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. Flector PATCH is contraindicated in the setting of coronary artery bypass graft (CABG) surgery see and. 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. Indications and Usage for Flector.
Slideshow Flector Dosage and Administration General Dosing Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals see. The recommended dose of Flector PATCH is one (1) patch to the most painful area twice a day. Special Precautions. Inform patients that, if Flector PATCH begins to peel-off, the edges of the patch may be taped down.
If problems with adhesion persist, patients may overlay the patch with a mesh netting sleeve, where appropriate (e.g. To secure patches applied to ankles, knees, or elbows). The mesh netting sleeve (e.g.
Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non-breathable). Do not apply Flector PATCH to non-intact or damaged skin resulting from any etiology e.g.
Exudative dermatitis, eczema, infected lesion, burns or wounds. Do not wear a Flector PATCH when bathing or showering. Wash your hands after applying, handling or removing the patch. Avoid eye contact. Do not use combination therapy with Flector PATCH and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. Dosage Forms and Strengths Flector (diclofenac epolamine) Patch (10 × 14 cm) containing 180 mg of diclofenac epolamine, embossed with Flector PATCH 1.3%.
Contraindications Flector PATCH is contraindicated in the following patients:. Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product see.
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. In the setting of coronary artery bypass graft (CABG) surgery see. Flector Patch is contraindicated for use on non-intact or damaged skin resulting from any etiology, including exudative dermatitis, eczema, infection lesions, burns or wounds. Warnings and Precautions Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.
However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.
Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events see.
Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG see. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of Flector PATCH in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Flector PATCH is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients.
Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients:. Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding.
For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Flector PATCH until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding see. Hepatotoxicity In clinical trials of oral diclofenac containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In a large open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks.
Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac.
Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more than 90 days. Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms.
The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac.
If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), Flector PATCH should be discontinued immediately. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and 'flu-like' symptoms).
If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Flector PATCH immediately, and perform a clinical evaluation of the patient. To minimize the potential risk for an adverse liver related event in patients treated with Flector PATCH, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Flector PATCH with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).
Hypertension NSAIDs, including Flector PATCH, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs see. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers ARBs) see. Avoid the use of Flector PATCH in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.
If Flector PATCH is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 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 is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of Flector PATCH in patients with advanced renal disease. The renal effects of Flector PATCH may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating Flector PATCH.
Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Flector PATCH see. Avoid the use of Flector PATCH in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Flector PATCH is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. Anaphylactic Reactions Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma see and.
Seek emergency help if an anaphylactic reaction occurs. 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, Flector PATCH is contraindicated in patients with this form of aspirin sensitivity see. When Flector PATCH is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. Serious Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.
These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Flector PATCH at the first appearance of skin rash or any other sign of hypersensitivity.
Flector PATCH is contraindicated in patients with previous serious skin reactions to NSAIDs see. Premature Closure of Fetal Ductus Arteriosus Diclofenac may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Flector PATCH, in pregnant women starting at 30 weeks of gestation (third trimester) see. Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Flector PATCH has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including Flector PATCH, may increase the risk of bleeding events.
Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding see. Masking of Inflammation and Fever The pharmacological activity of Flector PATCH in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically see,.
Accidental Exposure in Children Even a used Flector Patch contains a large amount of diclofenac epolamine (as much as 170 mg). The potential therefore exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used Flector Patch. It is important for patients to store and dispose of Flector Patch out of the reach of children and pets. Eye Exposure Avoid contact of Flector Patch with eyes and mucosa. Advise patients that if eye contact occurs, immediately wash out the eye with water or saline and consult a physician if irritation persists for more than an hour. Oral Nonsteroidal Anti-inflammatory Drugs Concomitant use of oral and topical NSAIDs may result in a higher rate of hemorrhage, more frequent abnormal creatinine, urea and hemoglobin.
