August 27, 2016
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Voltaren Gel

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Voltaren Gel




CLINICAL PHARMACOLOGY

Mechanism Of Action

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of VOLTAREN® GEL, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis in vitro. Diclofenac concentrationsreached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins aremediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics

The pharmacokinetics of VOLTAREN® GEL were assessed in healthy volunteers following repeated applications during 7 days of VOLTAREN® GEL to 1 knee (4 x 4 g per day) or to 2 knees and 2 hands (4 x 12 g per day) versus the recommended oral dose of diclofenac sodium forthe treatment of osteoarthritis (3 x 50 mg per day). A summary of the pharmacokinetic parameters is presented in Table 2.

Table 3: Pharmacokinetic Parameters and Comparison of VOLTAREN® GEL to Oral Diclofenac Sodium Tablets After Repeated Administration

Treatment Cmax (ng/mL) Mean ± SD % of Oral (CI) Tmax (hr) Median Range AUC0-24 (ng•h/mL) Mean ± sD % of Oral (CI)
VOLTAREN® GEL 4 x 4 g per day (=160 mg diclofenac sodium per day) 15 ± 7.3 0.6%
(0.5-0.7)
14 (0-24) 233 ±128 5.8%
(5-6.7)
VOLTAREN® GEL 4 x 12 g per day (=480 mg diclofenac sodium per day) 53.8 ± 32 2.2%
(1.9-2.6)
10 (0-24) 807±478 19.7%
(17-22.8)
Diclofenac sodium tablets, orally 3 x 50 mg per day (=150 mg diclofenac sodium per day) 2270 ± 778 100% 6.5 (1-14) 3890± 1710 100%
Cmax = maximum plasma concentration, tmax=time of Cmax. AUC0-24=area under the concentration time curve.
SD=standard deviation. CI=confidence interval.

Systemic exposure (area under the concentration-time curve) and maximum plasma concentrations of diclofenac are significantly lower with VOLTAREN® GEL than with comparable oral treatment of diclofenac sodium.

Systemic exposure with recommended use of VOLTAREN® GEL (4 x 4 g per day applied to 1knee) is on average 17 times lower than with oral treatment. (Basis: treatment with VOLTAREN® GEL of 1 knee, 4 times a day versus 50 mg, 3 times a day of oral diclofenac tablets.) The amount of diclofenac sodium that is systemically absorbed from VOLTAREN® GEL is on average 6% of the systemic exposure from an oral form of diclofenac sodium.

The average peak plasma concentration with recommended use of VOLTAREN® GEL (4 x 4 gper day applied to 1 knee) is 158 times lower than with the oral treatment.

The pharmacokinetics of VOLTAREN® GEL has been tested under conditions of moderate heat (application of a heat patch for 15 minutes prior to gel application) and of moderate exercise(first gel application followed by a 20-minute treadmill exercise). No clinically relevant differences of systemic absorption and of tolerability were found between applications ofVOLTAREN® GEL (4 x 4 g per day on 1 knee) with and under the conditions tested. However, the pharmacokinetics of VOLTAREN® GEL were not tested under the condition of heat application following gel application. Therefore, concurrent use of VOLTAREN® GEL and heat is not recommended.

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs werereduced, although the clearance of free NSAID was not altered. The clinical significance of thisinteraction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [see DRUG INTERACTIONS].

Clinical Studies

Pivotal Studies In Osteoarthritis Of The Superficial Joints Of The Extremities

Study 1 evaluated the efficacy of VOLTAREN® GEL for the treatment of osteoarthritis of the knee in a 12-week, randomized, double-blind, multicenter, placebo-controlled, parallel-grouptrial. VOLTAREN® GEL was administered at a dose of 4 g, 4 times daily, on 1 knee (16 g perday). Pain as assessed by the patients at Week 12 using the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) Pain Subindex was lower in the VOLTAREN® GEL group than the placebo group.

Study 2 evaluated the efficacy of VOLTAREN® GEL for the treatment of osteoarthritis in subjects with osteoarthritis of the hand in an 8-week, randomized, double-blind, multicenter,placebo-controlled, parallel-group study. VOLTAREN® GEL was administered at a dose of 2 g per hand, 4 times daily, on both hands (16 g per day). Pain in the target hand as assessed by the patients at Weeks 4 and 6 on a visual analog scale from 0 to 100 was lower in the VOLTAREN® GEL group than the placebo group.

Table 4: Efficacy outcomes of VOLTAREN® GEL in Studies 1 and 2

    VOLTAREN® GEL Placebo (Vehicle) Adjusted Difference (Placebo -VOLTAREN® GEL)
Study 1 (Knee) WOMAC Pain *# at Week 12 Sample Size 127 119  
Mean Outcome 28 37 Δ=7†
95% Confidence Interval     (1, 12)
Study 2 (Hand#) Pain Intensity at Week 4 Sample Size 198 187  
Mean Outcome 43 50 Δ=7‡
95% Confidence Interval     (2, 12)
Study 2 (Hand) Pain Intensity# at Week 6 Sample Size 198 187  
Mean Outcome 40 47 Δ=7‡
95% Confidence Interval     (1, 13)
* WOMAC = Western Ontario McMaster Osteoarthritis Index.
# Scale from 0 (best) to 100 (worst).
† Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment and center and baseline covariate.
‡ Difference is adjusted using an analysis of covariance (ANCOVA) model with main effects of treatment, center, indicator of pain in the CMC-1joint, and baseline as a covariate, and the treatment-by-CMC-1 strata.

Last reviewed on RxList: 6/7/2016
This monograph has been modified to include the generic and brand name in many instances.

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