DICLOFENAC: 86,819 Adverse Event Reports & Safety Profile

Diclofenac sodium and misoprostol delayed-release tablets, USP is a combination product containing diclofenac sodium, an NSAID with analgesic properties, and misoprostol, a gastrointestinal (GI) mucosal protective prostaglandin-1 (PGE1) analog. Diclofenac sodium and misoprostol delayed-release tablets are white to off-white, round, biconvex, and approximately 11 mm in diameter. Each tablet consists of an enteric-coated core containing 50 mg (diclofenac sodium and misoprostol delayed-release tablets 50 mg/200 mcg) or 75 mg (diclofenac sodium and misoprostol delayed-release tablets 75 mg/200 mcg) of diclofenac sodium (equivalent to 46.39 mg or 69.58 mg of diclofenac, respectively) surrounded by an outer mantle containing 200 mcg misoprostol. Diclofenac sodium, USP is a phenylacetic acid derivative that is a white to off-white, virtually odorless, crystalline powder. Diclofenac sodium, USP is freely soluble in methanol, soluble in ethanol, and practically insoluble in chloroform and in dilute acid. Diclofenac sodium, USP is sparingly soluble in water. Its chemical formula and name are: C 14 H 10 Cl 2 NO 2 Na [M.W. = 318.14] 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt. Misoprostol is a water-soluble, viscous liquid that contains approximately equal amounts of two diastereomers. Its chemical formula and name are: C 22 H 38 O 5 [M.W. = 382.54] (±) methyl 11α,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate. Inactive ingredients in diclofenac sodium and misoprostol delayed-release tablets include: colloidal silicon dioxide; corn starch; crospovidone; hydrogenated castor oil; hypromellose; lactose monohydrate; magnesium stearate; methacrylic acid copolymer; microcrystalline cellulose; povidone; sodium hydroxide; talc; triethyl citrate. FDA approved dissolution test specifications differ from USP

AND USAGE Diclofenac sodium is a non-steroidal anti-inflammatory drug indicated for the relief of the pain of osteoarthritis of joints amenable to topical treatment, such as the knees and those of the hands. ( 1 ) Diclofenac sodium topical gel was not evaluated for use on joints of the spine, hip, or shoulder. ( 14.1 ) 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.

Instructions For Use

Diclofenac Sodium Topical Gel, 1% 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. 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. 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 1-866-604-3268. 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.

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. What are the ingredients in diclofenac sodium topical gel? Active ingredient: diclofenac sodium, USP 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); excursions permitted between 15°C to 30°C (59°F to 86°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. Manufactured by: Cipla Ltd.

Verna

Goa, India Manufactured for: Cipla USA, Inc. 10 Independence Boulevard, Suite 300 Warren NJ 07059 Revised: 10/2020 image description image description

AND ADMINISTRATION

• Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 )
• Osteoarthritis: The recommended dosage for maximal GI protection is one tablet (containing 50 mg of diclofenac and 200 mcg of misoprostol) three times daily. A dosage of diclofenac higher than 150 mg/day is not recommended. ( 2.2 )
• Rheumatoid Arthritis: The recommended dosage for maximal GI protection is one tablet (containing 50 mg of diclofenac and 200 mcg of misoprostol) three or four times daily. A dosage of diclofenac higher than 200 mg/day is not recommended. ( 2.3 )
• For dosage modifications due to intolerance, see the full Prescribing Information. ( 2.2 , 2.3 )

2.1 Important Dosage Information Carefully consider the potential benefits and risks of diclofenac sodium and misoprostol delayed-release tablets and other treatment options before deciding to use diclofenac sodium and misoprostol delayed-release tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span> . After observing the response to initial therapy with diclofenac sodium and misoprostol delayed-release tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. Diclofenac sodium and misoprostol delayed-release tablets are not recommended for patients who would not receive the appropriate dosage of both active ingredients. Diclofenac sodium and misoprostol delayed-release tablets, fixed combination products, are administered as Diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg (50 mg diclofenac sodium and 200 mcg misoprostol) or Diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg (75 mg diclofenac sodium and 200 mcg misoprostol).

