Flector (Page 4 of 5)

12.2 Pharmacodynamics

Flector Patch applied to intact skin provides local analgesia by releasing diclofenac epolamine from the patch into the skin.

12.3 Pharmacokinetics

Absorption

Following a single application of the Flector Patch on the upper inner arm, peak plasma concentrations of diclofenac (range 0.7 – 6 ng/mL) were noted between 10 – 20 hours of application. Plasma concentrations of diclofenac in the range of 1.3 – 8.8 ng/mL were noted after five days with twice-a-day Flector Patch application.

Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with Flector Patch, were lower (<1%) than after a single oral 50-mg diclofenac sodium tablet.

The pharmacokinetics of Flector Patch has been tested in healthy volunteers at rest or undergoing moderate exercise (cycling 20 min/h for 12 h at a mean HR of 100.3 bpm). No clinically relevant differences in systemic absorption were observed, with peak plasma concentrations in the range of 2.2 – 8.1 ng/mL while resting, and 2.7 – 7.2 ng/mL during exercise.

Distribution

Diclofenac has a very high affinity (>99%) for human serum 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

The plasma elimination half-life of diclofenac after application of Flector Patch is approximately 12 hours. 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. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either diclofenac epolamine or Flector Patch.

Mutagenesis

Diclofenac epolamine is not mutagenic in Salmonella typhimurium strains, nor does it induce an increase in metabolic aberrations in cultured human lymphocytes, or the frequency of micronucleated cells in the bone marrow micronucleus test performed in rats.

Impairment of Fertility

Male and female Sprague Dawley rats were administered 1, 3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60 days prior to conception and during mating period, females treated for 14 days prior to mating through day 19 of gestation). Diclofenac epolamine treatment with 6 mg/kg/day resulted in increased early resorptions and postimplantation losses; however, no effects on the mating and fertility indices were found. The 6 mg/kg/day dose corresponds to 3-times the maximum recommended daily exposure in humans based on a body surface area comparison.

14 CLINICAL STUDIES

14.1 Ankle sprains

Efficacy of Flector Patch was demonstrated in two of four studies of patients with minor sprains, strains, and contusions. Patients were randomly assigned to treatment with the Flector Patch, or a placebo patch identical to the Flector Patch minus the active ingredient. In the first of these two studies, patients with ankle sprains were treated once daily for a week. In the second study, patients with sprains, strains and contusions were treated twice daily for up to two weeks. Pain was assessed over the period of treatment. Patients treated with the Flector Patch experienced a greater reduction in pain as compared to patients randomized to placebo patch as evidenced by the responder curves presented below.

Figure 1: Patients Achieving Various Levels of Pain Relief at Day 3; 14-Day Study

Figure 1
(click image for full-size original)

Figure 2: Patients Achieving Various Levels of Pain Relief at End of Study; 14-Day Study

Figure 2
(click image for full-size original)

Figure 3: Patients Achieving Various Levels of Pain Relief at Day 3; 7-Day Study

Figure 3
(click image for full-size original)

Figure 4: Patients Achieving Various Levels of Pain Relief at End of Study; 7-Day Study

Figure 4
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

The Flector Patch is supplied in resealable envelopes, each containing 5 patches (10 cm × 14 cm), with 6 envelopes per box (NDC 60793-411-30). Each individual patch is embossed with “FLECTOR PATCH <DICLOFENAC EPOLAMINE TOPICAL PATCH> 1.3%”.

  • Each patch contains 180 mg of diclofenac epolamine in an aqueous base (13 mg of active per gram of adhesive or 1.3%).
  • The product is intended for topical use only.
  • Keep out of reach of children and pets.
  • ENVELOPES SHOULD BE SEALED AT ALL TIMES WHEN NOT IN USE.
  • Curad® Hold Tite™ is a trademark of Medline Industries, Inc., and Surgilast® Tubular Elastic Dressing is a trademark of Derma Sciences, Inc.

Storage

Store at 25ºC (77ºF); excursions permitted to 15º-30ºC (59º-86ºF) [see USP Controlled Room Temperature].

Distributed by: King Pharmaceuticals Inc.
501 Fifth Street
Bristol TN 37620 USA
Telephone: 1-888-840-8884 www.FlectorPatch.com

Manufactured for: IBSA Institut Biochimique SA, CH-6903 Lugano, Switzerland
Manufactured by: Teikoku Seiyaku Co., Ltd., Sanbonmatsu, Kagawa 769-2695 Japan
FI/165 1086
Ed. VII/08.11Version August, 2011

17 PATIENT COUNSELING INFORMATION

See Medication Guide

17.1 Information on Medication Guide

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 Flector Patch.

17.2 Cardiovascular Effects

Flector Patch, like other NSAIDs, may cause serious CV 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)].

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