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| Product NDC Code | 45865-983 | ||||
|---|---|---|---|---|---|
| Drug Name | Diclofenac sodium topical solution |
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| Type | Brand | ||||
| Pharm Class | Anti-Inflammatory Agents, Non-Steroidal [CS], Cyclooxygenase Inhibitors [MoA], Decreased Prostaglandin Production [PE], Nonsteroidal Anti-inflammatory Drug [EPC] |
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| Active Ingredients |
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| Route | TOPICAL | ||||
| Dosage Form | SOLUTION | ||||
| RxCUI drug identifier | 857700 | ||||
| Application Number | ANDA206715 | ||||
| Labeler Name | medsource pharmaceuticals | ||||
| Packages |
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| Check if available Online | Get Medication Prices online with Discount |
Overdosage of Diclofenac Sodium Topical Solution
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare. [see Warnings and Precautions ( 5.1 , 5.2 . 5.4 , 5.6 )] . Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Emesis is not recommended due to a possibility of aspiration and subsequent respiratory irritation by DMSO contained in Diclofenac Sodium topical solution, 1.5% w/w. Consider activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdose treatment, contact a poison control center (1-800-222- 1222).
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1) ] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Hypertension [see Warnings and Precautions (5.4) ] Heart Failure and Edema [see Warnings and Precautions (5.5) ] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6) ] Anaphylactic Reactions [see Warnings and Precautions (5.7) ] Serious Skin Reactions [see Warnings and Precautions (5.9) ] Hematologic Toxicity [see Warnings and Precautions (5.11) ] Most common adverse reactions with Diclofenac Sodium topical solution, 1.5% w/w are application site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Diclofenac Sodium topical solution, 1.5% w/w of 911 patients treated between 4 and 12 weeks (mean duration of 49 days) in seven Phase 3 controlled trials, as well as exposure of 793 patients treated in an open-label study, including 463 patients treated for at least 6 months, and 144 patients treated for at least 12 months. The population mean age was approximately 60 years, 89% of patients were Caucasians, 64% were females, and all patients had primary osteoarthritis. The most common adverse events with Diclofenac Sodium topical solution, 1.5% w/w were application site skin reactions. These events were the most common reason for withdrawing from the studies. Application Site Reactions In controlled trials, the most common treatment-related adverse events in patients receiving Diclofenac Sodium topical solution, 1.5% w/w were application site skin reactions. Application site reactions were characterized by one or more of the following: dryness, erythema, induration, vesicles, paresthesia, pruritus, vasodilation, acne, and urticaria. The most frequent of these reactions were dry skin (32%), contact dermatitis characterized by skin erythema and induration (9%), contact dermatitis with vesicles (2%) and pruritus (4%). In one controlled trial, a higher rate of contact dermatitis with vesicles (4%) was observed after treatment of 152 subjects with the combination of Diclofenac Sodium topical solution, 1.5% w/w and oral diclofenac. In the open label uncontrolled long-term safety study, contact dermatitis occurred in 13% and contact dermatitis with vesicles in 10% of patients, generally within the first 6 months of exposure, leading to a withdrawal rate for an application site event of 14%. Adverse Events Common to the NSAID Class In controlled trials, subjects treated with Diclofenac Sodium topical solution, 1.5% w/w experienced some adverse events associated with the NSAID class more frequently than subjects using placebo (constipation, diarrhea, dyspepsia, nausea, flatulence, abdominal pain, edema; see Table 1 ). The combination of Diclofenac Sodium topical solution, 1.5% w/w and oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%), and hemoglobin (13% vs. 9%), but no difference in elevation of liver transaminases. Table 1 lists all adverse reactions occurring in ≥1% of patients receiving Diclofenac Sodium topical solution, 1.5% w/w, where the rate in the Diclofenac Sodium topical solution, 1.5% w/w group exceeded