DailyMed Label: Diclofenac Sodium 1.5%

DailyMed Label: Diclofenac Sodium 1.5%

2024

DailyMed Prescription

Diclofenac Sodium 1.5%

Diclofenac Sodium Topical

SOLA Pharmaceuticals

NDC: 70512-038

NDC: 70512-038

Diclofenac Sodium Topical Solution USP, 1.5% w/w is a nonsteroidal anti-inflammatory drug, available as a clear, colorless to faintly pink orange solution for topical application. Diclofenac Sodium Topical Solution USP contains 1.5% w/w diclofenac sodium, a benzeneacetic acid derivative that is a nonsteroidal anti-inflammatory drug (NSAID), designated chemically as 2-[(2,6-dichlorophenyl)amino]-benzeneacetic acid, monosodium salt. It is a white to off-white crystalline powder, hygroscopic that is freely soluble in methanol, soluble in ethanol (96 %), sparingly soluble in water, practically insoluble in chloroform and in ether. The molecular weight is 318.14. Its molecular formula is C 14 H 10 Cl 2 NNaO 2 and it has the following structural formula: Each 1 mL of solution contains 16.05 mg of diclofenac sodium. The inactive ingredients in diclofenac sodium topical solution USP include: alcohol, dimethyl sulfoxide (DMSO, 45.5% w/w), glycerin, propylene glycol and purified water. MOLECULE

Diclofenac sodium is indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s) (1). Diclofenac sodium is indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s) (1).

2.1 General Dosing Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see WARNING AND PRECAUTIONS (5.2)] 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. 2.2 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 natural or artificial 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). · 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. · Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. · The recommended dose is 40 drops on each painful knee, 4 times a day. (2) · Apply diclofenac sodium topical solution to clean, dry skin. (2.1) · 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. 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. (2.1) · 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. · Until the treated knee(s) is completely dry, avoid skin-to-skin contact between other people and the treated knee(s). (2.2) · Do not get diclofenac sodium topical solution in your eyes, nose or mouth (2.2).

Diclofenac Sodium Topical Solution USP: 1.5% w/w Diclofenac Sodium Topical Solution USP: 1.5% w/w

Diclofenac sodium is contraindicated in the following patients: · Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product. [see WARNINGS AND PRECAUTIONS (5.7, 5.9)]. · History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see WARNINGS AND PRECAUTIONS (5.7, 5.8)]. · In the setting of coronary artery bypass graft (CABG) surgery [see WARNINGS AND PRECAUTIONS (5.1)]. · Known hypersensitivity to diclofenac or any components of the drug product. (4) · History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. (4) · In the setting of CABG surgery (4)