Do not use combination therapy with Flector Patch and an oral NSAID unless the benefit outweighs the risk. Common Adverse Events (by body system and preferred term) in ≥ 1% of Patients treated with Flector PATCH or Placebo Patch Category Diclofenac N=572 Placebo N=564 N Percent N Percent The table lists adverse events occurring in placebo-treated patients because the placebo-patch was comprised of the same ingredients as Flector PATCH except for diclofenac. Adverse events in the placebo group may therefore reflect effects of the non-active ingredients.
Includes: application site dryness, irritation, erythema, atrophy, discoloration, hyperhidriosis, and vesicles. Includes: gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth. Includes: hypoesthesia, dizziness, and hyperkinesias. Application Site Conditions 64 11 70 12 Pruritus 31 5 44 8 Dermatitis 9 2 3. 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 Flector PATCH 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. 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 the NSAID alone see.
Intervention: Concomitant use of Flector PATCH and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding see. Flector PATCH is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact:. NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention:.
During concomitant use of Flector PATCH and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Flector PATCH 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. 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 Flector PATCH with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects see. Digoxin Clinical Impact: The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of Flector PATCH 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 Flector PATCH and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention: During concomitant use of Flector PATCH and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of Flector PATCH and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of Flector PATCH and cyclosporine, monitor patients for signs of 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. Intervention: The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of Flector PATCH and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of Flector PATCH and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C prior to 30 weeks gestation; Category D starting 30 weeks gestation. Risk Summary Use of NSAIDs, including Flector PATCH, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Flector PATCH, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of Flector PATCH 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 2-4% for major malformations, and 15-20% for pregnancy loss.
In animal reproduction studies, diclofenac epolamine administered orally to pregnant rats and rabbits during the period of organogenesis produced embryotoxicity at approximately 3 and 7 times, respectively, the topical exposure from the maximum recommended human dose (MRHD) of Flector PATCH. In rats, increased incidences of skeletal anomalies and maternal toxicity were also observed at this dose. Diclofenac epolamine administered orally to both male and female rats prior to mating and throughout the mating period, and during gestation and lactation in females produced embryotoxicity at doses approximately 3 and 7 times, respectively, the topical exposure from the MRHD see. 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 Flector PATCH 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 Pregnant Sprague Dawley rats were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 15.
Maternal toxicity, embryotoxicity, and increased incidence of skeletal anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnant New Zealand White rabbits were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6 to 18.
No maternal toxicity was noted; however, embryotoxicity was evident at 6 mg/kg/day group which corresponds to 7 times the maximum recommended daily exposure in humans based on a body surface area comparison. Male rats were orally administered diclofenac epolamine (1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period, and females were given the same doses 14 days prior to mating and through mating, gestation, and lactation. Embryotoxicity was observed at 6 mg/kg diclofenac epolamine (3 times the maximum recommended daily exposure in humans based on a body surface area comparison), and was manifested as an increase in early resorptions, post-implantation losses, and a decrease in live fetuses. The number of live born and total born were also reduced as was F1 postnatal survival, but the physical and behavioral development of surviving F1 pups in all groups was the same as the deionized water control, nor was reproductive performance adversely affected despite a slight treatment-related reduction in body weight.
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 Flector PATCH and any potential adverse effects on the breastfed infant from the Flector PATCH or from the underlying maternal condition. Data One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). The relative bioavailability for Flector PATCH is.
Each adhesive patch contains 180 mg of diclofenac epolamine (13 mg per gram adhesive) in an aqueous base. It also contains the following inactive ingredients: 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, D-sorbitol, fragrance (Dalin PH), gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. Flector - Clinical Pharmacology Mechanism of Action Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of diclofenac, 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. Pharmacodynamics Flector PATCH applied to intact skin provides local analgesia by releasing diclofenac epolamine from the patch into the skin. Pharmacokinetics Absorption Following a single application of the Flector PATCH on the upper inner arm, peak plasma concentrations of diclofenac (range 0.7 – 6 ng/mL) were noted between 10 – 20 hours of application.
