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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 topical administration to healthy human volunteers of single and multiple maximum doses of PENNSAID, 40 drops (approximately 1.2 mL) to each knee (80 drops total dose), the following diclofenac pharmacokinetic parameters were obtained: (see Table 2).
Table 2: Single-Dose (80
drops) and Multiple Dose (80 drops four times daily for 7 days) PENNSAID
|Pharmacokinetic Parameters||Diclofenac sodium|
|Normal Adults [N=18]
(Age: 18-55 years)
|Normal Adults [N=19]
(Age: 18-55 years)
|Single Dose||Multiple Dose Four times daily for 7 days|
|AUC0-t||177.5 ± 72.6 ng.h/mL||695.4 ± 348.9 ng.h/mL|
|AUC0-inf||196.3 ± 68.5 ng.h/mL||745.2 ± 374.7 ng.h/mL|
|Plasma Cmax||8.1 ± 5.9 ng/mL||19.4 ± 9.3 ng/mL|
|Plasma Tmax (h)||11.0 ± 6.4||4.0 ± 6.5|
|Plasma t1/2 (h)||36.7 ± 20.8||79.0 ± 38.1|
|Kel (h-1)||0.024 ± 0.010||0.011 ± 0.004|
|CL/F (L/h)||244.7 ± 84.71||-|
|1 Apparent total body clearance|
Diclofenac systemic exposure from PENNSAID application (4 times daily for 1 week) was approximately 1/3 of the diclofenac systemic exposure from the Solaraze (diclofenac topical gel) application (twice daily for 4 weeks).
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 CPY2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CPY2C8 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.
The effect of PENNSAID on platelet function was evaluated in 10 healthy human volunteers as a sub-study of a multiple-dose pharmacokinetic study [see above]. Average (range) platelet aggregation time following stimulation with adenosine diphosphate, collagen, epinephrine and arachidonic acid was 101.3% (73.3 to 128.1), 99.8% (69.6 to 112.9), 109.9% (66.2 to 178.1) and 99.0% (15.5 to 126.6) of baseline value, respectively. These results indicate that there was no effect on platelet aggregation after application of the maximum clinical dose for 7 days [see above].
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.
Pivotal Studies in Osteoarthritis of the Knee
The use of PENNSAID for the treatment of the signs and symptoms of osteoarthritis of the knee was evaluated in two double-blind controlled trials conducted in the US and Canada, involving patients treated with PENNSAID at a dose of 40 drops four times a day for 12 weeks. PENNSAID was compared to topical placebo (2.3% DMSO with other excipients) and/or topical vehicle solution (45.5% w/w DMSO with other excipients), applied directly to the study knee. In both trials, PENNSAID treatment resulted in statistically significant clinical improvement compared to placebo and/or vehicle, in all three primary efficacy variables-pain, physical function (Western Ontario and McMaster Universities LK3.1 OA Index (WOMAC) pain and physical function dimensions) and Patient Overall Health Assessment (POHA)/Patient Global Assessment (PGA). Numerical results are summarized in Tables 3 and 4.
Table 3: Change in treatment outcomes after 12 weeks
of treatment in one study of efficacy of PENNSAID®
|Efficacy Variable||Study I Mean baseline score and mean change in efficacy variables after 12 weeks of treatment|
|Mean Baseline score||PENNSAID®
|WOMAC pain score (Likert 3.1, 0–20)||13||-6||-4.7||-4.7|
|WOMAC physical function (Likert 3.1, 0–68)||42||-15.7||-12.3||-12.1|
|1placebo formulation included 2.3% DMSO
2vehicle formulation included 45.5% DMSO
Table 4: Change in treatment
outcomes after 12 weeks of treatment in one study of efficacy of PENNSAID
|Efficacy Variable||Study II Mean baseline score and mean change in efficacy variables after 12 weeks of treatment|
|Mean Baseline score||PENNSAID
|WOMAC pain score (Likert 3.1, 0–20)||13||-5.9||-4.4|
|WOMAC physical function (Likert 3.1, 0–68)||42||-15.3||-10.3|
|1vehicle formulation included 45.5% DMSO|
Last reviewed on RxList: 10/31/2013
This monograph has been modified to include the generic and brand name in many instances.
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