2.2 Recommended Dosage in Patients with Osteoarthritis The recommended dosage for the treatment of osteoarthritis for maximal GI mucosal protection is diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg three times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg two times a day can be used, but these dosages are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 150 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows: Osteoarthritis Regimen Diclofenac sodium (mg/day) Misoprostol (mcg/day) Diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg three times a day 150 600 two times a day * 100 400 Diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day * 150 400 * Fo r patients who experience intolerance; these dosages are less effective in preventing ulcers .

2.3 Recommended Dosage in Patients with Rheumatoid Arthritis The recommended dosage for the treatment of rheumatoid arthritis is diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg three or four times a day. For patients who experience intolerance, diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day or diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg two times a day can be used, but are less effective in preventing ulcers. A daily dosage of diclofenac sodium greater than 200 mg/day is not recommended. Daily doses of the components delivered with these regimens are as follows: Rheumatoid Arthritis Regimen Diclofenac sodium (mg/day) Misoprostol (mcg/day) Diclofenac sodium and misoprostol delayed-release tablets, 50 mg/200 mcg four times a day 200 800 three times a day 150 600 two times a day * 100 400 Diclofenac sodium and misoprostol delayed-release tablets, 75 mg/200 mcg two times a day * 150 400 * F or patients who experience intolerance; these dosages are less effective in preventing ulcers

2.4 Additional Dosage Recommendations Diclofenac sodium and misoprostol delayed-release tablets contain misoprostol, which provides protection against gastric and duodenal ulcers <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . For gastric ulcer prevention, the 200 mcg four and three times a day regimens are therapeutically equivalent, but more protective than the two times a day regimen. For duodenal ulcer prevention, the four times a day regimen is more protective than the three or two times a day regimens. However, the four times a day regimen is less well tolerated than the three times a day regimen because of usually self-limited diarrhea related to the misoprostol dose <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , and the two times a day regimen may be better tolerated than three times a day in some patients. Dosages may be individualized using the separate products (misoprostol and diclofenac sodium), after which the patient may be switched to the appropriate diclofenac sodium and misoprostol delayed-release tablets dosage. If clinically indicated, misoprostol co-therapy with diclofenac sodium and misoprostol delayed-release tablets to optimize the misoprostol dose and/or frequency of administration, may be appropriate. Do not exceed a total misoprostol dose of 800 mcg/day, and do not administer more than 200 mcg of misoprostol at any one time. When concomitant use of CYP2C9 inhibitors is necessary, the maximum total daily dose of diclofenac is 100 mg per day. Do not exceed a dosage of diclofenac sodium and misoprostol delayed-release tablets 50 mg twice daily <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . For additional information, refer to the Prescribing Information for the individual products of diclofenac sodium and misoprostol.

Diclofenac sodium and misoprostol delayed-release tablets are contraindicated in the following patients:

• Pregnancy. Use of misoprostol, a component of diclofenac sodium and misoprostol delayed-release tablets, during pregnancy can result in maternal and fetal harm, including uterine rupture, abortion, premature birth, or birth defects [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )]
• In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions ( 5.2 )]
• Active gastrointestinal bleeding [see Warnings and Precautions ( 5.3 )]
• 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 ( 5.8 , 5.9 )]
• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium and misoprostol, other prostaglandins, or any components of the drug product [see Warnings and Precautions ( 5.8 , 5.10 )]
• Pregnancy ( 4 )
• In the setting of CABG surgery ( 4 )
• Active gastrointestinal bleeding ( 4 )
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 )
• Known hypersensitivity to diclofenac sodium, misoprostol, or any components of the drug product ( 4 )

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.2 ) ] Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] Hypertension [ see Warnings and Precautions ( 5.4 ) ]

Heart

Failure and Edema [ see Warnings and Precautions ( 5.5 ) ]

Renal

Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ]

Anaphylactic

Reactions [ see Warnings and Precautions ( 5.7 ) ]

Serious Skin

Reactions [ see Warnings and Precautions ( 5.9 ) ]

Hematologic

Toxicity [See Warnings and Precautions( 5.12 )] The most common adverse reactions with diclofenac sodium topical solution are application site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Diclofenac sodium topical solution The data described below reflect exposure to diclofenac sodium topical solution of 130 patients treated for 4 weeks (mean duration of 28 days) in one Phase 2 controlled trial. This population&apos;s mean age was approximately 60 years, 85% of patients were Caucasian, 65% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution were application site skin reactions. These events were the most common reason for withdrawing from the study.