What Is In A Flector Patch
Plasma concentrations of diclofenac in the range of 1.3 – 8.8 ng/mL were noted after five days with twice-a-day Flector PATCH application. Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with Flector PATCH, were lower (99%) for human serum 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 The plasma elimination half-life of diclofenac after application of Flector PATCH is approximately 12 hours.
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.
Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Specific Populations The pharmacokinetics of Flector Patch has not been investigated in children, patients with hepatic or renal impairment, or specific racial groups. 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 for clinically significant drug interactions of NSAIDs with aspirin see. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either diclofenac epolamine or Flector PATCH.
Mutagenesis Diclofenac epolamine is not mutagenic in Salmonella typhimurium strains, nor does it induce an increase in metabolic aberrations in cultured human lymphocytes, or the frequency of micronucleated cells in the bone marrow micronucleus test performed in rats. Impairment of Fertility The effect of diclofenac epolamine on fertility in animals has been summarized in 8.1 under Animal Data. Male and female Sprague Dawley rats were administered 1, 3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60 days prior to conception and during mating period, females treated for 14 days prior to mating through day 19 of gestation).
Diclofenac epolamine treatment with 6 mg/kg/day resulted in increased early resorptions and post-implantation losses; however, no effects on the mating and fertility indices were found. The 6 mg/kg/day dose corresponds to 3 times the maximum recommended daily exposure in humans based on a body surface area comparison. Clinical Studies Ankle Sprains Efficacy of Flector PATCH was demonstrated in two of four studies of patients with minor sprains, strains, and contusions. Patients were randomly assigned to treatment with the Flector PATCH, or a placebo patch identical to the Flector PATCH minus the active ingredient. In the first of these two studies, patients with ankle sprains were treated once daily for a week. In the second study, patients with sprains, strains and contusions were treated twice daily for up to two weeks.
Pain was assessed over the period of treatment. Patients treated with the Flector PATCH experienced a greater reduction in pain as compared to patients randomized to placebo patch as evidenced by the responder curves presented below ( Figures 1-4). Figure 1: Patients Achieving Various Levels of Pain Relief at Day 3; 14-Day Study. How Supplied/Storage and Handling The Flector PATCH is supplied in resealable envelopes, each containing 5 patches (10 cm × 14 cm), with 6 envelopes per box (NDC 60793-411-30). Each individual patch is embossed with 'Flector PATCH 1.3%'. Each patch contains 180 mg of diclofenac epolamine in an aqueous base (13 mg of active per gram of adhesive or 1.3%). The product is intended for topical use only.
Keep out of reach of children and pets. Envelops should be sealed at all times when not in use. Curad® Hold Tite™ is a trademark of Medline Industries, Inc., and Surgilast® Tubular Elastic Dressing is a trademark of Derma Sciences, Inc. Storage Store at 20°C to 25°C (68°C to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) see USP Controlled Room Temperature. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed, as well as the Directions for Use on the product packaging. Inform patients, families, or their caregivers of the following information before initiating therapy with Flector PATCH 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.
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. 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 Flector PATCH and seek immediate medical therapy see. 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.
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 and. Serious Skin Reactions Advise patients to stop Flector PATCH immediately if they develop any type of rash and to contact their healthcare provider as soon as possible see. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including Flector PATCH, may be associated with a reversible delay in ovulation see Fetal Toxicity Inform pregnant women to avoid use of Flector PATCH and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus see and.
Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of Flector PATCH 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 and. 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 Flector PATCH until they talk to their healthcare provider see. Eye Exposure Instruct patients to avoid contact of Flector Patch 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 see. Special Application Instructions.
Instruct patients that, if Flector PATCH begins to peel-off, the edges of the patch may be taped down. If problems with adhesion persist, patients may overlay the patch with a mesh netting sleeve, where appropriate (e.g. To secure patches applied to ankles, knees, or elbows). The mesh netting sleeve (e.g. Curad® Hold Tite™, Surgilast® Tubular Elastic Dressing) must allow air to pass through and not be occlusive (non-breathable).
