DICLOFENAC SODIUM_- diclofenac_solution

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. Absorption: Distribution: Elimination Specific Populations: Drug Interaction Studies 7.

Diclofenac sodium topical solution, USP 2% is indicated for the treatment of the pain of osteoarthritis of the knee(s). Diclofenac sodium topical solution, USP 2% is a nonsteroidal anti-inflammatory drug indicated for the treatment of the pain of osteoarthritis of the knee(s).

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. 2) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5. Avoid showering/bathing for at least 30 minutes after the application of diclofenac sodium topical solution to the treated knee.

The following adverse reactions are discussed in greater detail in other sections of the labeling: see Warnings and Precautions ( 5. 1 see Warnings and Precautions ( 5. 2 see Warnings and Precautions ( 5. 3 see Warnings and Precautions ( 5. 4 see Warnings and Precautions ( 5. 5 see Warnings and Precautions ( 5. 6 see Warnings and Precautions ( 5. 7 see Warnings and Precautions ( 5. 9 see Warnings and Precautions ( 5. 12 The most common adverse reactions with diclofenac sodium topical solution are application site reactions. 1 To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www. gov/medwatch. ( 6 Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Diclofenac sodium topical solution Application Site Reactions Other Common Adverse Reactions Table 1: Incidence of Adverse Reactions Occurring in >1% of Subjects with Osteoarthritis Using Diclofenac Sodium Topical Solution and More Often than in Subjects with OA Using Vehicle Control (Pooled) Adverse Reaction Diclofenac Sodium Topical Vehicle Control N=129 n (%) 4 (3%) 1 (<1%) Application site induration 2 (2%) 1 (<1%) Contusion 2 (2%) 1 (<1%) Sinus congestion 2 (2%) 1 (<1%) Nausea 2 (2%) 0 Diclofenac sodium topical solution 1. 5% The safety of diclofenac sodium topical solution 2% is based in part, on prior experience with diclofenac sodium topical solution 1. The data described below reflect exposure to diclofenac sodium topical solution 1. 5% 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 Caucasian, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with diclofenac sodium topical solution 1. 5% were application site skin reactions. These events were the most common reason for withdrawing from the studies. Application Site Reactions In controlled trials, 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 vesicles (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 1. 5% 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%. Other Common Adverse Reactions Table 2 lists all adverse reactions occurring in >=1% of patients receiving diclofenac sodium topical solution 1. 5%, where the rate in the diclofenac sodium topical solution 1. 5% 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 2: Adverse Reactions Occurring in >=1% of Patients Treated with Diclofenac Sodium Topical Solution 1. 5% in Placebo and Oral Diclofenac-Controlled Trials Treatment Group: Diclofenac Sodium Topical Topical Placebo Adverse Reaction N (%) N (%) Dry Skin (Application Site) 292 (32) 17 (5) Contact Dermatitis (Application Site) 83 (9) 6 (2) Dyspepsia 72 (8) 13 (4) Abdominal Pain 54 (6) 10 (3) Flatulence 35 (4) 1 (<1) Pruritus (Application Site) 34 (4) 7 (2) Diarrhea 33 (4) 7 (2) Nausea 33 (4) 3 (1) Pharyngitis 40 (4) 13 (4) Constipation 29 (3) 1 (<1) Edema 26 (3) 0 Rash (Non-Application Site) 25 (3) 5 (2) Infection 25 (3) 8 (2) Ecchymosis 19 (2) 1 (<1) Dry Skin (Non-Application Site) 19 (2) 1 (<1) Contact Dermatitis, vesicles 18 (2) 0 Paresthesia (Non-Application Site) 14 (2) 3 (<1) Accidental Injury 22 (2) 7 (2) Pruritus (Non-Application Site) 15 (2) 2 (<1) Sinusitis 10 (1) 2 (<1) Halitosis 11 (1) 1 (<1) Application Site Reaction 11 (1) 3(<1) In postmarketing surveillance, the following adverse reactions have been reported during post-approval use of diclofenac sodium topical solution 1. 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 Cardiovascular Gastrointestinal Metabolic and Nutritional Musculoskeletal Nervous Respiratory Skin and Appendages Other Skin and Appendages Adverse Reactions Special Senses Vascular.

Diclofenac sodium topical solution is contraindicated in the following patients: 5. 1 Known hypersensitivity to diclofenac or any components of the drug product. (4) (4) (4).