5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NASAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see WARNINGS AND PRECAUTIONS (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see CONTRAINDICATIONS (4)]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of diclofenac sodium in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated Patients · Use the lowest effective dosage for the shortest possible duration. · Avoid administration of more than one NSAID at a time. · Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. · Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. · If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue diclofenac sodium until a serious GI adverse event is ruled out. · In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see DRUG INTERACTIONS (7)]. 5.3 Hepatotoxicity In clinical trials, of oral diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac for 2 to 6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3 to 8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue diclofenac sodium immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver-related event in patients treated with diclofenac sodium, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics). 5.4 Hypertension NSAIDs, including diclofenac sodium, can lead to new onset of hypertension, or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see DRUG INTERACTIONS (7)]. Monitor blood pressure (BP) closely during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see DRUG INTERACTIONS (7)]. Avoid the use of diclofenac sodium in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of diclofenac sodium in patients with advanced renal disease. The renal effects of diclofenac sodium may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium [see DRUG INTERACTIONS (7)]. Avoid the use of diclofenac sodium in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, diclofenac sodium is contraindicated in patients with this form of aspirin sensitivity [see CONTRAINDICATIONS (4)]. When diclofenac sodium is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium is contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS (4)]. Do not apply diclofenac sodium topical solution to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as diclofenac sodium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue diclofenac sodium and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including diclofenac, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including diclofenac sodium, at about 20 weeks gestation or later in pregnancy may cause 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.Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium treatment extends beyond 48 hours. Discontinue diclofenac sodium if oligohydramnios occurs and follow up according to clinical practice [ see USE IN SPECIFIC POPULATIONS (8.1) ]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with diclofenac sodium has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including diclofenac sodium, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see DRUG INTERACTIONS (7)]. The effects of diclofenac sodium on platelet function were studied in 10 healthy subjects administered 80 drops four times a day for 7 days. There was no significant change in platelet aggregation following one week of treatment [see CLINICAL PHARMACOLOGY (12.4)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of diclofenac sodium in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.6)]. 5.15 Sun Exposure Instruct patients to avoid exposure to natural or artificial sunlight on treated knee(s) because studies in animals indicated topical diclofenac treatment resulted in an earlier onset of ultraviolet light-induced skin tumors. The potential effects of diclofenac sodium on skin response to ultraviolet damage in humans are not known. 5.16 Eye Exposure Avoid contact of diclofenac sodium with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. 5.17 Oral Nonsteroidal Anti-Inflammatory Drugs Concomitant use of oral NSAIDs with diclofenac sodium resulted in a higher rate of rectal hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Therefore, do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. · Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) · Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) · Heart Failure and Edema : Avoid use of diclofenac sodium in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) · Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of diclofenac sodium in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) · Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs (5.7) · Exacerbation of Asthma Related to Aspirin Sensitivity : Diclofenac sodium is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) · Serious Skin Reactions : Discontinue diclofenac sodium at first appearance of skin rash or other signs of hypersensitivity (5.9) · Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically (5.10). · Fetal Toxicity : Limit use of NSAIDs, including diclofenac sodium, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1) · Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7) · Exposure to light : Avoid exposure of treated knee(s) to natural or artificial sunlight. (5.15) · Eye Contact : Avoid contact of diclofenac sodium with eyes and mucosa. (5.16) · Oral Nonsteroidal Anti-inflammatory Drugs : Avoid concurrent use with oral NSAIDs. (5.17)

The following adverse reactions are discussed in greater detail in other sections of the labeling:

See Table 2 for clinically significant drug interactions with diclofenac. Table 2: Clinically Significant Drug Interactions with Diclofenac Drugs That Interfere with Hemostasis Clinical Impact · Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. · Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention Monitor patients with concomitant use of diclofenac sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.11)] Aspirin Clinical Impact: 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 NSAID alone [see WARNINGS AND PRECAUTIONS (5.2)] Intervention Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS (5.11)]. Diclofenac sodium is not a substitute for low dose aspirin for cardiovascular protection. ACE inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: · NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). · In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: · During concomitant use of diclofenac sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained · During concomitant use of diclofenac sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS(5.6)] · When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., 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 with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS (5.6)]. Digoxin Clinical Impact : The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin. Intervention: During concomitant use of diclofenac sodium and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: 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 and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact; Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention : During concomitant use of diclofenac sodium and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of diclofenac sodium and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of diclofenac sodium and cyclosporine, monitor patients for signs or worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS (5.2)]. Concomitant use of oral NSAIDs with diclofenac sodium 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. 9%). Intervention: The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations Pemetrexed Clinical Impact: Concomitant use of diclofenac sodium 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 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.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., 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.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly using diclofenac sodium with drugs that interfere with hemostasis. Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended (7) · ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta- Blockers: Concomitant use with diclofenac sodium may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) · ACE Inhibitors and ARBs: Concomitant use with diclofenac sodium in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) · Diuretics: NSAIDS can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) · Digoxin: Concomitant use with diclofenac sodium can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7)

8.1 Pregnancy Risk Summary Use of NSAIDs, including diclofenac sodium, 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 use between about 20 and 30 weeks of gestation, and avoid diclofenac sodium 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, 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 embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, no evidence of teratogenicity was observed in mice, rats, or rabbits given diclofenac daily during the period of organogenesis at doses up to approximately 0.6, 0.6, and 1.3 times, respectively, the maximum recommended human dose (MRHD) of diclofenac sodium, despite the presence of maternal and fetal toxicity at these doses [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as diclofenac sodium, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. 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. In the U.S. 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 Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including diclofenac sodium, can cause premature closure of the fetal ductus arteriosus ( 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 treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium and follow up according to clinical practice ( see Data ). Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the 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 dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. 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 teratogenicity 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, 154 mg/day, based on body surface area (BSA) comparison), and in rats and rabbits at oral doses up to 10 mg/kg/day (approximately 0.6 and 1.3 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 rats, maternally toxic doses of diclofenac were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Labor or Delivery: There are no studies on the effects of diclofenac sodium during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. 8.2 Lactation Risk Summary Based on available data, diclofenac may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CATAFLAM and any potential adverse effects on the breastfed infant from the CATAFLAM or from the underlying maternal condition. 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). 8.3 Females and Males of Reproductive Potential Infertility Females: Based on the mechanism of action, the use of prostaglandin-mediated NSAIDS, including diclofenac sodium, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including diclofenac sodium, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are a 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 (5.1, 5.2, 5.3, 5.6, 5.13)]. Of the 911 patients treated with diclofenac sodium 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 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 for this elderly population. Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of diclofenac sodium in women who have difficulties conceiving (8.3) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. REVISED August 2021

