DailyMed Label: Diclofenac Sodium Gel

DailyMed Label: Diclofenac Sodium Gel

2022

DailyMed Prescription

Diclofenac Sodium Gel

Diclofenac Sodium Gel

Direct_Rx

NDC: 72189-379

NDC: 72189-379

NDC: 72189-379

Diclofenac Sodium Topical Gel, 3%, intended for dermatologic use, contains the active ingredient, diclofenac sodium, USP in a clear, transparent, colorless to slightly yellow gel base. Diclofenac sodium, USP is a white to slightly yellowish, hygroscopic crystalline powder, and melts at about 284°C. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in water, slightly soluble in acetone, and partially insoluble in chloroform and ether. The chemical name for diclofenac sodium is: Sodium [o-(2,6-dichloranilino) phenyl] acetate Diclofenac sodium has a molecular weight of 318.13. The CAS number is CAS-15307-79-6. The structural formula is represented below: [structure] Diclofenac Sodium Gel, 3% also contains benzyl alcohol, sodium hyaluronate, polyethylene glycol monomethyl ether, and purified water. 1 g of Diclofenac Sodium Topical Gel, 3% contains 30 mg of the active substance, diclofenac sodium, USP.

Diclofenac sodium gel is indicated for the topical treatment of actinic keratoses (AK).

Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Apply diclofenac sodium gel gently to lesion areas twice daily. to adequately cover each lesion. Use 0.5 g of gel (pea size) on each 5 cm x 5 cm lesion site. The recommended duration of therapy is from 60 days to 90 days. Complete healing of the lesion(s) or optimal therapeutic effect may not be evident for up to 30 days following cessation of therapy. Lesions that do not respond to therapy should be re-evaluated and management reconsidered. Avoid contact of diclofenac sodium gel with eyes and mucous membranes.

Topical gel, 3%. Each gram of Diclofenac Sodium Topical Gel contains 30 mg of diclofenac sodium, USP in a clear, transparent, colorless to slightly yellow gel base. Diclofenac Sodium Gel, 3% is supplied in 100 g tubes.

Diclofenac sodium gel is contraindicated in the following patients: • With known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product [see Warnings and Precautions (5.1, 5.3) and Description (11)] • With the 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 (5.1, 5.2)] • Application on damaged skin resulting from any etiology, including exudative dermatitis, eczema, infected lesions, burns or wounds [see Warnings and Precautions (5.3)] • In the setting of coronary bypass graft (CABG) surgery [see Warnings and Precautions (5.4)]

5.1 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 (5.2)]. Seek emergency help if an anaphylactic reaction occurs. 5.2 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 gel is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When diclofenac sodium gel is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.3 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 gel at the first appearance of skin rash or any other sign of hypersensitivity. Diclofenac sodium gel is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. Do not apply diclofenac sodium gel to open skin wounds, infections, or exfoliative dermatitis, as it may affect absorption and tolerability of the drug [see Contraindications (4)]. 5.4 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 NSAID-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. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG. 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 gel in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium gel is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.5 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious 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 gel 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)]. 5.6 Hepatotoxicity In clinical trials with diclofenac sodium gel, 2 to 3% of subjects had elevations of liver function tests (LFTs) [see Clinical Trials Experience (6.1)]. To minimize the potential risk for an adverse liver-related event in patients treated with diclofenac sodium gel, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium gel with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics). 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 gel 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 gel immediately, and perform a clinical evaluation of the patient. 5.7 Hypertension NSAIDs, including diclofenac sodium gel, can lead to new onset of hypertension or worsening of pre-existing 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) during the initiation of NSAID treatment and throughout the course of therapy. 5.8 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)]. Avoid the use of diclofenac sodium gel in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac sodium gel is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.9 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. 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 is usually followed by recovery to the pretreatment state. No information is available from controlled clinical trials regarding the use of diclofenac sodium gel in patients with advanced renal disease. The renal effects of diclofenac sodium gel may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium gel. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium gel [see Drug Interactions (7)]. Avoid the use of diclofenac sodium gel in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium gel 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. 5.10 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 gel. 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 gel and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including diclofenac sodium gel, in pregnant women at about 30 weeks gestation and later. NSAIDs, including diclofenac sodium gel, 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, 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, after careful consideration of alternative treatment options for actinic keratoses, NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit diclofenac sodium gel use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac treatment extends beyond 48 hours. Discontinue diclofenac sodium gel 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 gel has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including diclofenac sodium gel, 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)]. 5.13 Masking of Inflammation and Fever The pharmacological activity of diclofenac sodium gel 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 (5.5, 5.6, 5.9)]. 5.15 Photosensitivity Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using diclofenac sodium gel. If patients need to be outdoors while using diclofenac sodium gel, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. Advise patients to discontinue treatment with diclofenac sodium gel at the first evidence of sunburn. 5.16 Exposure to Eyes and Mucosal Membranes Avoid contact of diclofenac sodium gel with eyes and mucosa. Advise patients that if contact in the eye, or mucosal membranes occurs, immediately wash out the eye or mucosal membranes 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 and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin. Do not use diclofenac sodium gel in combination with an oral NSAID unless the benefit outweighs the risk and periodic laboratory evaluations are conducted.

