium topical gel to clean, dry skin that does not have any cuts, open wounds, infections, or rashes. 
• Do not use heating pads or apply bandages to where you have applied diclofenac sodium topical gel.
• Avoid exposing skin where you apply diclofenac sodium topical gel to sunlight and artificial light, such as tanning booths.
• Do not use sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other topical medicines on the same skin areas where you have applied diclofenac sodium topical gel.  
• Do not get diclofenac sodium topical gel in your eyes, nose, or mouth. Diclofenac sodium topical gel is only to be used on your skin (topical use). If you get diclofenac sodium topical gel in your eyes, rinse your eyes right away with water or saline. Talk with your healthcare provider if eye irritation lasts for more than one hour.

What if I miss a dose?

• If you miss a dose of diclofenac sodium topical gel, continue with your next scheduled dose using the prescribed amount of diclofenac sodium topical gel. Do not double the dose.   

Applying 2 grams (2 g) of diclofenac sodium topical gel to hands, wrists, or elbows:

Step 1. Remove the dosing card that is attached inside the diclofenac sodium topical gel carton. Use the dosing card to correctly measure each dose of diclofenac sodium topical gel. To measure the correct amount of diclofenac sodium topical gel, place the dosing card on a flat surface so that you can read the print. If the print is backwards, flip dosing card over (see Figure A). If you lose or misplace your dosing card, you can ask your pharmacist for a new one or call 1-800-398-5876. Ask your healthcare provider or pharmacist to show you how to correctly measure your dose of diclofenac sodium topical gel while you are waiting to receive your new dosing card.

Step 2. Squeeze diclofenac sodium topical gel onto the dosing card evenly, up to the 2 g line (a 2.25 inch length of gel). Make sure that the gel covers the 2 g area of the dosing card (see Figure B). Put the cap back on the tube of diclofenac sodium topical gel. Ask your healthcare provider or pharmacist if you are not sure how to correctly measure your dose of diclofenac sodium topical gel.

Step 3. Apply the gel to your hand, wrist, or elbow. You can use the dosing card to apply the gel (see Figure C). Then, use your hands to gently rub the gel into the skin (see Figure D). Do not share your dosing card with another person. Make sure to cover the entire affected hand, wrist, or elbow with the gel. Remember that the hand includes the palm of your hand, the top of your hand, and your fingers.

Step 4. After using the dosing card, hold end with fingertips, rinse and dry. Store the dosing card until next use. Do not shower or bathe for at least 1 hour after applying diclofenac sodium topical gel. Do not wash your treated hands for at least 1 hour after applying the diclofenac sodium topical gel.

Step 5. After applying diclofenac sodium topical gel, wait 10 minutes before covering the treated skin with gloves or clothing.



Figures B To D (Image 03)

Applying 4 grams (4 g) of diclofenac sodium topical gel to feet, ankles, or knees:

•  Step 1. Refer to Step 1 above.

Step 2. Squeeze diclofenac sodium topical gel onto the dosing card evenly up to the 4 g line (a 4.5 inch length of gel), making sure the gel covers the 4 g area of the dosing card (see Figure E). Put the cap back on the tube of diclofenac sodium topical gel. Ask your healthcare provider or pharmacist if you are not sure how to correctly measure your dose of diclofenac sodium topical gel.

Step 3. Apply diclofenac sodium topical gel to your foot, ankle, or knee. You can use the dosing card to apply the gel (see Figure F). Then, use your hands to gently rub the gel into the skin (see Figure G). Do not share your dosing card with another person. Make sure to cover your entire foot, ankle, or knee area with the gel. For example, cover the skin above, below, inside and outside the knee cap. Remember that the foot includes the sole of your foot, the top of your foot, and your toes.

Refer to Steps 4 and 5 above. Wash your hands after applying diclofenac sodium topical gel to your foot, ankle, or knee.



Figures E To G (Image 04)

What are the ingredients in diclofenac sodium topical gel?
Active ingredient: diclofenac sodium

Inactive ingredients: carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution.

How should I store diclofenac sodium topical gel? Store at 20°C to 25°C (68°F to 77°F). Do not freeze diclofenac sodium topical gel. Store the dosing card with your diclofenac sodium topical gel.

Keep diclofenac sodium topical gel, the dosing card, and all medicines out of the reach of children.

This Medication Guide and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Marketed by:

Par Pharmaceutical

Chestnut Ridge, NY 10977

Manufactured by:

Novartis Pharma Produktions GmbH

Wehr, Germany

Relabeled by:

Proficient Rx LP

Thousand Oaks, CA 91320

Revised: February 2016

See Medication Guide and Patient Instructions Inside of Carton

NDC 63187-753-00

Diclofenac Sodium Topical Gel 1%

For Topical Use Only

Rx only

Net Wt 100 g

Use the Dosing Card Attached Inside Carton

63187-753-00 (Image 05)