Application Site

Reactions: In this controlled trial, application site reactions were characterized by one or more of the following: dryness (22%), exfoliation (7%), erythema (4%), pruritus (2%), pain (2%), induration (2%), rash (2%), and scabbing (<1%).

Other Common Adverse

Reactions: Table 1 lists all adverse reactions occurring in >1% of patients receiving diclofenac sodium topical solution, where the rate in the diclofenac sodium topical solution group exceeded vehicle, from a controlled study conducted in patients with osteoarthritis.

Table

1: Incidence of Adverse Reactions Occurring in >1% of Subjects with Osteoarthritis Using Diclofenac Sodium Topical Solution and More Often than in Subjects with OA Using Vehicle Control (Pooled)

Adverse Reaction Diclofenac Sodium Topical

Solution N=130 n (%)

Vehicle

Control N=129 n (%) Urinary tract infection 4 (3%) 1 (<1%) Application site induration 2 (2%) 1 (<1%)

Contusion

2 (2%) 1 (<1%) Sinus congestion 2 (2%) 1 (<1%)

Nausea

2 (2%) 0 Diclofenac Sodium Topical Solution 1.5% The safety of diclofenac sodium topical solution 2% is based in part, on prior experience with diclofenac sodium topical solution 1.5%. The data described below reflect exposure to diclofenac sodium topical solution 1.5% of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasian, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution 1.5% were application site skin reactions. These events were the most common reason for withdrawing from the studies.

Application Site

Reactions: In controlled trials, application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of diclofenac sodium topical solution 1.5% and oral diclofenac. In the open-label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%.

Other Common Adverse

Reactions: In controlled trials, subjects treated with diclofenac sodium topical solution 1.5% experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 2). The combination of diclofenac sodium topical solution 1.5% and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases.

Table

2 lists all adverse reactions occurring in ≥1% of patients receiving diclofenac sodium topical solution 1.5%, where the rate in the diclofenac sodium topical solution 1.5% group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence.

Table

2: Adverse Reactions Occurring in ≥1% of Patients Treated with Diclofenac Sodium Topical 1.5% Solution inPlacebo and Oral Diclofenac-Controlled Trials Treatment Group: Diclofenac Sodium Topical Solution 1.5% N=911 Topical Placebo N=332 Adverse Reaction N (%) N (%)

Dry

Skin (Application Site) 292 (32) 17 (5)

Contact

Dermatitis (Application Site) 83 (9) 6 (2)

Dyspepsia

72 (8) 13 (4)

Abdominal Pain

54 (6) 10 (3)

Flatulence

35 (4) 1 (<1) Pruritus (Application Site) 34 (4) 7 (2)

Diarrhea

33 (4) 7 (2)

Nausea

33 (4) 3 (1)

Pharyngitis

40 (4) 13 (4)

Constipation

29 (3) 1 (<1)

Edema

26 (3) 0 Rash (Non-Application Site) 25 (3) 5 (2)

Infection

25 (3) 8 (2)

Ecchymosis

19 (2) 1 (<1)

Dry

Skin (Non-Application Site) 19 (2) 1 (<1)

Contact

Dermatitis, vesicles (Application Site) 18 (2) 0 Paresthesia (Non-Application Site) 14 (2) 3 (<1)

Accidental Injury

22 (2) 7 (2) Pruritus (Non-Application Site) 15 (2) 2 (<1)

Sinusitis

10 (1) 2 (<1)

Halitosis

11 (1) 1(<1)

