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The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Cardiovascular Thrombotic Events [see WARNINGS AND PRECAUTIONS]
- GI Bleeding, Ulceration and Perforation [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Heart Failure and Edema [see WARNINGS AND PRECAUTIONS]
- Renal Toxicity and Hyperkalemia [see WARNINGS AND PRECAUTIONS]
- Anaphylactic Reactions [see WARNINGS AND PRECAUTIONS]
- Serious Skin Reactions [see WARNINGS AND PRECAUTIONS]
- Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]
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 PENNSAID of 130 patients treated for 4 weeks (mean duration of 28 days) in one Phase 2 controlled trial. This population'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 PENNSAID 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 PENNSAID, where the rate in the PENNSAID 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 PENNSAID and More Often than in
Subjects with OA Using Vehicle Control (Pooled)
|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%)|
The safety of PENNSAID 2% is based in part, on prior experience with PENNSAID 1.5%. The data described below reflect exposure to PENNSAID 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 PENNSAID 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 PENNSAID 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 PENNSAID 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 PENNSAID 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 PENNSAID 1.5%, where the rate in the PENNSAID 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 PENNSAID 1.5% Topical Solution
in Placebo and Oral Diclofenac-Controlled Trials
|Treatment Group:||PENNSAID 1.5%
|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)|
|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)|
In postmarketing surveillance, the following adverse reactions have been reported during post- approval use of PENNSAID 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.
Cardiovascular: palpitation, cardiovascular disorder
Metabolic and Nutritional: creatinine increased
Musculoskeletal: leg cramps, myalgia
Nervous: depression, dizziness, drowsiness, lethargy, paresthesia at application site
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
Read the PENNSAID (diclofenac sodium topical solution) Side Effects Center for a complete guide to possible side effects
See Table 3 for clinically significant drug interactions with diclofenac.
Table 3: Clinically
Significant Drug Interactions with Diclofenac
|Drugs That Interfere with Hemostasis|
|Intervention:||Monitor patients with concomitant use of PENNSAID 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]|
|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 AND PRECAUTIONS]|
|Intervention:||Concomitant use of PENNSAID and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS]. PENNSAID is not a substitute for low dose aspirin for cardiovascular protection.|
|ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers|
|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 PENNSAID with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS].|
|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 PENNSAID and digoxin, monitor serum digoxin levels.|
|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 PENNSAID and lithium, monitor patients for signs of lithium toxicity.|
|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 PENNSAID and methotrexate, monitor patients for methotrexate toxicity.|
|Clinical Impact:||Concomitant use of PENNSAID and cyclosporine may increase cyclosporine’s nephrotoxicity.|
|Intervention:||During concomitant use of PENNSAID 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 AND PRECAUTIONS]
Concomitant use of oral NSAIDs with PENNSAID 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 PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
|Clinical Impact:||Concomitant use of PENNSAID and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).|
|Intervention:||During concomitant use of PENNSAID 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.
Read the PENNSAID Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 5/23/2016
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