Diclofenac Sodium: Package Insert and Label Information (Page 4 of 5)

8.2 Lactation

Risk Summary

Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CATAFLAM and any potential adverse effects on the breastfed infant from the CATAFLAM or from the underlying maternal condition.

Data

One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period).

8.3 Females and Males of Reproductive Potential

Infertility
Females
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDS, including diclofenac sodium topical solution, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium topical solution, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Elderly patients, compared to younger patients, are a greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)] .

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.

10 OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1,5.2,5.4,5.6)] .

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in diclofenac sodium topical solution. Consider activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdose treatment, contact a poison control center (1-800-222-1222).

11 DESCRIPTION

Diclofenac sodium topical solution, USP 1.5% is a nonsteroidal anti-inflammatory drug, available as a clear, colorless to faintly pink-orange solution for topical application.

Diclofenac sodium topical solution, USP contains 1.5% w/w diclofenac sodium, USP, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug (NSAID), designated chemically as 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. It is a white to off-white crystalline powder, hygroscopic, and odorless that is freely soluble in methanol, soluble in alcohol, and sparingly soluble in water. The molecular weight is 318.13. Its molecular formula is C ₁₄ H ₁₀ Cl ₂ NNaO ₂ and it has the following structural formula:

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

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

The mechanism of action of diclofenac sodium topical solution, 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 concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators 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.

12.3 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 3).

Table 3: Single-Dose (80 drops) and Multiple Dose (80 drops four times daily for 7 days) D iclofenac 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
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
K el (h -1)	0.024 ± 0.010	0.011 ± 0.004
CL/F (L/h)	244.7 ± 84.7 1	–
1 Apparent total body clearance

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.

Elimination

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.

Specific 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.

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)] .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day corresponding to approximately 0.35- and 0.7-fold (mouse and rat, respectively) of the maximum recommended human topical dose (MRHD) of diclofenac sodium topical solution (based on apparent bioavailability and body surface area comparison).

In a dermal carcinogenicity study conducted in albino mice, daily topical applications of diclofenac sodium for two years at concentrations up to 0.035% diclofenac sodium (a 43-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) did not increase neoplasm incidence.

In a photococarcinogenicity study conducted in hairless mice, topical application of diclofenac sodium at doses up to 0.035% diclofenac sodium (a 43-fold lower diclofenac sodium concentration than present in diclofenac sodium topical solution) resulted in an earlier median time of onset of tumors.

Mutagenesis

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.

Impairment of Fertility

Fertility studies have not been conducted with diclofenac sodium topical solution. Diclofenac sodium administered to male and female rats at doses up to 4 mg/kg/day (1.4-fold of the MRHD of diclofenac sodium topical solution based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies have not been conducted to determine the safety of DMSO on fertility.

13.2 Animal Toxicology and/or Pharmacology

Ocular Effects

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 diclofenac sodium topical solution. 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.

14 CLINICAL STUDIES

14.1 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 US 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 4 and 5.

Table 4: Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of d iclofenac 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 topical solution N=154	Topical placebo 1 N=155	Topical vehicle 2 N=161
WOMAC pain score (Likert 3.1, 0 to 20)	13	-6.0	-4.7	-4.7
WOMAC physical function (Likert 3.1, 0 to 68)	42	-15.7	-12.3	-12.1
POHA (0 to 4)	2.3	-1.0	-0.4	-0.6
1 placebo formulation included 2.3% DMSO 2 vehicle formulation included 45.5% DMSO

Table 5: 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 topical solution N=164	Topical vehicle 1 N=162
WOMAC pain score (Likert 3.1, 0 to 20)	13	-5.9	-4.4
WOMAC physical function (Likert 3.1, 0 to 68)	42	-15.3	-10.3
PGA (0 to 4)	3.1	-1.3	-1.0
1 vehicle formulation included 45.5% DMSO

Diclofenac sodium topical solution, USP 1.5% w/w is supplied as a clear, colorless to faintly pink-orange solution containing 16.05 mg of diclofenac sodium, USP per 1 mL of solution, in a white high density polyethylene bottle with a white low-density dropper cap. It is available as follows:

NDC: 70518-0871-00

PACKAGING: 1 in 1 CARTON, 150 mL in 1 BOTTLE TYPE 0

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Repackaged and Distributed By:

Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762