Application Site

Reaction (not otherwise specified) 11 (1) 3 (<1)

6.2 Postmarketing Experience In postmarketing surveillance, the following adverse reactions have been reported during post- approval use of diclofenac sodium topical solution 1.5%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: abdominal pain, accidental injury, allergic reactions, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, neck rigidity, pain Cardiovascular: palpitation, cardiovascular disorder Gastrointestinal: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, lip swelling, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis, swollen tongue Metabolic and Nutritional: creatinine increased Musculoskeletal: leg cramps, myalgia Nervous: depression, dizziness, drowsiness, lethargy, paresthesia at application site Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis, throat swelling Skin and Appendages: At the Application Site: rash, skin burning sensation; Other Skin and Appendages Adverse Reactions: eczema, skin discoloration, urticaria Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion Vascular: blood pressure increased, hypertension To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/mnedwatch

6.2 Postmarketing Experience In postmarketing surveillance, the following adverse reactions have been reported during post- approval use of diclofenac sodium topical solution 1.5%. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: abdominal pain, accidental injury, allergic reactions, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, neck rigidity, pain Cardiovascular: palpitation, cardiovascular disorder Gastrointestinal: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, lip swelling, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis, swollen tongue Metabolic and Nutritional: creatinine increased Musculoskeletal: leg cramps, myalgia Nervous: depression, dizziness, drowsiness, lethargy, paresthesia at application site Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis, throat swelling Skin and Appendages: At the Application Site: rash, skin burning sensation; Other Skin and Appendages Adverse Reactions: eczema, skin discoloration, urticaria Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion Vascular: blood pressure increased, hypertension To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/mnedwatch

AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 )

Heart

Failure and Edema: Avoid use of Diclofenac Potassium in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5)

Renal

Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of Diclofenac Potassium in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6)

Anaphylactic

Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: Diclofenac Potassium is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8)

Serious Skin

Reactions: Discontinue Diclofenac Potassium at first appearance of skin rash or other signs of hypersensitivity ( 5.9)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically ( 5.10 ).

Fetal

Toxicity: Limit use of NSAIDs, including Diclofenac Potassium, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ).

Hematologic

Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

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 10-14 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 Potassium in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If Diclofenac

Potassium is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

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 3-6 months, and in about 2%-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 Potassium 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 )].

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 3-6 months, and in about 2%-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 Potassium 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 )].

5.3 Hepatotoxicity In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium 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 the 3,700 patients and included marked elevations (greater 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 (greater than 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 NSAID 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. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female sex, doses of 150 mg or more, and duration of use for more then 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with Diclofenac Potassium, 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 Potassium should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and &quot;flu-like&quot; symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Diclofenac Potassium immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver-related event in patients treated with Diclofenac Potassium, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Diclofenac Potassium with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).

5.4 Hypertension NSAIDs, including Diclofenac Potassium, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Avoid the use of Diclofenac Potassium in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

If Diclofenac

Potassium is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6 Renal Toxicity and Hyperkalemia Renal Toxicity 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, 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 Potassium in patients with advanced renal disease. The renal effects of Diclofenac Potassium may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating Diclofenac Potassium. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Diclofenac Potassium <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Avoid the use of Diclofenac Potassium in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function.

If Diclofenac

Potassium is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions (5.8) ]</span>. Seek emergency help if an anaphylactic reaction occurs.

5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Diclofenac Potassium is contraindicated in patients with this form of aspirin sensitivity <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>.

When Diclofenac

Potassium is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Diclofenac Potassium at the first appearance of skin rash or any other sign of hypersensitivity.

Diclofenac

Potassium is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ].

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Diclofenac Potassium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue Diclofenac Potassium and evaluate the patient immediately.

5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including Diclofenac Potassium, in pregnant women at about 30 weeks gestation and later. NSAIDs, including Diclofenac Potassium, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs, including Diclofenac Potassium, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit Diclofenac Potassium use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Diclofenac Potassium treatment extends beyond 48 hours.

Discontinue Diclofenac

Potassium if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1) ].

