DICLOFENAC SODIUM 1.5%- diclofenac sodium topical solution_solution

12. CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics Diclofenac, the active component of diclofenac sodium topical solution has anti-inflammatory, antinociception, and antipyretic effects. 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 2). Table 2: Single-Dose (80 drops) and Multiple Dose (80 drops four times daily for 7 days) Diclofenac Sodium Topical Solution Pharmacokinetic Parameters Diclofenac sodium Normal Adults [N=18] Normal Adults [N=19] Pharmacokinetic (Age: 18-55 years) (Age: 18-55 years) Parameters Single Dose Multiple Dose Four times daily for 7 days AUC0-t 177.5 +/- 72.6 ng.h/mL 695.4 +/- 348.9 ng.h/mL AUC0-inf 196.3 +/- 68.5 ng.h/mL 745.2 +/- 374.7 ng.h/mL Plasma Cmax 8.1 +/- 5.9 ng/mL 19.4 +/- 9.3 ng/mL Plasma Tmax (h) 11.0 +/- 6.4 4.0 +/- 6.5 Plasma t1/2 (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* - * 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. 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. 12.4 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)].

Diclofenac sodium topical solution is a nonsteroidal anti-inflammatory drug (NSAID) indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s).

DOSAGE AND ADMINISTRATION 2. 1 General Instructions For the relief of the signs and symptoms of osteoarthritis of the knee(s), the recommended dose is 40 drops per knee, 4 times a day. Apply diclofenac sodium topical solution to clean, dry skin. To avoid spillage, dispense diclofenac sodium topical solution 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. Spread diclofenac sodium topical solution evenly around front, back and sides of the knee. Repeat this procedure until 40 drops have been applied and the knee is completely covered with solution. To treat the other knee, if symptomatic, repeat the procedure. Application of diclofenac sodium topical solution in an amount exceeding or less than the recommended dose has not been studied and is therefore not recommended. 2 Special Precautions Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee. Wash and dry hands after use. Do not apply diclofenac sodium topical solution to open wounds. Avoid contact of diclofenac sodium topical solution with eyes and mucous membranes. Do not apply external heat and/or occlusive dressings to treated knees. Avoid wearing clothing over the diclofenac sodium topical solution-treated knee(s) until the treated knee is dry. Protect the treated knee(s) from sunlight. Wait until the treated area is dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same knee you have just treated with diclofenac sodium topical solution. Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). For the relief of the signs and symptoms of osteoarthritis of the knee(s), the recommended dose is 40 drops on each painful knee, 4 times a day. (2) Apply diclofenac sodium topical solution to clean, dry skin. 1) Dispense diclofenac sodium topical solution 10 drops at a time either directly onto the knee or first into the hand and then onto the knee. 1) Wash hands completely after administering the product. Wait until the area is completely dry before covering with clothing or applying sunscreen, insect repellent, cosmetics, topical medications, or other substances. Do not get diclofenac sodium topical solution in your eyes, nose or mouth.

ADVERSE REACTIONS 6. 1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of another drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to diclofenac sodium topical solution of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasians, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution were application site skin reactions. These events were the most common reason for withdrawing from the studies. Application site reactions: In controlled trials, the most common treatment related adverse events in patients receiving diclofenac sodium topical solution were application site skin reactions. Application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vescicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of diclofenac sodium topical solution and oral diclofenac. In the open label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%. Adverse events common to the NSAID class: In controlled trials, subjects treated with diclofenac sodium topical solution experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 1). The combination of diclofenac sodium topical solution and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases. Table 1: lists all adverse reactions occurring in >=1% of patients receiving diclofenac sodium topical solution, where the rate in the diclofenac sodium topical solution group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence. Table 1: Adverse Reactions occurring in >=1% of patients treated with Diclofenac Sodium Topical Solution in placebo and oral diclofenac-controlled trials. 2 Postmarketing Experience In non en dash U. postmarketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium topical solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, lack of drug effect, neck rigidity, pain Cardiovascular: palpitation, cardiovascular disorder Digestive: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis Metabolic and Nutritional: creatinine increased Musculoskeletal: leg cramps, myalgia Nervous: depression, dizziness, drowsiness, lethargy, paresthesia, paresthesia at application site Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis Skin and Appendages: At the Application Site: contact dermatitis, contact dermatitis with vesicles, dry skin, pruritus, rash; Other Skin and Appendages Adverse Reactions: eczema, rash, pruritus, skin discoloration, urticaria Special senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion To report SUSPECTED ADVERSE REACTIONS, contact Teligent Pharma, Inc. at 1-856-697-1441 or FDA at 1-800-332-1088 or www. gov/medwatch. The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see WARNINGS AND PRECAUTIONS (5. 1)] To report SUSPECTED ADVERSE REACTIONS, contact Teligent Pharma, Inc.

