DiMentho (Page 2 of 5)

6. Adverse 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 (5.11)]

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.

The data described below reflect exposure to diclofenac sodium topical solution 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 Caucasians, 64% 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 studies.

Application Site Reactions

In controlled trials, the most common treatment-related adverse events in patients receiving diclofenac sodium topical solution were application site skin reactions. 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 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%.

Adverse Events Common to the NSAID Class

In controlled trials, subjects treated with diclofenac sodium topical solution 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 1). The combination of diclofenac sodium topical solution 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 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 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 1: Adverse reactions occurring in 1% of patients treated with Diclofenac Sodium Topical Solution in placebo and oral diclofenac-controlled trials.
Treatment Group: Diclofenac SodiumTopical Solution

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)
*Preferred Term according to COSTART

6.2 Post-marketing Experience

In non-U.S. post-marketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium topical solution. 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 reaction, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, lack of drug effect, neck rigidity, pain

Cardiovascular: palpitation, cardiovascular disorder

Digestive: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis

Metabolic and Nutritional: creatinine increased

Musculoskeletal: leg cramps, myalgia

Nervous: depression, dizziness, drowsiness, lethargy, paresthesia, paresthesia at application site

Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis

Skin and Appendages: At the Application Site: contact dermatitis, contact dermatitis with vesicles, dry skin, pruritus, rash; Other Skin and Appendages

Adverse Reactions: eczema, rash, pruritus, skin discoloration, urticaria

Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion

7. Drug Interactions

See Table 2 for clinically significant drug interactions with diclofenac.

Table 2: Clinically Significant Drug Interactions with Diclofenac
Drugs Tat 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 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 and Precautions (5.11) ]
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 NSAID alone [see Warnings and Precautions (5.2) ]
Intervention: Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].Diclofenac Sodium is 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 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 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 and Precautions (5.6)]
  • 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 with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin.
Intervention: During concomitant use of diclofenac sodium 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 and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of diclofenac sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact: Concomitant use of diclofenac sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention: During concomitant use of diclofenac sodium and cyclosporine, monitor patients for signs or 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 and Precautions (5.2)]. Concomitant use of oral NSAIDs with diclofenac sodium has been evaluated in one Phase 3 controlled trial and in combination with 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%).

Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory

evaluations.

Pemetrexed
Clinical Impact: Concomitant use of diclofenac sodium 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 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 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.

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