5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Diclofenac Potassium has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including Diclofenac Potassium, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.13 Masking of Inflammation and Fever The pharmacological activity of Diclofenac Potassium in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2, 5.3 , 5.6 )]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

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 10-14 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 Potassium in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If Diclofenac

Potassium is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

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 3-6 months, and in about 2%-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 Potassium 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 )].

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 3-6 months, and in about 2%-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 Potassium 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 )].

5.3 Hepatotoxicity In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium 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 the 3,700 patients and included marked elevations (greater 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 (greater than 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 NSAID 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. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female sex, doses of 150 mg or more, and duration of use for more then 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with Diclofenac Potassium, 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 Potassium should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and &quot;flu-like&quot; symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Diclofenac Potassium immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver-related event in patients treated with Diclofenac Potassium, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Diclofenac Potassium with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics).

5.4 Hypertension NSAIDs, including Diclofenac Potassium, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Avoid the use of Diclofenac Potassium in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

If Diclofenac

Potassium is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6 Renal Toxicity and Hyperkalemia Renal Toxicity 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, 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 Potassium in patients with advanced renal disease. The renal effects of Diclofenac Potassium may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating Diclofenac Potassium. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Diclofenac Potassium <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>. Avoid the use of Diclofenac Potassium in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function.

If Diclofenac

Potassium is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma <span class="opacity-50 text-xs">[see Contraindications (4) and Warnings and Precautions (5.8) ]</span>. Seek emergency help if an anaphylactic reaction occurs.

5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Diclofenac Potassium is contraindicated in patients with this form of aspirin sensitivity <span class="opacity-50 text-xs">[see Contraindications (4) ]</span>.

When Diclofenac

Potassium is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Diclofenac Potassium at the first appearance of skin rash or any other sign of hypersensitivity.

Diclofenac

Potassium is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ].

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as Diclofenac Potassium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue Diclofenac Potassium and evaluate the patient immediately.

5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including Diclofenac Potassium, in pregnant women at about 30 weeks gestation and later. NSAIDs, including Diclofenac Potassium, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs, including Diclofenac Potassium, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit Diclofenac Potassium use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Diclofenac Potassium treatment extends beyond 48 hours.

Discontinue Diclofenac

Potassium if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1) ].

5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Diclofenac Potassium has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including Diclofenac Potassium, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.13 Masking of Inflammation and Fever The pharmacological activity of Diclofenac Potassium in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2, 5.3 , 5.6 )]</span>.

PRECAUTIONS General Diclofenac sodium delayed-release tablets, cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. The pharmacological activity of diclofenac sodium delayed-release tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium delayed-release tablets and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS: Cardiovascular Thrombotic Events ).

Gastrointestinal

Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac sodium delayed-release tablets and seek immediate medical therapy (see WARNINGS: Hepatotoxicity ).

Heart

Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS: Heart Failure and Edema ).

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see WARNINGS: Anaphylactic Reactions ).

Serious Skin

Reactions, including DRESS Advise patients to stop taking diclofenac sodium delayed-release tablets immediately if they develop any type of reaction or fever and to contact their healthcare provider as soon as possible [ see Warnings ].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium delayed-release tablets, may be associated with a reversible delay in ovulation (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility ).

Fetal Toxicity

Inform pregnant women to avoid use of diclofenac sodium delayed-release tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with diclofenac sodium delayed-release tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy ].

Avoid Concomitant

Use of NSAIDs Inform patients that the concomitant use of diclofenac sodium delayed-release tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation and Drug Interactions ). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium delayed-release tablets until they talk to their healthcare provider (see PRECAUTIONS: Drug Interactions ). Masking of Inflammation and Fever The pharmacological activity of diclofenac sodium delayed-release tablets in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation , and Hepatotoxicity ).

Drug Interactions See Table

2 for clinically significant drug interactions with diclofenac.

Table

2.

Clinically Significant Drug

Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact:

• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).

Aspirin Clinical

Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ). Intervention: Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.

Ace

Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact:

• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention:
• During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
• During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ).
• When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics Clinical

Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).

