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Mechanism Of Action
The mechanism of action of diclofenac is similar to that of other nonsteroidal anti-inflammatory drugs. Diclofenac inhibits the enzyme, cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in the reduced formation of prostaglandins, thromboxanes and prostacylin. It is not completely understood how reduced synthesis of these compounds results in therapeutic efficacy.
Diclofenac, the active component of PENNSAID has anti-inflammatory, anti-nociception, and antipyretic effects.
After administration of PENNSAID topical solution (40 mg/knee every 12 h; total daily diclofenac exposure: 80 mg/knee) for 7.5 days, the mean (SD) AUC0-12 and mean (SD) Cmax were 77.27 (49.89) ng•h/mL and 12.16 (7.66) ng/mL, respectively, on Day 1; and 204.58 (111.02) ng•h/mL and 25.24 (12.95) ng/mL, respectively, at steady state on Day 8. After administration of PENNSAID 1.5% topical solution (19.3 mg/knee every 6 h; total daily diclofenac exposure 77.2 mg/knee), the mean (SD) AUC0-12 and mean (SD) Cmax were 27.46 (23.97) ng•h/mL and 2.30 (2.02) ng/mL, respectively, on Day 1; and 141.49 (92.47) ng•h/mL and 17.04 (11.28) ng/mL, respectively, at steady state on Day 8.
The pharmacokinetics and effect of PENNSAID were not evaluated under the conditions of heat application, occlusive dressings overlay, or exercise following product application. Therefore, concurrent use of PENNSAID under these conditions is not recommended.
Diclofenac is more than 99% bound to human serum proteins, primarily to albumin.
Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.
Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy-and 3'-hydroxy-4'-methoxy diclofenac. The major diclofenac metabolite, 4'-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy and 3'-hydroxy-diclofenac.
Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites.
Little or no free unchanged diclofenac is excreted in the urine.
Pediatric: The pharmacokinetics of PENNSAID has not been investigated in pediatric patients.
Race: Pharmacokinetic differences due to race have not been studied.
Animal Toxicology And/Or Pharmacology
No adverse effects were observed using indirect ophthalmoscopy after multiple-daily dermal application to rats for 26 weeks and minipigs for 52 weeks of DMSO at twice the concentration found in PENNSAID. Published studies of dermal or oral administration of DMSO to rabbits, dogs and pigs described refractive changes of lens curvature and cortical fibers indicative of myopic changes and/or incidences of lens opacity or discoloration when evaluated using slit-lamp biomicroscopy examination, although no ocular abnormalities were observed in rhesus monkeys during daily oral or dermal treatment with DMSO for 9 to 18 months.
Study In Osteoarthritis Of The Knee
The use of PENNSAID for the treatment of pain of osteoarthritis of the knee was evaluated in a single double-blind controlled trial conducted in the US, involving patients treated with PENNSAID at a dose of 2 pumps twice a day for 4 weeks. PENNSAID was compared to topical vehicle, applied directly to the study knee. In this trial, patients treated with PENNSAID experienced a greater reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale compared to patients treated with vehicle. Numerical results of the WOMAC pain subscale are summarized in Table 4.
Table 4: Change in Treatment Outcomes after 4 Weeks of
Treatment with PENNSAID
|WOMAC Pain Subscale*|
|Mean Change from Baseline||-4.5||-3.6|
|*WOMAC pain subscale is based on the sum of pain scores for five items using a 5-point Likert scale.|
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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