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 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.
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