Instruct patients not to apply Flector PATCH to non-intact or damaged skin resulting from any etiology e.g. Exudative dermatitis, eczema, infected lesion, burns or wounds.
Instruct patients not to wear a Flector PATCH when bathing or showering. Instruct patients to wash hands after applying, handling or removing the patch. Distributor: Pfizer Inc New York, NY 10017 Manufacturer: Teikoku Seiyaku Co., Ltd., Sanbonmatsu, Kagawa 769-2695 Japan Manufactured for: IBSA Institut Biochimique SA, CH-6903 Lugano, Switzerland Flector is a registered trademark of IBSA Institut Biochimique SA, licensed by Alpharma Pharmaceuticals LLC, a subsidiary of Pfizer Inc.
Issued: May, 2016. Manufactured for: IBSA Institut Biochimique SA, CH-6903 Lugano, Switzerland Distributed by: Pfizer Inc., New York, NY10017 For more information, go to to www.FlectorPatch.com or call 1-800-438-1985. Flector is a registered trademark of IBSA Institut Biochimique SA, licensed by Alpharma Pharmaceuticals LLC, a subsidiary of Pfizer Inc. This Medication Guide has been approved by the U.S.
Food and Drug Administration. Issued or Revised: May, 2016 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.
Flector Uses Flector is used in relieving pain from various conditions. The medication is referred to as a nonsteroidal anti-inflammatory drug (NSAID).The drug is contraindicated in people with known hypersensitivity to diclofenac. Flector should not be given to patients who have experienced urticarial, or any allergic reaction to taking other. Severe anaphylactic-like reactions to NSAIDs may occur. The drug should never be applied to damaged or non-intact skin that has resulted from any etiology.
Pain. Flector Dosage Patients should read and adhere to the medication guide provided by the doctor or pharmacist before they begin using Flector. The following dosage is an average dose and may change from individual to individual. Follow your medical professional's directions for best results. The patch comes in a resealable envelope, and the required dose is one patch to the most painful area 2 times in a day. When a patient is opening the patch for the first time, the patient should cut it as instructed.
The patch should be removed, and the envelope resealed. It is important to reseal the envelope after each opening, or the remaining patches may not stick as required. After removing the clear liner, the patch should be applied to the skin to cover the most painful area. The patch should not be applied to cuts, burns or irritated skins.
The patch should be changed after every 12 hours or as a physician instructs. After usage, the patch should be folded in half and disposed out of children's reach. The edges of the patch may be taped down in case the patch begins to peel off.
Cardiovascular (CV) risk. NSAIDs cause an increased risk of serious CV thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. FLECTOR Patch is contraindicated in the setting of coronary artery bypass graft (CABG) surgery Gastrointestinal (GI) risk. NSAIDs cause an increased risk of serious 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 FLECTOR Patch is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product. FLECTOR Patch is also contraindicated in patients with a 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 FLECTOR Patch should not be applied to non-intact or damaged skin resulting from any etiology, e.g., exudative dermatitis, eczema, infected lesions, burns, or wounds Avoid the use of FLECTOR Patch in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If FLECTOR Patch is used in patients with a recent MI, monitor patients for signs of cardiac ischemia Elevations of one or more liver tests may occur during therapy with FLECTOR Patch. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur, FLECTOR Patch should be discontinued immediately NSAIDs, including FLECTOR Patch, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Monitor blood pressure during the initiation of NSAID treatment and throughout the course of therapy Fluid retention and edema have been observed in some patients treated with NSAIDs. Avoid the use of FLECTOR Patch in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.