Diclofenac sodium topical solution is contraindicated in patients with a known hypersensitivity to diclofenac sodium or any other component of diclofenac sodium topical solution. Diclofenac sodium topical solution is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5. Diclofenac sodium topical solution is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5. Known hypersensitivity to diclofenac sodium. (4) History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. (4) Use in the perioperative period of coronary artery bypass graft (CABG) surgery.

USE IN SPECIFIC POPULATIONS 8. 1 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. 2 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. 3 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. 4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 5 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. Pregnancy: Not recommended for use during pregnancy. 1) Nursing Mothers: Use with caution, as it is not known if diclofenac is excreted in human milk.

Recent Major Changes
Dosage and Administration (2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 10/2013
Drug Interaction
DRUG INTERACTIONS Drug interactions with the use of diclofenac sodium topical solution have not been studied. The following drug interactions [sections 7. 7] are noted for oral diclofenac sodium. 1 Aspirin When diclofenac is administered with aspirin, the binding of diclofenac to protein is reduced, although the clearance of free diclofenac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. 2 Anticoagulants The effects of anticoagulants such as warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. 3 ACE-Inhibitors NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors. Consider this interaction in patients taking NSAIDs concomitantly with ACE-inhibitors. 4 Diuretics Clinical studies, as well as postmarketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. The response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, observe the patient closely for signs of renal failure [see Warnings and Precautions (5. 6)], as well as to assure diuretic efficacy. 5 Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs, including diclofenac, and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity. 6 Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Use caution when NSAIDs, including diclofenac, are administered concomitantly with methotrexate. 7 Cyclosporine Diclofenac, like other NSAIDs, may affect renal prostaglandins and increase the toxicity of certain drugs. Therefore, concomitant therapy with diclofenac may increase cyclosporine''s nephrotoxicity. Use caution when diclofenac is administered concomitantly with cyclosporine. 8 Oral Nonsteroidal Anti-Inflammatory Drugs Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12) and hemoglobin (13% vs. Therefore, do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. 9 Topical Treatments Instruct patients that before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication to the same skin surface of the knee treated with diclofenac sodium topical solution, they must wait until the treated area is completely dry. Concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects including increased GAI bleeding. 1) Concomitant use of anticoagulants and diclofenac have a risk of serious GI bleeding higher than users of either drug alone.

Overdosage
There have been no known experiences of overdose with diclofenac sodium topical solution. Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Manage patients using symptomatic and supportive care following an NSAID overdose. 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. Activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diureses, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdose treatment, call a poison control center (1-800-222-1222).
Nonclinical Toxicology
13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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.
Clinical Studies
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 en dash 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 Study1 ​Mean baseline score and mean change in efficacy variables after 12 weeks of treatment Efficacy Variable Mean Baseline Score Diclofenac Sodium N=154 ​Topical Placebo* N=155 ​Topical Vehicle N=161 WOMAC Pain Score (Likert 3.1, 0-20) 13 -6.0 -4.7 -4.7 WOMAC physical score (LIkert 3.1, 0-68) 42 -15.7 -12.3 -12.1 POHA (0-4) 2.3 -1.0 -0.4 -0.6 *placebo formulation included 2.3% DMSO +vehicle formulation included 45.5% DMSO Table 4: Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of Diclofenac Sodium Topical Solution Study II Mean baseline score and mean change in efficacy variables after 12 weeks of treatment Efficacy Variable​ Mean Baseline Score Diclofenac Sodium N=154 ​Topical Vehicle N=161 WOMAC Pain Score (Likert 3.1, 0-20) 13 -5.9 -4.4 WOMAC physical score (LIkert 3.1, 0-68) 42 -15.3 -10.3 PGA (0-4) 3.1 -1.3 -1.0 *vehicle formulation included 45.5% DMSO

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DICLOFENAC SODIUM 1.5%- diclofenac sodium topical solution_solution Product manual source documgent