placebo, from seven controlled studies conducted in patients with osteoarthritis. Since these trials were of different durations, these percentages do not capture cumulative rates of occurrence. Table 1: Adverse Reactions occurring in ≥1% of patients treated with Diclofenac Sodium topical solution, 1.5% w/w in placebo and oral diclofenac-controlled trials. Treatment Group: Diclofenac Sodium topical solution, 1.5% w/w N=911 Topical Placebo N=332 Adverse Reaction † N (%) N (%) Dry Skin (Application Site) 292 (32) 17 (5) Contact Dermatitis (Application Site) 83 (9) 6 (2) Dyspepsia 72(8) 13 (4) Abdominal Pain 54 (6) 10 (3) Flatulence 35 (4) 1 (<1) Pruritus (Application Site) 34 (4) 7 (2) Diarrhea 33 (4) 7 (2) Nausea 33 (4) 3 (1) Pharyngitis 40 (4) 13 (4) Constipation 29 (3) 1 (<1) Edema 26 (3) 0 Rash (Non-Application Site) 25 (3) 5 (2) Infection 25 (3) 8 (2) Ecchymosis 19 (2) 1 (<1) Dry Skin (Non-Application Site) 19 (2) 1 (<1) Contact Dermatitis, vesicles (Application Site) 18 (2) 0 Paresthesia (Non-Application Site) 14 (2) 3 (<1) Accidental Injury 22 (2) 7 (2) Pruritus (Non-Application Site) 15 (2) 2 (<1) Sinusitis 10 (1) 2 (<1) Halitosis 11 (1) 1 (<1) Application Site Reaction (not otherwise specified) 11 (1) 3 (<1) † Preferred Term according to COSTART 6.2 Postmarketing Experience In non-U.S. postmarketing surveillance, the following adverse reactions have been reported during post-approval use of Diclofenac Sodium topical solution, 1.5% w/w. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: abdominal pain, accidental injury, allergic reaction, asthenia, back pain, body odor, chest pain, edema, face edema, halitosis, headache, lack of drug effect, neck rigidity, pain Cardiovascular: palpitation, cardiovascular disorder Digestive: diarrhea, dry mouth, dyspepsia, gastroenteritis, decreased appetite, mouth ulceration, nausea, rectal hemorrhage, ulcerative stomatitis Metabolic and Nutritional: creatinine increased Musculoskeletal: leg cramps, myalgia Nervous: depression, dizziness, drowsiness, lethargy, paresthesia, paresthesia at application site Respiratory: asthma, dyspnea, laryngismus, laryngitis, pharyngitis Skin and Appendages: At the Application Site: contact dermatitis, contact dermatitis with vesicles, dry skin, pruritus, rash; Other Skin and Appendages Adverse Reactions: eczema, rash, pruritus, skin discoloration, urticaria Special Senses: abnormal vision, blurred vision, cataract, ear pain, eye disorder, eye pain, taste perversion
| Treatment Group: | Diclofenac Sodium topical solution, 1.5% w/w N=911 | Topical Placebo N=332 |
| Adverse Reaction † | N (%) | N (%) |
| Dry Skin (Application Site) | 292 (32) | 17 (5) |
| Contact Dermatitis (Application Site) | 83 (9) | 6 (2) |
| Dyspepsia | 72(8) | 13 (4) |
| Abdominal Pain | 54 (6) | 10 (3) |
| Flatulence | 35 (4) | 1 (<1) |
| Pruritus (Application Site) | 34 (4) | 7 (2) |
| Diarrhea | 33 (4) | 7 (2) |
| Nausea | 33 (4) | 3 (1) |
| Pharyngitis | 40 (4) | 13 (4) |
| Constipation | 29 (3) | 1 (<1) |
| Edema | 26 (3) | 0 |
| Rash (Non-Application Site) | 25 (3) | 5 (2) |
| Infection | 25 (3) | 8 (2) |
| Ecchymosis | 19 (2) | 1 (<1) |
| Dry Skin (Non-Application Site) | 19 (2) | 1 (<1) |
| Contact Dermatitis, vesicles (Application Site) | 18 (2) | 0 |
| Paresthesia (Non-Application Site) | 14 (2) | 3 (<1) |
| Accidental Injury | 22 (2) | 7 (2) |
| Pruritus (Non-Application Site) | 15 (2) | 2 (<1) |
| Sinusitis | 10 (1) | 2 (<1) |
| Halitosis | 11 (1) | 1 (<1) |
| Application Site Reaction (not otherwise specified) | 11 (1) | 3 (<1) |
Diclofenac Sodium Topical Solution Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS 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 topical solution, 1.5% w/w 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 topical solution, 1.5% w/w and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Diclofenac Sodium topical solution, 1.5% w/w 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 betablockers (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 topical solution, 1.5% w/w and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w 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 topical solution, 1.5% w/w 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 topical solution, 1.5% w/w 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 topical solution, 1.5% w/w 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 topical solution, 1.5% w/w and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w 