Air. If FLECTOR Patch is used in patients with severe heart failure, monitor patients for signs of worsening heart failure Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Avoid the use of FLECTOR Patch in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma. Patients should seek emergency help if an anaphylactic reaction occurs NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which can be fatal and may occur without warning.
FLECTOR Patch should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity Avoid use of NSAIDs, including FLECTOR Patch, in pregnant women starting at 30 weeks of gestation Anemia has occurred in NSAID-treated patients. If a patient treated with FLECTOR Patch has any signs or symptoms of anemia, monitor hemoglobin or hematocrit NSAIDs, including FLECTOR Patch, may increase the risk of bleeding events Do not use combination therapy with FLECTOR Patch and an oral NSAID unless the benefit outweighs the risk Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals Overall, the most common adverse events associated with FLECTOR Patch were skin reactions at the site of treatment. Other common adverse events included gastrointestinal disorders such as nausea, dysgeusia and dyspepsia, and nervous system disorders such as headache, paresthesia, and somnolence Safety and effectiveness in pediatric patients have not been established Indication FLECTOR Patch is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions Please see. Cardiovascular (CV) risk.
NSAIDs cause an increased risk of serious CV thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. FLECTOR Patch is contraindicated in the setting of coronary artery bypass graft (CABG) surgery Gastrointestinal (GI) risk. NSAIDs cause an increased risk of serious 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 FLECTOR Patch is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac or any components of the drug product.
FLECTOR Patch is also contraindicated in patients with a 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 FLECTOR Patch should not be applied to non-intact or damaged skin resulting from any etiology, e.g., exudative dermatitis, eczema, infected lesions, burns, or wounds Avoid the use of FLECTOR Patch in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If FLECTOR Patch is used in patients with a recent MI, monitor patients for signs of cardiac ischemia Elevations of one or more liver tests may occur during therapy with FLECTOR Patch. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur, FLECTOR Patch should be discontinued immediately NSAIDs, including FLECTOR Patch, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Monitor blood pressure during the initiation of NSAID treatment and throughout the course of therapy Fluid retention and edema have been observed in some patients treated with NSAIDs. Avoid the use of FLECTOR Patch in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.
If FLECTOR Patch is used in patients with severe heart failure, monitor patients for signs of worsening heart failure Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Avoid the use of FLECTOR Patch in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma. Patients should seek emergency help if an anaphylactic reaction occurs NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which can be fatal and may occur without warning. FLECTOR Patch should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity Avoid use of NSAIDs, including FLECTOR Patch, in pregnant women starting at 30 weeks of gestation Anemia has occurred in NSAID-treated patients.
If a patient treated with FLECTOR Patch has any signs or symptoms of anemia, monitor hemoglobin or hematocrit NSAIDs, including FLECTOR Patch, may increase the risk of bleeding events Do not use combination therapy with FLECTOR Patch and an oral NSAID unless the benefit outweighs the risk Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals Overall, the most common adverse events associated with FLECTOR Patch were skin reactions at the site of treatment. Other common adverse events included gastrointestinal disorders such as nausea, dysgeusia and dyspepsia, and nervous system disorders such as headache, paresthesia, and somnolence Safety and effectiveness in pediatric patients have not been established Indication FLECTOR Patch is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions Please see.
Cardiovascular Risk. NSAIDs 1 may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. Flector® Patch is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Gastrointestinal Risk. NSAIDs cause an increased risk of serious gastrointestinal 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 are at greater risk for serious gastrointestinal events. 1 Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug. DESCRIPTION Flector® Patch (10 cm x 14 cm) is comprised of an adhesive material containing 1.3% diclofenac epolamine which is applied to a non-woven polyester felt backing and covered with a polypropylene film release liner.
The release liner is removed prior to topical application to the skin. Diclofenac epolamine is a non-opioid analgesic chemically designated as 2-(2,6-dichlorophenyl) aminobenzeneacetic acid, (2-(pyrrolidin-1-yl) ethanol salt, with a molecular formula of C 20H 24C l2N 2O 3 (molecular weight 411.3), an n-octanol/water partition coefficient of 8 at pH 8.5, and the following structure. Each adhesive patch contains 180 mg of diclofenac epolamine (13 mg per gram adhesive) in an aqueous base.
