NuDiclo SoluPak

Name: NuDiclo SoluPak

Use in specific populations

Pregnancy

Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation.

Teratogenic Effects:

There are no adequate and well-controlled studies of diclofenac sodium topical solution in pregnant women. Diclofenac sodium topical solution should not be used by pregnant women as its safe use has not been adequately determined and starting at 30 weeks gestation, diclofenac and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. Developmental studies in animals demonstrated that diclofenac sodium administration did not produce teratogenicity despite the induction of maternal toxicity and fetal toxicity in mice at doses up to 20 mg/kg/day (0.6-fold the maximum recommended human dose [MRHD] of 154 mg/day based on body surface area comparison), and in rats and rabbits at doses up to 10 mg/kg/day (approximately 0.6-fold and 1.3-fold the MRHD, respectively). Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in diclofenac sodium topical solution) are equivocal as to potential teratogenicity.

Nonteratogenic Effects:

In rats, maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival.

Labor and Delivery

The effects of diclofenac sodium topical solution on labor and delivery in pregnant women are unknown. In rat studies maternal exposure to diclofenac, as with other NSAID drugs, known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased offspring survival.

Nursing Mothers

It is not known whether this drug is excreted in human milk; however, there is a case report in the literature indicating that diclofenac can be detected at low levels in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from diclofenac sodium topical solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the 911 patients treated with diclofenac sodium topical solution in seven controlled Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with diclofenac sodium topical solution in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to diclofenac sodium topical solution for this elderly population. As with any NSAID, use caution in treating the elderly (65 years and older) and it may be useful to monitor renal function since they are more likely to have decreased baseline renal function.

Description

Diclofenac sodium topical solution is a clear, colorless to faintly pink-orange solution for topical application.

Diclofenac sodium topical solution contains 1.5% w/w diclofenac sodium, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug (NSAID), designated chemically as 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. The molecular weight is 318.14. Its molecular formula is C 14H 10Cl 2NNaO 2 and it has the following structural formula:

Each 1 mL of solution contains 16.05 mg of diclofenac sodium. In addition diclofenac sodium topical solution contains the following inactive ingredients: dimethyl sulfoxide USP (DMSO, 45.5% w/w), propylene glycol, alcohol, glycerin and purified water.

Clinical pharmacology

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.

Pharmacodynamics

Diclofenac, the active component of diclofenac sodium topical solution has anti-inflammatory, anti-nociception, and antipyretic effects.

Pharmacokinetics

After topical administration to healthy human volunteers of single and multiple maximum doses of diclofenac sodium topical solution, 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) Diclofenac Sodium Topical Solution Pharmacokinetic Parameters
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
* Apparent total body clearance
AUC 0-t 177.5 ± 72.6 ng.h/mL 695.4 ± 348.9 ng.h/mL
AUC 0-inf 196.3 ± 68.5 ng.h/mL 745.2 ± 374.7 ng.h/mL
Plasma C max 8.1 ± 5.9 ng/mL 19.4 ± 9.3 ng/mL
Plasma T max (h) 11.0 ± 6.4 4.0 ± 6.5
Plasma t 1/2 (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 ± 84.7 * -

Absorption

Diclofenac systemic exposure from diclofenac sodium topical solution 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).

Distribution

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.

Metabolism

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.

Excretion

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.

Special Populations

Pediatric: The pharmacokinetics of diclofenac sodium topical solution has not been investigated in pediatric patients.

Race: Pharmacokinetic differences due to race have not been studied.

Platelets

The effect of diclofenac sodium topical solution on platelet function was evaluated in 10 healthy human volunteers as a sub-study of a multiple-dose pharmacokinetic study [see Pharmacokinetics (12.3)]. 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 Pharmacokinetics (12.3)].

Clinical studies

Pivotal Studies in Osteoarthritis of the Knee

The use of diclofenac sodium topical solution for the treatment of the signs and symptoms of osteoarthritis of the knee was evaluated in two double-blind controlled trials conducted in the U.S. and Canada, involving patients treated with diclofenac sodium topical solution at a dose of 40 drops four times a day for 12 weeks. Diclofenac sodium topical solution 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, diclofenac sodium topical solution 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 Diclofenac Sodium Topical Solution


Efficacy Variable
Study I
Mean baseline score and mean change in efficacy variables after 12 weeks of treatment
Mean Baseline score Diclofenac sodium
N=154
Topical placebo *
N=155
Topical vehicle †
N=161
* placebo formulation included 2.3% DMSO † vehicle formulation included 45.5% DMSO
WOMAC pain score
(Likert 3.1, 0-20)
13 -6.0 -4.7 -4.7
WOMAC physical function
(Likert 3.1, 0-68)
42 -15.7 -12.3 -12.1
POHA
(0-4)
2.3 -1.0 -0.4 -0.6
Table 4: Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of Diclofenac Sodium Topical Solution


Efficacy Variable
Study II
Mean baseline score and mean change in efficacy variables after
12 weeks of treatment
Mean Baseline score Diclofenac sodium
N=164
Topical vehicle *
N=162
* vehicle formulation included 45.5% DMSO
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
PGA (0-4) 3.1 -1.3 -1.0

Inactive ingredients

acrylates/C10-30 alkyl acrylate crosspolymer, cetyl acetate, methylparaben, PPG-20 methyl glucose ether distearate, propylene glycol, propylparaben, stearate-100, stearic acid, stearyl alcohol, triethanolamine, water

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