Voltaren Gel - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Voltaren Gel - Scientific Information

Manufacture: Endo Pharmaceuticals Inc.
Country: United States
Condition: Osteoarthritis, Pain
Class: Topical non-steroidal anti-inflammatories
Form: Cream, gel, liniment or balm, lotion, ointment, etc
Ingredients: diclofenac sodium,carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution.

Description

VOLTAREN GEL (diclofenac sodium topical gel) is a non-steroidal anti-inflammatory drug (NSAID) for topical use only. It contains the active ingredient, diclofenac sodium, in an opaque, white gel base. Diclofenac sodium is a white to slightly yellow crystalline powder. Diclofenac sodium is a benzeneacetic acid derivative. The chemical name is 2 -[(2,6-dichlorophenyl)amino]benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C14H10Cl2NNaO2. It has the following structural formula:

VOLTAREN GEL also contains carbomer homopolymer Type C, cocoyl caprylocaprate, fragrance, isopropyl alcohol, mineral oil, polyoxyl 20 cetostearyl ether, propylene glycol, purified water, and strong ammonia solution.

Clinical Pharmacology

Mechanism of Action

The mechanism of action of diclofenac is similar to that of other non-steroidal 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.

Pharmacodynamics

Diclofenac, the active component of VOLTAREN GEL has anti-inflammatory, anti-nociception, and anti-pyretic effects.

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 for the treatment of osteoarthritis (3 x 50 mg per day). A summary of the pharmacokinetic parameters is presented in Table 1.

Table 1. 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 1 knee) 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 g per 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 of VOLTAREN 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years at doses up to 2 mg/kg/day resulted in no significant increases in tumor incidence corresponding to a human equivalent dose approximately 0.5- and 1-fold (mouse and rat, respectively) of the maximum human topical dose of VOLTAREN GEL (based on bioavailability and body surface area comparison).

In a dermal carcinogenicity study conducted in albino mice, daily topical applications of a diclofenac sodium gel product for two years at concentrations up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in VOLTAREN GEL) did not increase neoplasm incidence.

In a photococarcinogenicity study conducted in hairless mice, topical application of a diclofenac sodium gel product at doses up to 0.035% diclofenac sodium (a 29-fold lower diclofenac sodium concentration than present in VOLTAREN GEL) resulted in an earlier median time of onset of tumors.

Diclofenac was not mutagenic or clastogenic in a battery of genotoxicity tests that included the bacterial reverse mutation assay, in vitro mouse lymphoma point mutation assay, chromosomal aberration studies in Chinese hamster ovarian cells in vitro, and in vivo rat chromosomal aberration assay of bone marrow cells.

Diclofenac did not affect male or female fertility in rats at doses up to 4 mg/kg/day which induced toxicity, corresponding to a human equivalent dose approximately 2-fold greater than the maximum human topical dose of VOLTAREN GEL (based on bioavailability and body surface area comparison).

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-group trial. VOLTAREN GEL was administered at a dose of 4 g, 4 times daily, on 1 knee (16 g per day). 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 2. Efficacy outcomes of VOLTAREN GEL in Studies 1 and 2 VOLTAREN GEL Placebo (Vehicle) Adjusted
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 ∆ = 7†
95% Confidence Interval (1, 12)
Study 2 (Hand) Pain Intensity #at Week 4 Sample Size 198 187
Mean Outcome 43 50 ∆ = 7††
95% Confidence Interval (2, 13)
Study 2 (Hand) Pain Intensity #at Week 6 Sample Size 198 187
Mean Outcome 40 47 ∆ = 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 for pain in the CMC-1 joint, and baseline as a covariate, and the treatment-by-CMC-1 indicator interaction. Difference is weighted by size of CMC-1 strata.