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 gel 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 (5.5)]. Aspirin Clinical Impact: • 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 (5.5)]. Intervention: • Concomitant use of diclofenac sodium gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. Diclofenac sodium gel 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 gel 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 gel 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 (5.9)]. • 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 gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.9)]. Digoxin Clinical Impact: • 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 gel 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 gel and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: • Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: • During concomitant use of diclofenac sodium gel and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: • Concomitant use of diclofenac sodium gel and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: • During concomitant use of diclofenac sodium gel and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: • Concomitant use of diclofenac sodium gel with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity [see Warnings and Precautions (5.5)]. Intervention: • The concomitant use of diclofenac sodium gel with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: • Concomitant use of diclofenac sodium gel 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 gel 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 of 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.

8.1 Pregnancy Risk Summary Use of NSAIDs, including diclofenac sodium gel, 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 gel use between about 20 and 30 weeks of gestation and avoid diclofenac sodium gel use at about 30 weeks of gestation and later in pregnancy. 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. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including diclofenac sodium gel, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. 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 malformations was observed in mice, rats, or rabbits given diclofenac during the period of organogenesis at doses at least 15 times, the maximum recommended human dose (MRHD) of diclofenac sodium gel (see Data). Based on published animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization, and 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 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 gel, can cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment If after careful consideration of alternative treatment options for actinic keratoses, 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 gel treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue diclofenac sodium gel and follow up according to clinical practice. Labor or Delivery There are no studies on the effects of diclofenac sodium gel 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 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 The multiples provided in this labeling are based on an MRHD that assumes 10% bioavailability following topical application of 2 g diclofenac sodium gel per day (1 mg/kg diclofenac sodium). Reproductive studies performed with diclofenac sodium alone at oral doses up to 20 mg/kg/day (15 times the MRHD based on body surface area (BSA) comparisons) in mice, 10 mg/kg/day (15 times the MRHD based on BSA comparisons) in rats, and 10 mg/kg/day (30 times the MRHD based on BSA comparisons) in rabbits have revealed no evidence of malformations despite the induction of maternal toxicity. In rats, 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. 8.2 Lactation Risk Summary Data from published literature cases with oral preparations of diclofenac indicate the presence of small amounts of diclofenac in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diclofenac sodium gel and any potential adverse effects on the breastfed infant from the diclofenac sodium gel 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). The systemic bioavailability after topical application of diclofenac sodium gel is lower than after oral dosing [see Clinical Pharmacology (12.3)]. 8.3 Females and Males of Reproductive Potential Female Infertility Based on the mechanism of action, the use of prostaglandin mediated NSAIDs, including diclofenac sodium gel, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women [see Clinical Pharmacology (12.1)]. Published animal studies have shown that administration of 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 gel, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Actinic keratoses is not a condition seen within the pediatric population. diclofenac sodium gel should not be used by children. 8.5 Geriatric Use 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 (5.4, 5.5, 5.6, 5.9, 5.14)]. Of the 211 subjects treated with diclofenac sodium gel in controlled clinical trials, 143 subjects were 65 years of age and over. Of those 143 subjects, 55 subjects were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Each gram of Diclofenac Sodium Topical Gel, 3% contains 30 mg of diclofenac sodium, USP. Diclofenac Sodium Gel, 3% is available as follows: NDC 68462-355-94 100 g tube (1 tube per carton) Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from heat. Avoid freezing.