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 topical solution, 1.5% w/w 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 topical solution, 1.5% w/w and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. Pemetrexed Clinical Impact: Concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w 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 topical solution, 1.5% w/w with drugs that interfere with hemostasis. Concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with Diclofenac Sodium topical solution, 1.5% w/w may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs : Concomitant use with Diclofenac Sodium topical solution, 1.5% w/w 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 topical solution, 1.5% w/w can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 )
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| | Monitor patients with concomitant use of Diclofenac Sodium topical solution, 1.5% w/w 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 |
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| | 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 |
| | Concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding |
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| | 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. |
| | During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
| | |
| | The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin. |
| | During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and digoxin, monitor serum digoxin levels. |
| | |
| | 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. |
| | During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and lithium, monitor patients for signs of lithium toxicity. |
| | |
| | Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| | During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and methotrexate, monitor patients for methotrexate toxicity. |
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| | Concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| | During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and cyclosporine, monitor patients for signs or worsening renal function. |
| | |
| | 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 |
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| | Concomitant use of Diclofenac Sodium topical solution, 1.5% w/w and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| | During concomitant use of Diclofenac Sodium topical solution, 1.5% w/w 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. |
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of Diclofenac Sodium topical solution 1.5% w/w, 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, 1.5% w/w, 40 drops (approximately 1.2 mL) to each knee (80 drops total dose), the following diclofenac pharmacokinetic parameters were obtained: (see Table 3 ). Table 3: 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 Pharmacokinetic Parameters Diclofenac sodium Normal Adults [N=18] (Age: 18-55 years) Normal Adults [N=19] (Age: 18-55 years) Single Dose Multiple Dose Four times daily for 7 days AUC 0-t 177.5 ± 72.6 ng.h/mL 695.4 ± 348.9 ng.h/mL AUC 0-inf 196.3 ± 68.5 ng.h/mL 745.2 ± 374.7 ng.h/mL Plasma C max 8.1 ± 5.9 ng/mL 19.4 ± 9.3 ng/mL Plasma T max (h) 11.0 ± 6.4 4.0 ± 6.5 Plasma t 1/2 (h) 36.7 ± 20.8 79.0 ± 38.1 Kel (h -1 ) 0.024 ± 0.010 0.011 ± 0.004 CL/F (L/h) 244.7 ± 84.7 1 -- 1 Apparent total body clearance Absorption Diclofenac systemic exposure from Diclofenac Sodium topical solution, 1.5% w/w 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, 1.5% w/w 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 Parameters | Diclofenac sodium | |
| Normal Adults [N=18] (Age: 18-55 years) | Normal Adults [N=19] (Age: 18-55 years) | |
| Single Dose | | |
| AUC 0-t | 177.5 ± 72.6 ng.h/mL | 695.4 ± 348.9 ng.h/mL |
| AUC 0-inf | 196.3 ± 68.5 ng.h/mL | 745.2 ± 374.7 ng.h/mL |
| Plasma C max | 8.1 ± 5.9 ng/mL | 19.4 ± 9.3 ng/mL |
| Plasma T max (h) | 11.0 ± 6.4 | 4.0 ± 6.5 |
| Plasma t 1/2 (h) | 36.7 ± 20.8 | 79.0 ± 38.1 |
| Kel (h -1) | 0.024 ± 0.010 | 0.011 ± 0.004 |
| CL/F (L/h) | 244.7 ± 84.7 1 | -- |
