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Clinical Studies 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
|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
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
Drug interactions with the use of PENNSAID have not been studied. The following drug interactions [Sections 7.1 to 7.7] are noted for oral diclofenac sodium.
When diclofenac is administered with aspirin, the binding of diclofenac to protein is reduced, although the clearance of free diclofenac is not altered. The clinical significance of this interaction is not known; however, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects.
The effects of anticoagulants such as warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. The response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, observe the patient closely for signs of renal failure [see WARNINGS AND PRECAUTIONS], as well as to assure diuretic efficacy.
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs, including diclofenac, and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Monitor renal function when prescribing PENNSAID concomitantly with methotrexate.
Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac may increase cyclosporine's nephrotoxicity. Monitor renal function when prescribing PENNSAID concomitantly with cyclosporine.
Oral Nonsteroidal Anti-Inflammatory Drugs
Concomitant use of oral NSAIDs with PENNSAID 1.5% 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%). Therefore, do not use combination therapy with PENNSAID and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Instruct patients that before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same skin surface of the knee treated with PENNSAID they must wait until the treated area is completely dry.
Read the PENNSAID Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/30/2014
This monograph has been modified to include the generic and brand name in many instances.
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