Klofensaid II (Page 5 of 7)

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 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 IMean baseline score and mean change in efficacy variables after 12 weeks of treatment
Mean Baseline score Diclofenac sodiumN=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 IIMean baseline score and mean change in efficacy variables after12 weeks of treatment
Mean Baseline score Diclofenac sodiumN=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

16. HOW SUPPLIED/STORAGE AND HANDLING

Diclofenac Sodium Topical Solution is supplied as a clear, colorless to faintly pink-orange solution containing 16.05 mg of diclofenac sodium per mL of solution, in a white high density polyethylene bottle with a white low-density dropper cap.

NDC Number & Size

150 mL bottle NDC # 59088-372-10

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled RoomTemperature].

17. PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Medication Guide and Instructions for Use).

17.1 Patient/Caregiver Instructions

Inform patients of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Encourage patients to read the NSAID Medication Guide that accompanies each prescription dispensed prior to using diclofenac sodium topical solution [see Medication Guide and Instructions for Use].

17.2 Cardiovascular Effects

Diclofenac sodium topical solution, like other NSAIDs, may cause serious DV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath weakness, slurring of speech, and to ask for medical advice when observing any indicative sign or symptoms. Inform patients of the importance of this follow-up [see Warnings and Precautions (5.1)].

17.3 Gastrointestinal Effects

Diclofenac sodium topical solution, like other NSAIDs, may cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, inform patients to be alert for the signs and symptoms of ulceration and bleeding, and to ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Instruct patients of the importance of this follow-up [see Warnings and Precautions (5.2)].

17.4 Hepatotoxicity

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

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