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.12.1 Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of Diclofenac Sodium topical solution 1.5% w/w, 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.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics After topical administration to healthy human volunteers of single and multiple maximum doses of Diclofenac Sodium topical solution, 1.5% w/w, 40 drops (approximately 1.2 mL) to each knee (80 drops total dose), the following diclofenac pharmacokinetic parameters were obtained: (see Table 3 ). Table 3: 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 Pharmacokinetic Parameters Diclofenac sodium Normal Adults [N=18] (Age: 18-55 years) Normal Adults [N=19] (Age: 18-55 years) Single Dose Multiple Dose Four times daily for 7 days AUC 0-t 177.5 ± 72.6 ng.h/mL 695.4 ± 348.9 ng.h/mL AUC 0-inf 196.3 ± 68.5 ng.h/mL 745.2 ± 374.7 ng.h/mL Plasma C max 8.1 ± 5.9 ng/mL 19.4 ± 9.3 ng/mL Plasma T max (h) 11.0 ± 6.4 4.0 ± 6.5 Plasma t 1/2 (h) 36.7 ± 20.8 79.0 ± 38.1 Kel (h -1 ) 0.024 ± 0.010 0.011 ± 0.004 CL/F (L/h) 244.7 ± 84.7 1 -- 1 Apparent total body clearance Absorption Diclofenac systemic exposure from Diclofenac Sodium topical solution, 1.5% w/w 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, 1.5% w/w 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 Parameters | Diclofenac sodium | |
| Normal Adults [N=18] (Age: 18-55 years) | Normal Adults [N=19] (Age: 18-55 years) | |
| Single Dose | | |
| AUC 0-t | 177.5 ± 72.6 ng.h/mL | 695.4 ± 348.9 ng.h/mL |
| AUC 0-inf | 196.3 ± 68.5 ng.h/mL | 745.2 ± 374.7 ng.h/mL |
| Plasma C max | 8.1 ± 5.9 ng/mL | 19.4 ± 9.3 ng/mL |
| Plasma T max (h) | 11.0 ± 6.4 | 4.0 ± 6.5 |
| Plasma t 1/2 (h) | 36.7 ± 20.8 | 79.0 ± 38.1 |
| Kel (h -1) | 0.024 ± 0.010 | 0.011 ± 0.004 |
| CL/F (L/h) | 244.7 ± 84.7 1 | -- |
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Diclofenac Sodium topical solution, 1.5% w/w is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac sodium 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)
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Diclofenac Sodium topical solution 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 contains 1.5% w/w of 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 or slightly yellowish crystalline powder, slightly hygroscopic, and odorless that is freely soluble in methanol, soluble in alcohol, slightly soluble in acetone and sparingly soluble in water. 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, 1.5% w/w include: dimethyl sulfoxide USP (DMSO, 45.5% w/w), propylene glycol, alcohol, glycerin and purified water. Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION 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, 1.5% w/w to clean, dry skin. (2.1) Dispense Diclofenac Sodium topical solution, 1.5% w/w 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, 1.5% w/w 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, 1.5% w/w in your eyes, nose or mouth (2.2) . 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, 1.5% w/w to clean, dry skin. To avoid spillage, dispense Diclofenac Sodium topical solution, 1.5% w/w 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, 1.5% w/w 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, 1.5% w/w 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, 1.5% w/w to the treated knee. Wash and dry hands after use. Do not apply Diclofenac Sodium topical solution, 1.5% w/w to open wounds. Avoid contact of Diclofenac Sodium topical solution, 1.5% w/w 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, 1.5% w/w-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, 1.5% w/w. 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, 1.5% w/w and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Diclofenac Sodium topical solution: 1.5% w/w Diclofenac Sodium topical solution 1.5% w/w (3)
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Diclofenac Sodium topical solution, 1.5% w/w is indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s) (1). Diclofenac Sodium topical solution, 1.5% w/w is a nonsteroidal anti-inflammatory drug indicated for the treatment of signs and symptoms of osteoarthritis of the knee(s). ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.Diclofenac Sodium Topical Solution Diclofenac Sodium GLYCERIN WATER DICLOFENAC SODIUM DICLOFENAC DIMETHYL SULFOXIDE PROPYLENE GLYCOL ALCOHOL clear, colorless to faintly pink-orange
Animal pharmacology and or toxicology
Information from studies of the drug in animals, if the data were not relevant to nor included in other parts of the labeling. Most labels do not contain this field.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, 1.5% w/w. 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.