Digoxin Clinical

Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.

Lithium Clinical

Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.

Methotrexate Clinical

Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine Clinical

Impact: Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ). Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.

Pemetrexed Clinical

Impact: Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed- associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. CYP2C9 Inhibitors or Inducers: Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.1 times maximum recommended human dose (MRHD) of diclofenac sodium delayed-release tablets, 200 mg/day, based on body surface area (BSA) comparison ) have revealed no significant increases in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.007 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.02 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.

Mutagenesis

Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. Impairment of Fertility Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.2 times the MRHD based on BSA comparison) did not affect fertility. Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac sodium delayed-release tablets, 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 delayed-release tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pregnancy Risk Summary

Use of NSAIDs, including diclofenac sodium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium delayed-release tablets use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium delayed-release tablets use at about 30 weeks of gestation and later in pregnancy [ see WARNINGS; Fetal Toxicity ].

Premature

Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac sodium delayed-release tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0.5, 0.5, and 1 times, respectively, the maximum recommended human dose (MRHD) of diclofenac sodium delayed-release tablets, 200 mg/day, despite the presence of maternal and fetal toxicity at these doses [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus ( see WARNINGS; Fetal Toxicity ).

Oligohydramnios/Neonatal

Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium delayed-release tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium delayed-release tablets and follow up according to clinical practice ( see WARNINGS; Fetal Toxicity ).

Data Human Data Premature

Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.5 times the maximum recommended human dose [MRHD] of diclofenac sodium delayed-release tablets, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.5 and 1 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0.1 and 0.2 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans. Labor or Delivery There are no studies on the effects of diclofenac sodium delayed-release tablets during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Nursing Mothers Risk Summary

Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium delayed-release tablets and any potential adverse effects on the breastfed infant from the diclofenac sodium delayed-release tablets or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS: Cardiovascular Thrombotic Events , Gastrointestinal Bleeding, Ulceration, and Perforation , Hepatotoxicity , Renal Toxicity and Hyperkalemia , PRECAUTIONS: Laboratory Monitoring ). Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY , ADVERSE REACTIONS ).

General

Diclofenac sodium delayed-release tablets, cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. The pharmacological activity of diclofenac sodium delayed-release tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with diclofenac sodium delayed-release tablets and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see WARNINGS: Cardiovascular Thrombotic Events ).

Gastrointestinal

Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop diclofenac sodium delayed-release tablets and seek immediate medical therapy (see WARNINGS: Hepatotoxicity ).

Heart

Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS: Heart Failure and Edema ).

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur (see WARNINGS: Anaphylactic Reactions ).

Serious Skin

Reactions, including DRESS Advise patients to stop taking diclofenac sodium delayed-release tablets immediately if they develop any type of reaction or fever and to contact their healthcare provider as soon as possible [ see Warnings ].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including diclofenac sodium delayed-release tablets, may be associated with a reversible delay in ovulation (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility ).

Fetal Toxicity

Inform pregnant women to avoid use of diclofenac sodium delayed-release tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with diclofenac sodium delayed-release tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy ].

Avoid Concomitant

Use of NSAIDs Inform patients that the concomitant use of diclofenac sodium delayed-release tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation and Drug Interactions ). Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with diclofenac sodium delayed-release tablets until they talk to their healthcare provider (see PRECAUTIONS: Drug Interactions ).

Masking of Inflammation and Fever The pharmacological activity of diclofenac sodium delayed-release tablets in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation , and Hepatotoxicity ).

Drug Interactions Studies Voriconazole When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the C max and AUC of diclofenac increased by 114% and 78%, respectively (see PRECAUTIONS: Drug Interactions ).

Aspirin

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known.

See Table

2 for clinically significant drug interactions of NSAIDs with aspirin (see PRECAUTIONS: Drug Interactions ).

Drug Interactions See Table

2 for clinically significant drug interactions with diclofenac.

Table

2.

Clinically Significant Drug

Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of diclofenac potassium tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS : HEMATOLOGIC TOXICITY).