Infertility 8. 3 Risk Summary Use of NSAIDs, including diclofenac sodium topical solution, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of diclofenac sodium topical solution use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium topical solution use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac sodium topical solution, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryo fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of malformations were observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses up to approximately 0. 3 times, respectively, the maximum recommended human dose (MRHD) of 162 mg diclofenac sodium via diclofenac sodium topical solution, despite the presence of maternal and fetal toxicity at these doses [ see Data The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions see Data Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If diclofenac sodium topical solution treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium topical solution and follow up according to clinical practice ( see Data Labor or Delivery There are no studies on the effects of diclofenac sodium topical solution during labor or delivery. In animal studies, NSAIDs, including diclofenac inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproductive and developmental studies in animals demonstrated that diclofenac sodium administration during organogenesis did not produce malformations despite the induction of maternal toxicity and fetal toxicity in mice at oral doses up to 20 mg/kg/day (approximately 0. 6 times the maximum recommended human dose [MRHD] of diclofenac sodium topical solution, 162 mg diclofenac sodium/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0. 3-times, respectively, the MRHD based on BSA comparison). Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in diclofenac sodium topical solution) are equivocal as to potential teratogenicity. In a study in which pregnant rats were orally administered 2 or 4 mg/kg diclofenac (0. 24 times the MRHD, respectively, based on BSA comparison) from Gestation Day 15 through Lactation Day 21, significant maternal toxicity (peritonitis, mortality) was noted. These maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats. In published studies, diclofenac administration to pregnant rats prolonged gestation and produced liver toxicity and neuronal loss in offspring (1 mg/kg, IP; 0. 06 times the MRHD based on BSA comparison), impaired nephrogenesis in the kidney (3. 6 mg/kg, IP; 0. 2 times the MRHD based on BSA comparison) and caused adverse effects on the developing testes (6. 1 mg/kg, oral; 0. 4 times the MRHD based on BSA comparison). Risk Summary 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). Infertility Females Males 13. 1 Safety and effectiveness in pediatric patients have not been established. Elderly patients, compared to younger patients, are at 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. 14 Of the 911 patients treated with diclofenac sodium topical solution 1. 5% 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 1. 5% 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 1. 5% for this elderly population.

See Table 3 for clinically significant drug interactions with diclofenac. Table 3: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have increased the risk of serious bleeding compared to the use of either drug alone. Intervention: Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e. , warfarin), antiplatelet agents (e. , aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5. 12 Aspirin Clinical Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5. 2 Intervention: Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5. 12 ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). Intervention: During concomitant use of Diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. see Warnings and Precautions ( 5. 6 Diuretics Clinical Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e. , furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in see Warnings and Precautions ( 5. 6 Digoxin Clinical The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels. Lithium Clinical NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e. , neutropenia, thrombocytopenia, renal dysfunction) Intervention: During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Concomitant use of diclofenac with other NSAIDs or salicylates (e. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5. 2 Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. 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. Pemetrexed Clinical Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e. , diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e. , meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Drugs that Interfere with Hemostasis (e. warfarin, aspirin, SSRIs/SNRIs) 7 ACE Inhibitors, Angiotensin Receptor Blockers (ARB) or Beta-Blockers 7 ACE Inhibitors and ARBs 7 Diuretics 7 Digoxin 7.

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 overdosage treatment, contact a poison control center (1- 800-222-1222).
NONCLINICAL TOXICOLOGY
Carcinogenesis 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 57- 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 57-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 (approximately 3. 4 times the MRHD of diclofenac sodium topical solution based on apparent bioavailability and body surface area comparison) did not affect fertility. Studies conducted in rats found no effect of dermally applied DMSO on fertility, reproductive performance, or offspring performance. However, published studies report that treatment of adult male rats with diclofenac by the oral route at 10 mg/kg (0. 6 times the MRHD) for 14 days and at 0. 25 mg/kg (0. 01 times the MRHD) for 30 days produced adverse effects on male reproductive hormones and testes. Ocular Effects.
CLINICAL STUDIES
Diclofenac sodium topical solution Table 4: Change in Treatment Outcomes after 4 Weeks of Treatment with Diclofenac Sodium Topical Solution Efficacy Variable Treatment Diclofenac Sodium Topical Solution N=130 Vehicle Control N=129 WOMAC Pain Subscale* Baseline 12.4 12.6 * WOMAC pain subscale is based on the sum of pain scores for five items using a 5-point Likert scale.

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