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day corresponding to approximately 0.35- and 0.7-fold (mouse and rat, respectively) of the maximum recommended human topical dose (MRHD) of Diclofenac Sodium topical solution, 1.5% w/w (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, 1.5% w/w) 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, 1.5% w/w) 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, 1.5% w/w. 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, 1.5% w/w 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.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies in mice and rats administered diclofenac sodium as a dietary constituent for 2 years resulted in no significant increases in tumor incidence at doses up to 2 mg/kg/day corresponding to approximately 0.35- and 0.7-fold (mouse and rat, respectively) of the maximum recommended human topical dose (MRHD) of Diclofenac Sodium topical solution, 1.5% w/w (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, 1.5% w/w) 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, 1.5% w/w) 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, 1.5% w/w. 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, 1.5% w/w 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, 1.5% w/w. 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.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.pdp
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.RECENT MAJOR CHANGES Boxed Warning 5/2016 Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016 Warnings and Precautions, Heart Failure and Edema (5.5) 5/2016
Diclofenac Sodium Topical Solution: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) and Instructions for Use that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Diclofenac Sodium topical solution, 1.5% w/w and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1) ] . Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2) ] . Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Diclofenac Sodium topical solution, 1.5% w/w and seek immediate medical therapy [see Warnings and Precautions (5.3) ] . Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5) ] . Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g. difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7) ] . Serious Skin Reactions Advise patients to stop Diclofenac Sodium topical solution, 1.5% w/w immediately if they develop any type of generalized rash and contact their physicians as soon as possible. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including Diclofenac Sodium topical solution, 1.5% w/w, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3) ] . Fetal Toxicity Inform pregnant women to avoid use of Diclofenac Sodium topical solution, 1.5% w/w and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1) ] . Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of Diclofenac Sodium topical solution, 1.5% w/w with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7) ] . Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with Diclofenac Sodium topical solution, 1.5% w/w until they talk to their healthcare provider [see Drug Interactions (7) ] . Eye Exposure Instruct patients to avoid contact of Diclofenac Sodium topical solution, 1.5% w/w with the 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. Prevention of Secondary Exposure Instruct patients to avoid skin-to-skin contact between other people and the knee(s) to which Diclofenac Sodium topical solution, 1.5% w/w was applied until the knee(s) is completely dry. Application Site Reactions Diclofenac Sodium topical solution, 1.5% w/w can cause a localized skin reaction at the application site. Advise patients to contact their physicians as soon as possible if they develop any type of localized application site rash. Special Application Instructions Instruct patients not to apply Diclofenac Sodium topical solution, 1.5% w/w to open skin wounds, infections, inflammations, or exfoliative dermatitis, as it may affect absorption and reduce tolerability of the drug. Instruct patients to wait until the area treated with Diclofenac Sodium topical solution, 1.5% w/w is completely dry before applying sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medication. Instruct patients to minimize or avoid exposure of treated knee(s) to natural or artificial sunlight. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 Rev: 08/2018
Instructions for use
Information about safe handling and use of the drug product.Instructions for Use Diclofenac Sodium topical solution, 1.5% w/w Read the Medication Guide that comes with Diclofenac Sodium topical solution, 1.5% w/w first. Be sure that you read, understand and follow these Instructions for Use before you use Diclofenac Sodium topical solution, 1.5% w/w for the first time. Important: For use on the skin only (topical). Do not get Diclofenac Sodium topical solution, 1.5% w/w in your eyes, nose or mouth. Before you use Diclofenac Sodium topical solution, 1.5% w/w: Apply Diclofenac Sodium topical solution, 1.5% w/w 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, 1.5% w/w to treat pain from osteoarthritis in your knee or knees. Apply Diclofenac Sodium topical solution, 1.5% w/w on clean, dry skin that does not have any cuts, infections or rashes. Use Diclofenac Sodium topical solution, 1.5% w/w four times a day on your knee or knees as prescribed. Your total dose for each knee is 40 drops of Diclofenac Sodium topical solution, 1.5% w/w, each time you use it. If you get Sodium topical solution, 1.5% w/w 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, 1.5% w/w: Step 1. Wash your hands with