Aspirin Clinical

Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: GASTROINTESTINAL BLEEDING, ULCERATION, AND PERFORATION ). Intervention: Concomitant use of diclofenac potassium tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS : HEMATOLOGIC TOXICITY). Diclofenac potassium tablets are not a substitute for low dose aspirin for cardiovascular protection.

Ace

Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of diclofenac potassium tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac potassium tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: RENAL TOXICITY AND HYPERKALEMIA ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Diuretics Clinical

Impact: Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac potassium tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: RENAL TOXICITY AND HYPERKALEMIA ).

Digoxin Clinical

Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of diclofenac potassium tablets and digoxin, monitor serum digoxin levels.

Lithium Clinical

Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac potassium tablets and lithium, monitor patients for signs of lithium toxicity.

Methotrexate Clinical

Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of diclofenac potassium tablets and methotrexate, monitor patients for methotrexate toxicity.

Cyclosporine Clinical

Impact: Concomitant use of diclofenac potassium tablets and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of diclofenac potassium tablets and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: GASTROINTESTINAL BLEEDING, ULCERATION, AND PERFORATION ). Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.

Pemetrexed Clinical

Impact: Concomitant use of diclofenac potassium tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac potassium tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 mL/min to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. CYP2C9 Inhibitors or Inducers Clinical Impact: Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g., voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac. Intervention: A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: PHARMACOKINETICS ). Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.1 times the maximum recommended human dose (MRHD) of diclofenac potassium tablets, 200 mg/day, based on body surface area (BSA) comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.007 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.02 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.

Mutagenesis

Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. Impairment of Fertility Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.2 times the MRHD based on BSA comparison) did not affect fertility. Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including diclofenac potassium tablets, 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 potassium tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pregnancy Risk Summary

Use of NSAIDs, including diclofenac potassium tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac potassium tablets use between about 20 and 30 weeks of gestation, and avoid diclofenac potassium tablets use at about 30 weeks of gestation and later in pregnancy (see WARNINGS: Fetal Toxicity ).

Premature

Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac potassium tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. There are no adequate and well-controlled studies of diclofenac potassium tablets in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0.5, 0.5, and 1 times, respectively, the maximum recommended human dose (MRHD) of diclofenac potassium tablets, despite the presence of maternal and fetal toxicity at these doses (see Data) . Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as diclofenac, resulted in increased pre-and postimplantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac potassium tablets, can cause premature closure of the fetal ductus arteriosus (see WARNINGS: Fetal Toxicity ).

Oligohydramnios/Neonatal

Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac potassium tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac potassium tablets and follow up according to clinical practice (see WARNINGS: Fetal Toxicity ).

Data Human Data Premature

Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal

Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal Data

Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0.5 times the maximum recommended human dose [MRHD] of diclofenac potassium tablets, 200 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.5 and 1 times, respectively, the MRHD based on BSA comparison). In a study in which pregnant rats were orally administered 2 mg/kg or 4 mg/kg diclofenac (0.1 and 0.2 times the MRHD based on BSA) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans. Labor or Delivery There are no studies on the effects of diclofenac potassium tablets during labor or delivery. In animal studies, NSAIDs, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Nursing Mothers Risk Summary

Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for diclofenac potassium tablets and any potential adverse effects on the breastfed infant from the diclofenac potassium tablets or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see WARNINGS: Cardiovascular Thrombotic Events , Gastrointestinal Bleeding, Ulceration, and Perforation , Hepatotoxicity , Renal Toxicity and Hyperkalemia , PRECAUTIONS: Laboratory Monitoring ). Diclofenac is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY , ADVERSE REACTIONS ).

Active Ingredient (NSAID) - arthritis pain reliever Active ingredient Diclofenac sodium (NSAID*) 1% *nonsterodial anti-inflammatory drug

Inactive ingredients carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, strong ammonia solution Questions or comments? call 1-855-274-4122 Distributed By: Innovus Pharmaceuticals, Inc. 5740 Kietzke Lane #300 Reno, Nevada 89511 www.crclehealth.com Made in India Code: TS/DRUGS/58039/2020