DICLOFENAC (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (approximately 0.2 times the maximum recommended human dose [MRHD] of Diclofenac Capsules based on body surface area [BSA] comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (approximately 0.014 times the MRHD based on BSA comparison) in males and 1 mg/kg/day (approximately 0.04 times the MRHD based on BSA comparison) in females did not reveal any oncogenic potential.

Mutagenesis

Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal aberration studies in Chinese hamsters.

Impairment of Fertility

Diclofenac sodium administered to male and female rats at 4 mg/kg/day (approximately 0.4 times the MRHD based on BSA comparison) did not affect fertility.

14 CLINICAL STUDIES

Acute Pain

The efficacy of Diclofenac Capsules in the management of acute pain was demonstrated in a single multicenter, randomized, double-blind, placebo-controlled, parallel arm study comparing Diclofenac Capsules 18 mg and 35 mg taken three times a day, placebo, and celecoxib in patients with pain following bunionectomy. The study enrolled 428 patients with a mean age of 40 years (range 18 to 65 years) and a minimum pain intensity rating of at least 40 mm on a 100-mm visual analog scale (VAS) during the 9-hour period after discontinuation of the anesthetic block following bunionectomy surgery. Patients were randomized equally across the treatment groups.

The mean and range (in parenthesis) of pain intensities on the VAS at baseline were 74 mm (44 to 100 mm), 77 mm (41 to 100 mm), and 76 mm (40 to 100 mm) for the Diclofenac Capsules 35 mg, Diclofenac Capsules 18 mg, and placebo groups, respectively. One tablet of hydrocodone/acetaminophen 10 mg/325 mg was permitted every 4 to 6 hours as rescue medication. About 82% of patients in the Diclofenac Capsules 35 mg group, 85% of the patients in the Diclofenac Capsules 18 mg group, and 97% of patients in the placebo group took rescue medication for pain management during the study.

The average pain intensities over time are depicted for the treatment groups in Figure 1. Both Diclofenac Capsules 18 mg and 35 mg demonstrated efficacy in pain intensity reduction compared with placebo, as measured by the sum of pain intensity difference over 0 to 48 hours after the first dose.

Figure 1 Average Pain Intensity Over 48 Hours for Diclofenac Capsules 18 mg, Diclofenac Capsules 35 mg, and Placebo Groups

Figure 1
(click image for full-size original)

Osteoarthritis Pain

The efficacy of Diclofenac Capsules in the management of osteoarthritis pain was demonstrated in a single multicenter, randomized, double-blind, placebo-controlled, parallel-arm study comparing Diclofenac Capsules 35 mg taken twice a day or three times a day and placebo in patients with osteoarthritis of the knee or hip. The study enrolled 305 patients with a mean age of 62 (range 41 to 90 years). Osteoarthritis pain was measured using the Western Ontario and McMaster University Osteoarthritis Index Pain Subscale (WOMAC Pain Subscale). Mean baseline WOMAC Pain Subscale Score across treatment groups was 75 mm using a 0 to 100 mm visual analog scale.

The primary efficacy parameter was the change from baseline at 12 weeks in the WOMAC Pain Subscale. Diclofenac Capsules 35 mg three times a day reduced osteoarthritis pain compared with placebo, as measured by WOMAC Pain Subscale Score. The distribution (%) of patients achieving various percentage reductions in pain intensity at Week 12 are depicted in Figure 2.

Figure 2 Distribution (%) of Patients Achieving Various Percentage Reductions in Pain Intensity at Week 12

Figure 2
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

Diclofenac Capsules are supplied as:

  • 18 mg – blue body and light green cap (imprinted IP-203 on the body and 18 mg on the cap in white ink)
    • NDC (73480-240-90), Bottles of 90 capsules
  • 35 mg – blue body and green cap (imprinted IP-204 on the body and 35 mg on the cap in white ink)
    • NDC (73480-242-90), Bottles of 90 capsules

Storage

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

Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Diclofenac Capsules and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1) ].

Gastrointestinal Bleeding, Ulceration, and Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2) ].

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Diclofenac Capsules and seek immediate medical therapy [see Warnings and Precautions (5.3) ].

Heart Failure and Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5) ].

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)].

Serious Skin Reactions

Advise patients to stop Diclofenac Capsules immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9) ].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including Diclofenac Capsules, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3) ].

Fetal Toxicity

Inform pregnant women to avoid use of Diclofenac Capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of Diclofenac Capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use of NSAIDs and Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with Diclofenac Capsules until they talk to their healthcare provider [see Drug Interactions (7) ].

Manufactured (under license from iCeutica Pty Ltd) for and Distributed by:
TriVue Pharmaceuticals, Inc.
Birmingham, AL 35235

US Patent Nos. 8679544, 8999387, 9017721, 9173854, 9180095, 9180096, and 9186328

Rev. 08/2020

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