soap and water before and after applying Diclofenac Sodium topical solution, 1.5% w/w Step 2. Put 10 drops of Diclofenac Sodium topical solution, 1.5% w/w either on your hand or directly on your knee (see Figure A). Step 3. Spread Diclofenac Sodium topical solution, 1.5% w/w 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, 1.5% w/w. Step 4. If your healthcare provider has prescribed Diclofenac Sodium topical solution, 1.5% w/w for both knees, repeat steps 2 and 3 for the other knee. After you use Diclofenac Sodium topical solution, 1.5% w/w: Wash your hands with soap and water right away after applying Diclofenac Sodium topical solution, 1.5% w/w. Do not: touch the treated knee or allow another person to touch the knee treated with Diclofenac Sodium topical solution, 1.5% w/w until your knee is completely dry. cover your knee with clothing until your knee is completely dry. put sunscreen, insect repellant, lotion, moisturizer, cosmetics, or other topical medicines on your knee until it is completely dry. take a shower or a bath for at least 30 minutes after you put Diclofenac Sodium topical solution, 1.5% w/w on your knee. use heating pads or cover the treated area with bandages where you have applied Diclofenac Sodium topical solution, 1.5% w/w. 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, 1.5% w/w? Store Diclofenac Sodium topical solution, 1.5% w/w at room temperature between 68°F to 77°F (20°C to 25°C). Keep product stored upright at all times. Keep Diclofenac Sodium topical solution, 1.5% w/w and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 Rev: 08/2018 26700 Ingenus Figure A Figure B Figure C
Spl medguide
Information about the patient medication guide that accompanies the drug product. Certain drugs must be dispensed with an accompanying medication guide. This field may contain information about when to consult the medication guide and the contents of the medication guide.Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: with increasing doses of NSAIDs with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: anytime during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with: past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” increasing doses of NSAIDs longer use of NSAIDs smoking drinking alcohol older age poor health advanced liver disease bleeding problems NSAIDs should only be used: exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy. are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include : stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: shortness of breath or trouble breathing chest pain weakness in one part or side of your body slurred speech swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea more tired or weaker than usual diarrhea itching your skin or eyes look yellow indigestion or stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 This Medication Guide has been approved by the U.S. Food and Drug Administration . Rev: 08/2018
Clinical studies
This field may contain references to clinical studies in place of detailed discussion in other sections of the labeling.14 CLINICAL STUDIES 14.1 Studies in Osteoarthritis of the Knee The use of Diclofenac Sodium topical solution, 1.5% w/w for the treatment of the signs and symptoms of osteoarthritis of the knee was evaluated in two double-blind controlled trials conducted in the US and Canada, involving patients treated with Diclofenac Sodium topical solution, 1.5% w/w at a dose of 40 drops four times a day for 12 weeks. Diclofenac Sodium topical solution, 1.5% w/w was compared to topical placebo (2.3% DMSO with other excipients) and/or topical vehicle solution (45.5% w/w DMSO with other excipients), applied directly to the study knee. In both trials, Diclofenac Sodium topical solution, 1.5% w/w treatment resulted in statistically significant clinical improvement compared to placebo and/or vehicle, in all three primary efficacy variables―pain, physical function (Western Ontario and McMaster Universities LK3.1 OA Index (WOMAC) pain and physical function dimensions) and Patient Overall Health Assessment (POHA)/Patient Global Assessment (PGA). Numerical results are summarized in Tables 4 and 5. Table 4: Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of Diclofenac Sodium topical solution, 1.5% w/w Efficacy Variable Study I Mean baseline score and mean change in efficacy variables after 12 weeks of treatment Mean Baseline score Diclofenac Sodium topical solution, 1.5% w/w N=154 Topical placebo 1 N=155 Topical vehicle 2 N=161 WOMAC pain score (Likert 3.1, 0-20) 13 -6.0 -4.7 -4.7 WOMAC physical function (Likert 3.1, 0-68) 42 -15.7 -12.3 -12.1 POHA (0-4) 2.3 -1.0 -0.4 -0.6 1 placebo formulation included 2.3% DMSO 2 vehicle formulation included 45.5% DMSO Table 5: Change in treatment outcomes after 12 weeks of treatment in one study of efficacy of Diclofenac Sodium topical solution, 1.5% w/w Efficacy Variable Study II Mean baseline score and mean change in efficacy variables after 12 weeks of treatment Mean Baseline score Diclofenac Sodium topical solution, 1.5% w/w N=164 Topical vehicle 1 N=162 WOMAC pain score (Likert 3.1, 0-20) 13 -5.9 -4.4 WOMAC physical function (Likert 3.1, 0-68) 42 -15.3 -10.3 PGA (0-4) 3.1 -1.3 -1.0 1 vehicle formulation included 45.5% DMSO
| Efficacy Variable | Study I Mean baseline score and mean change in efficacy variables after 12 weeks of treatment | |||
| Mean Baseline score | Diclofenac Sodium topical solution, 1.5% w/w N=154 | Topical placebo 1 N=155 | Topical vehicle 2 N=161 | |
| WOMAC pain score (Likert 3.1, 0-20) | 13 | -6.0 | -4.7 | -4.7 |
| WOMAC physical function (Likert 3.1, 0-68) | 42 | -15.7 | -12.3 | -12.1 |
