Xiclofen

1. ​INDICATIONS & USAGE Xiclofen TM Ointment is indicated in adults over the age of 12 years old for the treatment of signs and symptoms of osteoarthritis of the joints, and of acute and chronic pain in muscles and joints associated with muscle soreness, strains, sprains, arthritis, simple backache, muscle stiffness, and more.

2. DOSAGE & ADMINISTRATION 2.1 General Dosing Instructions Use Xiclofen TM Ointment only on dry, intact (unbroken) skin. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Avoid contact with eyes and mucous membranes. Avoid showering or bathing for at least 1 hour after application of Xiclofen TM Ointment. Avoid concomitant use of Xiclofen TM Ointment on the treated skin site with other external products, including sunscreens, cosmetics, lotions, moisturizers, insect repellants, or other external medications. Do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic assessments. 2.2 Dosing and Instructions for Use Apply product directly to the skin, up to 4 times daily (8.5g per day). Clothing may be worn over the area of application. Wash hands with soap and water after handling Xiclofen TM Ointment. If irritation or a burning sensation occurs during application, stop use and advise your doctor. When Xiclofen TM Ointment is used concomitantly with other products containing non-steroidal anti-inflammatory agents, the amount absorbed from all formulations must be considered.

4. CONTRAINDICATIONS Xiclofen TM Ointment is contraindicated in patients with a known history of hypersensitivity to non-steroidal anti-inflammatory medications such as diclofenac sodium or methyl salicylate. History of asthma, urticaria, or allergic-type reactions after absorbing nonsteroidal anti-inflammatory drugs (NSAIDs) should also be considered.

5. WARNINGS, PRECAUTIONS & ADVERSE REACTIONS 5.1 Risk of Serious Cardiovascular and Gastrointestinal Events Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause an increased risk of serious cardiovascular (CV) 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. NSAIDs, including diclofenac, can lead to new onset of hypertension, or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Avoid the use of diclofenac sodium external in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac sodium external is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Avoid using NSAIDs within 14 days following coronary artery bypass graft (CABG) surgery. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation Nonsteroidal anti-inflammatory drugs (NSAIDs) can 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. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs). Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. 5.3 Hepatotoxicity In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis, with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Monitor for 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. 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). To minimize potential risk for an adverse liver-related event in patients treated with diclofenac sodium external, exercise caution when prescribing diclofenac external with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, antiepileptics). 5.4 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. Avoid the use of diclofenac sodium external in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium is used in patients with advanced renal disease, monitor patients for signs of worsening symptoms. 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. 5.5 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. Seek emergency help if an anaphylactic reaction occurs. 5.6 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 external is contraindicated in patients with this form of aspirin sensitivity. When diclofenac is used in patients with preexisting asthma, monitor patients for changes in the signs and symptoms. 5.7 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. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium external at the first appearance of any skin hypersensitivity. 5.8 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. If a patient treated with diclofenac sodium external has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including diclofenac, 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) may increase this risk. 5.9 Masking of Inflmmation and Fever The pharmacological activity of diclofenac in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.10 Sun Exposure Instruct patients to avoid exposure to natural or artificial sunlight after treatment of Xiclofen TM Ointment because studies in animals indicated external diclofenac treatment resulted in an earlier onset of ultraviolet light-induced skin tumors. The potential effects of diclofenac sodium external on skin response to ultraviolet damage in humans are not known. 5.11 Excessive Dosing Excessive dosing by applying larger amounts of Xiclofen TM Ointment could result in increased absorption of diclofenac sodium and methyl salicylate and high blood concentrations. Longer duration of application, application of more than the recommended dosage, smaller patients, or impaired elimination may all contribute to increasing the blood concentration of diclofenac sodium and methyl salicylate. 5.12 Application-Associated Pain During or immediately after treatment with Xiclofen TM Ointment, the skin at the site of application may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours. 5.13 Increase in Blood Pressure Patient with unstable or poorly controlled hypertension, or a recent history of cardiovascular or cerebrovascular events, may be at increased risk of adverse cardiovascular effects. Consider these factors prior to initiating Xiclofen TM Ointment treatment. Monitor blood pressure periodically during and following the treatment procedure and provide adequate support for treatment-related pain. 5.14 Sensory Function Decreases in sensory functions are generally minor and temporary (including thermal and other harmful stimuli). All patients with pre-existing sensory deficits should be clinically assessed for signs of sensory deterioration or loss prior to each prescription of Xiclofen TM Ointment. If sensory deterioration or loss is detected or pre-existing sensory deficit worsens, continued use of Xiclofen TM Ointment treatment should be reconsidered. 5.15 Precautions Allergic Reactions Xiclofen TM Ointment should be used with caution in patients with a history of drug sensitivities, especially if the etiologic agent is uncertain. External Heat Sources Placement of external heat sources, such as heating pads or electric blankets, over Xiclofen TM Ointment is not recommended. Eye Exposure The contact of Xiclofen TM Ointment with eyes should be avoided based on finding from previous studies with use of similar products. If eye contact occurs, immediately wash out the eye with water and saline and protect the eye until sensation returns. Non-Intact Skin Xiclofen TM Ointment is only recommended for use on intact skin. Application to broken or inflamed skin may result in increased irritation and/or increased absorption of ingredients. 5.16 Other Adverse Events Due to the nature and limitation of spontaneous reports in postmarketing surveillance, causality has not been established for additional reported adverse events including asthenia, confusion, disorientation, dizziness, headache, hyperesthesia, hypoesthesia, lightheadedness, metallic taste, nausea, nervousness, pain exacerbated, paresthesia, somnolence, taste alteration, vomiting, visual disturbances such as blurred vision, flushing, tinnitus, and tremor. 5.17 Systemic (Dose-Related) Reactions Systemic adverse reactions following appropriate use of Xiclofen TM Ointment are unlikely due to the small dose absorbed. 5.18 Oral Nonsteroidal Anti-Inflammatory Drugs Concomitant use of oral NSAIDs with diclofenac sodium external resulted in a higher rate of rectal hemorrhage, more frequent abnormal creatinine, urea, and hemoglobin. Therefore, do not use combination therapy with diclofenac sodium external and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.

6. DRUG INTERACTIONS Drugs That Interfere with Hemostasis Monitor patients with concomitant use of diclofenac sodium external 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. Aspirin Concomitant use of diclofenac sodium external and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment. Diuretics During concomitant use of diclofenac sodium external with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Digoxin During concomitant use of diclofenac sodium external and digoxin, monitor serum digoxin levels. Lithium During concomitant use of diclofenac sodium external and lithium, monitor patients for signs of lithium toxicity. Methotrexate During concomitant use of diclofenac sodium external and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine During concomitant use of diclofenac sodium external and cyclosporine, monitor patients for signs of worsening renal function. Pemetrexed Concomitant use of diclofenac sodium external and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity.

7. USE IN SPECIFIC POPULATIONS 7.1 Pregnancy Diclofenac may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including diclofenac sodium external, in pregnant women starting at 30 weeks of gestation. There are no adequate and well-controlled studies of diclofenac sodium external in pregnant women. 7.2 Lactation Based on available data, diclofenac may be present in human milk. Caution should be exercised when Xiclofen TM Ointment is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Xiclofen TM Ointment and any potential adverse effects on the breastfed infant. 7.3 Pediatric Use Safety and effectiveness in pediatric patients under the age of 12 has not been established. 7.4 Geriatric Use Elderly patients, compared to younger patients, are at a greater risk of NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If a risk is present, start dosing at the low end of the dosing range, and monitor patients for adverse effects.