12.1 Mechanism of Action The mechanism of action of diclofenac sodium in the treatment of actinic keratoses (AK) is unknown. 12.2 Pharmacodynamics The pharmacodynamics of diclofenac sodium gel in the treatment of actinic keratosis has not been assessed. 12.3 Pharmacokinetics Absorption Diclofenac levels were measured at the end of treatment from 60 patients with AK lesions treated with diclofenac sodium gel in three adequate and well-controlled clinical trials. Each patient was administered 0.5 g of diclofenac sodium gel twice a day for up to 105 days. There were up to three 5 cm x 5 cm treatment sites per patient on the face, forehead, hands, forearm, and scalp. Serum concentrations of diclofenac were, on average, at or below 20 ng/mL. Distribution Diclofenac binds tightly to serum albumin. Metabolism Biotransformation of diclofenac following oral administration involves conjugation at the carboxyl group of the side chain or single or multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much smaller extent than diclofenac. Metabolism of diclofenac following topical administration is thought to be similar to that after oral administration. The small amounts of diclofenac and its metabolites appearing in the plasma following topical administration makes the quantification of specific metabolites imprecise. Elimination Diclofenac and its metabolites are excreted mainly in the urine after oral dosing.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There did not appear to be any increase in drug-related neoplasms following daily topical applications of diclofenac sodium gel for 2 years at concentrations up to 0.035% diclofenac sodium and 2.5% hyaluronate sodium in albino mice. When administered orally for 2 years, diclofenac showed no evidence of carcinogenic potential in rats given diclofenac sodium at up to 2 mg/kg/day (3 times the MRHD based on BSA comparison), or in mice given diclofenac sodium at up to 0.3 mg/kg/day in males and 1 mg/kg/day in females (25% and 83%, respectively, of the MRHD based on BSA comparison). Diclofenac was not genotoxic in in vitro point mutation assays in mammalian mouse lymphoma cells and Ames microbial test systems, or when tested in mammalian in vivo assays including dominant lethal and male germinal epithelial chromosomal studies in mice, and nucleus anomaly and chromosomal aberration studies in Chinese hamsters. It was also negative in the transformation assay utilizing BALB/3T3 mouse embryo cells. Fertility studies have not been conducted with diclofenac sodium gel. Diclofenac sodium showed no evidence of impairment of fertility after oral treatment with 4 mg/kg/day (7 times the MRHD based on BSA comparison) in male or female rats.

Clinical trials were conducted involving a total of 427 subjects (213 treated with diclofenac sodium gel and 214 with a gel vehicle). Each subject had no fewer than five AK lesions in a major body area, which was defined as one of five 5 cm x 5 cm regions: scalp, forehead, face, forearm and hand. Up to three major body areas were studied in any subject. All subjects were 18 years of age or older (male and female) with no clinically significant medical problems outside of the AK lesions and had undergone a 60-day washout period from disallowed medications (masoprocol, 5-fluorouracil, cyclosporine, retinoids, trichloroacetic acid/lactic acid/peel, 50% glycolic acid peel) and hyaluronan-containing cosmetics. Subjects were excluded from participation for reasons of known or suspected hypersensitivity to any diclofenac sodium gel ingredient, pregnancy, allergies to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other dermatological conditions which might affect the absorption of the study medication. Application of dermatologic products such as sunscreens, cosmetics, and other drug products was not permitted. Subjects were instructed to apply a small amount of diclofenac sodium gel (approximately 0.5 g) onto the affected skin, using their fingers, and gently smoothing the gel over the lesion. In addition, all subjects were instructed to avoid sun exposure. Complete clearing of the AK lesions 30 days after completion of treatment was the primary efficacy variable. No long-term subject follow-ups, after the 30-day assessments, were performed for the detection of recurrence. Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (all locations) Diclofenac Sodium Gel Vehicle p-value Study 1 90 days treatment 27/58 (47%) 11/59 (19%) <0.001 Study 2 90 days treatment 18/53 (34%) 10/55 (18%) 0.061 Study 3 60 days treatment 15/48 (31%) 5/49 (10%) 0.021 30 days treatment 7/49 (14%) 2/49 ( 4%) 0.221 Complete Clearance of Actinic Keratosis Lesions 30 Days Post-Treatment (by location) Scalp Forehead Face Arm/Forearm Back of Hand Study 1 90 days treatment Diclofenac Sodium Gel 1/4 (25%) 17/30 (57%) 9/17 (53%) 4/12 (33%) 6/16 (38%) Vehicle 3/9 (33%) 8/24 (33%) 5/17 (29%) 4/12 (33%) 0/14 (0) p-value 0.7646 0.0908 0.1682 1.000 0.0650 Study 2 90 days treatment Diclofenac Sodium Gel 2/6 (33%) 9/19 (47%) 4/5 (80%) 5/8 (63%) 1/17 (6%) Vehicle 0/4 (0) 6/22 (27%) 2/8 (25%) 0/5 (0) 3/16 (19%) p-value 0.4235 0.1870 0.0727 0.0888 0.2818 Study 3 60 days treatment Diclofenac Sodium Gel 3/7 (43%) 13/31 (42%) 10/19 (53%) 0/1 (0) 2/8 (25%) Vehicle 0/6 (0) 5/36 (14%) 2/13 (15%) 0/2 (0) 1/9 (11%) p-value 0.2271 0.0153 0.0433 - 0.4637 30 days treatment Diclofenac Sodium Gel 2/5 (40%) 4/29 (14%) 3/14 (21%) 0/0 (0) 0/9 (0) Vehicle 0/5 (0) 2/29 (7%) 2/18 (11%) 0/1 (0) 1/9 (11%) p-value 0.2299 0.3748 0.4322 - 0.6521 All data combined Diclofenac Sodium Gel 8/22 (36%) 43/109 (39%) 26/55 (47%) 9/21 (43%) 9/50 (18%) Vehicle 3/24 (13%) 21/111 (19%) 11/56 (20%) 4/20 (20%) 5/48 (10%) p-value 0.0903 0.0013 0.0016 0.2043 0.3662

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