| POHA (0-4) | 2.3 | -1.0 | -0.4 | -0.6 |
| 1placebo formulation included 2.3% DMSO 2vehicle formulation included 45.5% DMSO | ||||
| Efficacy Variable | Study II Mean baseline score and mean change in efficacy variables after 12 weeks of treatment | ||
| Mean Baseline score | Diclofenac Sodium topical solution, 1.5% w/w N=164 | Topical vehicle 1 N=162 | |
| WOMAC pain score (Likert 3.1, 0-20) | 13 | -5.9 | -4.4 |
| WOMAC physical function (Likert 3.1, 0-68) | 42 | -15.3 | -10.3 |
| PGA (0-4) | 3.1 | -1.3 | -1.0 |
| 1vehicle formulation included 45.5% DMSO | |||
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.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 topical solution, 1.5% w/w in seven controlled, Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with Diclofenac Sodium topical solution, 1.5% w/w in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to Diclofenac Sodium topical solution, 1.5% w/w for this elderly population.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation. Risk Summary Use of NSAIDs, including Diclofenac Sodium topical solution, 1.5% w/w, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Diclofenac Sodium topical solution, 1.5% w/w, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of Diclofenac Sodium topical solution, 1.5% w/w in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in Diclofenac Sodium topical solution, 1.5% w/w) are equivocal as to potential teratogenicity. 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 topical solution, 1.5% w/w, 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, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of Diclofenac Sodium topical solution, 1.5% w/w during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data 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 topical solution, 1.5% w/w, 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, 1.5% w/w) 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.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS Pregnancy : Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation ( 5.10 , 8.1 ) Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of Diclofenac Sodium topical solution, 1.5% w/w in women who have difficulties conceiving (8.3) 8.1 Pregnancy Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation. Risk Summary Use of NSAIDs, including Diclofenac Sodium topical solution, 1.5% w/w, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Diclofenac Sodium topical solution, 1.5% w/w, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of Diclofenac Sodium topical solution, 1.5% w/w in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. Published reproductive and developmental studies of dimethyl sulfoxide (DMSO, the solvent used in Diclofenac Sodium topical solution, 1.5% w/w) are equivocal as to potential teratogenicity. 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 topical solution, 1.5% w/w, 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, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of Diclofenac Sodium topical solution, 1.5% w/w during labor or delivery. In animal studies, NSAIDS, including diclofenac, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data 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 topical solution, 1.5% w/w, 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, 1.5% w/w) 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. 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 diclofenac and any potential adverse effects on the breastfed infant from the diclofenac 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 topical solution, 1.5% w/w, 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 topical solution, 1.5% w/w, 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 topical solution, 1.5% w/w in seven controlled, Phase 3 clinical trials, 444 subjects were 65 years of age and over. There was no age-related difference in the incidence of adverse events. Of the 793 patients treated with Diclofenac Sodium topical solution, 1.5% w/w in one open-labeled safety trial, 334 subjects were 65 years of age and over including 107 subjects 75 and over. There was no difference in the incidence of adverse events with long-term exposure to Diclofenac Sodium topical solution, 1.5% w/w for this elderly population.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING Diclofenac Sodium topical solution, 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 dropper cap. NDC Number & Size 150 mL bottle NDC #50742-308-05 Storage Store at room temperature 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]. Keep product stored upright at all times.
Storage and handling
Information about safe storage and handling of the drug product.Storage Store at room temperature 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]. Keep product stored upright at all times.
Boxed warning
Information about contraindications or serious warnings, particularly those that may lead to death or serious injury.WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1) ]. Diclofenac Sodium topical solution, 1.5% w/w is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1) ]. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2) ]. WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning . Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) Diclofenac Sodium topical solution, 1.5% w/w is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) NSAIDs, cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and or GI bleeding are at greater risk for serious GI events. (5.2)
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API