16 HOW SUPPLIED/STORAGE AND HANDLING Diclofenac Sodium Topical Solution USP, 1.5% w/w 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 polyethylene dropper cap. NDC Number and Size 5 FL.OZ. (150 mL) bottle in cartons of one NDC # 70512-038-05 Storage Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [See USP Controlled Room Temperature].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies in mice and rats administered diclofenac sodium topical solution 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.

12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of diclofenac sodium, 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. 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, 1.5% w/w Pharmacokinetic Parameters 1 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. Elimination 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. Specific 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. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see DRUG INTERACTIONS (7)]. PHARMACOKINETIC

Instructions for Use Diflofenac Sodium Topical Solution USP, 1.5% w/w (dye-KLOE-fen-ak) Read the Medication Guide that comes with diclofenac sodium topical solution first. Be sure that you read, understand and follow these Instructions for Use before you use diclofenac sodium topical solution for the first time. Imporatnt: For use on the skin only (topical). Do not get diclofenac sodium topical solution in your eyes, nose or mouth. Before you use diclofenac sodium topical solution: Apply diclofenac sodium topical solution exactly as your healthcare provider tells you. Talk with your healthcare provider or pharmacist if you are not sure. Only use diclofenac sodium topical solution to treat pain from osteoarthritis in your knee or knees. Apply diclofenac sodium topical solution on clean, dry skin that does not have any cuts, infections, or rashes. Use diclofenac sodium topical solution 4 times each day on your knee or knees as prescribed. Your total dose for each knee is 40 drops of diclofenac sodium topical solution, each time you use it. If you get diclofenac sodium topical solution in your eyes, rinse your eyes right away with water or saline. Call your healthcare provider if your eyes are irritated for more than one hour. Steps for using diclofenac sodium topical solution: Step 1. Wash your hands with soap and water before applying diclofenac sodium topical solution. Step 2. Put 10 drops of diclofenac sodium topical solution either on your hand or directly on your knee (see Figure A ). Step 3. Spread diclofenac sodium topical solution evenly on the front, back, and sides of your knee (see Figures B and C ). Repeat steps 2 and 3, three times so that your knee is completely covered with a total of 40 drops of diclofenac sodium topical solution. Step 4. If your healthcare provider has prescribed diclofenac sodium topical solution for both knees, repeat steps 2 and 3 for the other knee. After you use diclofenac sodium topical solution: Wash your hands with soap and water right away after applying diclofenac sodium topical solution. Do not: touch the treated knee or allow another person to touch the knee treated with diclofenac sodium topical solution uinitl your knee is completely dry. cover your knee with clothing until your knee is completely dry. put sunscreen, insect repellant, lotion, mositurizer, cosmetics, or other topical medicines on your knee unitl it is completely dry. take a shower or a bath for at least 30 minutes after you put diclofenac sodium topical solution on your knee. use heating pads or cover the treated area with bandages where you have applied diclofenac sodium topical solution. use sunlamps and tanning beds. Protect your treated knee from sunlight. Wear clothes that cover your skin if you have to be in sunlight. How should I store diclofenac sodium topical solution? Store diclofenac sodium topical solution 25ºC (77ºF); excursions permitted to 15 to 30ºC (59 to 86ºF) (See USP Controlled Room Temperature). Keep diclofenac sodium topical solution and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. The brand(s) are trademarks of their respective owners. Manufactured for: SOLA Pharmaceuticals, LLC Baton Rouge, LA 70810 March 2021 ID#: 267408 Figure A Figure B

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