Diclofenac Sodium

• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. [

  see

  5.1 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, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

  
  
  

  To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [

  see Warnings and Precautions (5.2)

  ].

  
  
  

  Status Post Coronary Artery Bypass Graft (CABG) Surgery

  
  
  

  Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [

  see Contraindications (4)

  ].

  
  
  

  Post-MI Patients

  
  
  

  Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

  
  
  

  Avoid the use of diclofenac sodium topical solution in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium topical solution is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

  ].
• Diclofenac sodium topical solution i
  s contraindicated in the setting of coronary artery bypass graft (CABG) surgery [

  see 

  4. CONTRAINDICATIONS

  Diclofenac sodium topical solution

  is contraindicated in the following patients:

  • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [
    see Warnings and Precautions (5.7, 5.9)
    ]
  • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [
    see Warnings and Precautions (5.7, 5.8)
    ]
  • In the setting of coronary artery bypass graft (CABG) surgery [
    see Warnings and Precautions (5.1)
    ]

  • Known hypersensitivity to diclofenac or any components of the drug product. (4)
  • History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. (4)
  • In the setting of coronary artery bypass graft (CABG) surgery. (4)

   and

  5.1 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, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

  
  
  

  To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [

  see Warnings and Precautions (5.2)

  ].

  
  
  

  Status Post Coronary Artery Bypass Graft (CABG) Surgery

  
  
  

  Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [

  see Contraindications (4)

  ].

  
  
  

  Post-MI Patients

  
  
  

  Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

  
  
  

  Avoid the use of diclofenac sodium topical solution in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium topical solution is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

  ].

• NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [

  see

  5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

  NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

  
  
  

  Risk Factors for GI Bleeding, Ulceration, and Perforation

  
  
  

  Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

  
  
  

  Strategies to Minimize the GI Risks in NSAID-treated patients:

  
  
  

  • Use the lowest effective dosage for the shortest possible duration.
  • Avoid administration of more than one NSAID at a time.
  • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
  • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
  • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac sodium topical solution until a serious GI adverse event is ruled out.
  • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [
    see
    Drug Interactions (7)
    ].

  ].

Warnings and Precautions (

Diclofenac sodium topical solution is indicated for the treatment of the pain of osteoarthritis of the knee(s).

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

The recommended dose is 2 pump actuations on each painful knee, 2 times a day. 

• Apply diclofenac sodium topical solution, to clean, dry skin. 
  2.1 General Dosing Instructions

  Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [

  see Warnings and Precautions (5.2)

  ].

  
  
  

  For relief of the pain of osteoarthritis (OA) of the knee(s), the recommended dose is 40 mg of diclofenac sodium (2 pump actuations) on each painful knee, 2 times a day.

  
  
  

  Apply diclofenac sodium topical solution to clean, dry skin.

  
  
  

  The pump must be primed before first use. Instruct patients to fully depress the pump mechanism (actuation) 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle should be required.

  
  
  

  After the priming procedure, diclofenac sodium topical solution is properly dispensed by completely depressing the pump 2 times to achieve the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and then apply evenly around front, back, and sides of the knee.

  
  
  

  Application of diclofenac sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.

  
  
  
• Dispense 40 mg (2 pump actuations) directly onto the knee or first into the hand and then onto the knee. Spread evenly around front, back and sides of the knee. 
  2.1 General Dosing Instructions

  Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [

  see Warnings and Precautions (5.2)

  ].

  
  
  

  For relief of the pain of osteoarthritis (OA) of the knee(s), the recommended dose is 40 mg of diclofenac sodium (2 pump actuations) on each painful knee, 2 times a day.

  
  
  

  Apply diclofenac sodium topical solution to clean, dry skin.

  
  
  

  The pump must be primed before first use. Instruct patients to fully depress the pump mechanism (actuation) 4 times while holding the bottle in an upright position. This portion should be discarded to ensure proper priming of the pump. No further priming of the bottle should be required.

  
  
  

  After the priming procedure, diclofenac sodium topical solution is properly dispensed by completely depressing the pump 2 times to achieve the prescribed dosage for one knee. Deliver the product directly into the palm of the hand and then apply evenly around front, back, and sides of the knee.

  
  
  

  Application of diclofenac sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended.

  
  
  
• Wash hands completely after administering the product. 
  2.2 Special Precautions

  
  
  

  • Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee.
  • Wash and dry hands after use.
  • Do not apply diclofenac sodium topical solution to open wounds.
  • Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes.
  • Do not apply external heat and/or occlusive dressings to treated knees.
  • Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry.
  • Protect the treated knee(s) from natural and artificial sunlight.
  • Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution.
  • Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s).
  • Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
• Wait until the area is completely dry before covering with clothing or applying sunscreen, insect repellent, cosmetics, topical medications, or other substances. 
  2.2 Special Precautions

  
  
  

  • Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee.
  • Wash and dry hands after use.
  • Do not apply diclofenac sodium topical solution to open wounds.
  • Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes.
  • Do not apply external heat and/or occlusive dressings to treated knees.
  • Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry.
  • Protect the treated knee(s) from natural and artificial sunlight.
  • Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution.
  • Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s).
  • Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
• Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). 
  2.2 Special Precautions

  
  
  

  • Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee.
  • Wash and dry hands after use.
  • Do not apply diclofenac sodium topical solution to open wounds.
  • Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes.
  • Do not apply external heat and/or occlusive dressings to treated knees.
  • Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry.
  • Protect the treated knee(s) from natural and artificial sunlight.
  • Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution.
  • Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s).
  • Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
• Do not get diclofenac sodium topical solution in your eyes, nose, or mouth
  2.2 Special Precautions

  
  
  

  • Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee.
  • Wash and dry hands after use.
  • Do not apply diclofenac sodium topical solution to open wounds.
  • Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes.
  • Do not apply external heat and/or occlusive dressings to treated knees.
  • Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry.
  • Protect the treated knee(s) from natural and artificial sunlight.
  • Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution.
  • Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s).
  • Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
  .

Diclofenac sodium topical solution, USP: 2% w/w

• Infertility
  : NSAIDs are associated with reversible infertility. Consider withdrawal of diclofenac sodium topical solution in women who have difficulties conceiving.
  8.3 Females and Males of Reproductive Potential

  Infertility

  
  
  

  Females

  Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac sodium topical solution, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium topical solution, in women who have difficulties conceiving or who are undergoing investigation of infertility.
  
  

  
  
  Males
  
  

  
  
  Published studies in adult male rodents report that diclofenac, at clinically relevant doses, can produce adverse effects on male reproductive tissues. The impact of these findings on male fertility is not clear

  [See Nonclinical Toxicology (13.1)].