Diclofenac is one of the most frequently used drug substances worldwide. Products containing this active ingredient have been on the market since 1974 (originally launched in Japan) and today are available in nearly 120 countries worldwide for treatment of rheumatic and nonrheumatic disorders. A topical formulation (Voltaren® Emulgel) has been approved for the first time in Germany in 1986.
The low systemic bioavailability of diclofenac following percutaneous application of Diclofenac sodium 4% Spray Gel (DicloFlex®) reduces the high risk of adverse drug reactions known for peroral administration of diclofenac. This is supported by the safety data from the clinical trials as well as from the collected data in the marked.
Furthermore the side-effect profile of Diclofenac following per oral and cutaneous administration is well known and described in numerous monographs. For Diclofenac sodium 4% Spray Gel (DicloFlex®) the side-effect profile established in preclinical and clinical trials is in full accordance with published data for topical administration.
The identical topical Diclofenac formulation as Diclofenac sodium 4% Spray Gel (DicloFlex®) has been marketed in Italy under the trade names Dolaut® and Topfans® since 1999 and 2001.
In several preclinical and clinical trials it has been proven that Diclofenac sodium 4% Spray Gel (DicloFlex®) due to his extraordinary low systemic availability has placebo-like-side-effects and permeates fast through the skin.
NSAID’s like Diclofenac are known for their severe systemic side effects and are responsible for approximately one-quarter of all adverse drug reaction reports (30). Most common among these side effects are the gastropathic ones like gastric ulcers, gastric bleeding, and gastrointestinal perforations (30).
ObjectivesObjective was to compare the effects of Diclofenac sodium 4% Spray Gel (DicloFlex®) 40 mg 3 times daily with oral CELECOXIB 200 mg q. d. and PLACEBO on gastric prostaglandin synthesis, whole blood COX-1- and COX-2 activity and acute gastro-duodenal injury in humans. NAPROXEN 500 mg b.i.d. was included as a positive control.
Methods51 healthy subjects were randomised into this double-blind, 3-way crossover study. 39 completed 15-day treatment with either Diclofenac sodium 4% Spray Gel (DicloFlex®), CELECOXIB and PLACEBO (n=26) or NAPROXEN, CELECOXIB and PLACEBO (n=13). Gastro-duodenal injury was assessed endoscopically at baseline and 90 min after the final treatment dose when mucosal biopsy samples were taken for vortex-stimulated PGE2 synthesis, measured by enzyme immunoassay. Whole blood COX-1/COX-2 activity was assessed at baseline and the end of the study by measuring ex vivo platelet thromboxane (TX) B2 and lipopolysaccharide stimulated PGE2, assayed similarly.
ResultsDiclofenac sodium 4% Spray Gel (DicloFlex®) had no effect on Gastric mucosal prostaglandin synthesis compared to PLACEBO (Table 1), whilst both NAPROXEN and CELECOXIB significantly reduced it. NAPROXEN significantly inhibited both COX-1 and COX-2 activity in blood, and CELECOXIB inhibited COX-2. Diclofenac sodium 4% Spray Gel (DicloFlex®) did not inhibit either COX-1 or COX-2. NAPROXEN significantly increased the number of gastric erosions compared to placebo, but neither Diclofenac sodium 4% Spray Gel (DicloFlex®) nor CELECOXIB had a significant effect.
Goal of this study was to examine the tolerability of Diclofenac sodium 4% Spray Gel (DicloFlex®) on the skin after long term topical administration by regular use (28 days).
MethodsIn a single center, open, repeated-dose, maximum use tolerance study 62 healthy volunteers entered the trial (17). Diclofenac sodium 4% Spray Gel (DicloFlex®) was administered (5 sprays/application) to one knee 4 times per day for a period of 28 consecutive days. The intervals of application were approximately 6 hours. All adverse events were recorded beginning from the time the volunteer first received Diclofenac sodium 4% Spray Gel (DicloFlex®). At day 7, day 14, day 21 and day 28 of application, a trained dermatological assessor examined the application area of all volunteers and indicated on the case report form if any application site reaction was present. Subjects who reported a side effect or were observed to have an application site reaction were assessed to determine suitability to continue with the study.
ResultsOf the 62 healthy volunteers 2 were discontinued from the study on day 22 due to significant application site reactions. The number of volunteers with application site reactions discovered by the skin assessor were 3 (5%) on day 7, 13 (21%) on day 8, 19 (31%) on day 22, and 17 (27%) on day 28. In addition, 11 subjects (18%) reported one or more application site reactions. The most frequently reported symptoms are listed in Table 1. All reports were mild. One male volunteer suffered from a serious adverse event that was considered unrelated to study medication. On day 28 of the study he collapsed due to breathlessness and was taken to the hospital where he was treated with salbutamol and released from the hospital. He was diagnosed with bronchospasm and suffered from an upper respiratory tract infection.
There is no evidence from pharmacovigilance data , which raises safety concerns regarding the use of Diclofenac sodium 4% Spray Gel (DicloFlex®) Given the demonstrated low systemic bioavailability compared to oral preparations and appraising the safety data of about five years use in Italy a positive risk-to benefit assessment can be drawn for Diclofenac sodium 4% Spray Gel (DicloFlex®).