It also contains the following inactive ingredients: 1,3-butylene glycol, dihydroxyaluminum aminoacetate, disodium edetate, D-sorbitol, fragrance (Dalin PH), gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, tartaric acid, titanium dioxide, and purified water. CLINICAL PHARMACOLOGY Pharmacodynamics Flector® Patch applied to intact skin provides local analgesia by releasing diclofenac epolamine from the patch into the skin. Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID). In pharmacologic studies, diclofenac has shown anti-inflammatory, analgesic, and antipyretic activity.
As with other NSAIDs, its mode of action is not known; its ability to inhibit prostaglandin synthesis, however, may be involved in its anti-inflammatory activity, as well as contribute to its efficacy in relieving pain associated with inflammation. Pharmacokinetics Absorption Following a single application of the Flector Patch on the upper inner arm, peak plasma concentrations of diclofenac (range 0.7 – 6 ng/mL) were noted between 10 – 20 hours of application. Plasma concentrations of diclofenac in the range of 1.3 – 8.8 ng/mL were noted after five days with twice-a-day Flector Patch application. Systemic exposure (AUC) and maximum plasma concentrations of diclofenac, after repeated dosing for four days with Flector® Patch, were lower (99%) for human serum albumin. Metabolism and Excretion The plasma elimination half-life of diclofenac after application of Flector Patch is approximately 12 hours. Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites.
CLINICAL STUDIES Efficacy of Flector® Patch was demonstrated in two of four studies of patients with minor sprains, strains, and contusions. Patients were randomly assigned to treatment with the Flector® Patch, or a placebo patch identical to the Flector® Patch minus the active ingredient.
In the first of these two studies, patients with ankle sprains were treated once daily for a week. In the second study, patients with sprains, strains and contusions were treated twice daily for up to two weeks. Pain was assessed over the period of treatment. Patients treated with the Flector® Patch experienced a greater reduction in pain as compared to patients randomized to placebo patch as evidenced by the responder curves presented below.
INDICATIONS AND USAGE Carefully consider the potential benefits and risks of Flector® Patch and other treatment options before deciding to use Flector® Patch. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ). Flector® Patch is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions. CONTRAINDICATIONS Flector® Patch is contraindicated in patients with known hypersensitivity to diclofenac.
Flector® Patch should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see, and ). Flector® Patch is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see ). Flector® Patch should not be applied to non-intact or damaged skin resulting from any etiology e.g. Exudative dermatitis, eczema, infected lesion, burns or wounds. WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.
All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk.
To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.
The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see ). Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see ).
Hypertension NSAIDs, including Flector® Patch, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Flector® Patch, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Flector® Patch should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects- Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Flector® Patch, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy.
However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected.
This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects 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 a nonsteroidal anti-inflammatory drug 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, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Flector® Patch in patients with advanced renal disease. Therefore, treatment with Flector® Patch is not recommended in these patients with advanced renal disease. If Flector® Patch therapy is initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Flector® Patch. Flector® Patch should not be given to patients with the aspirin triad.
This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see and ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including Flector® Patch, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, Flector® Patch should be avoided because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS General Flector® Patch cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of Flector® Patch in reducing inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Flector® Patch. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs.
In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Flector® Patch. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Flector® Patch should be discontinued. Hematological Effects Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Flector® Patch, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Flector® Patch who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal.
Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Flector® Patch should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma. Eye Exposure Contact of Flector® Patch with eyes and mucosa, although not studied, should be avoided. If eye contact occurs, immediately wash out the eye with water or saline.
Consult a physician if irritation persists for more than an hour. Accidental Exposure in Children Even a used Flector® Patch contains a large amount of diclofenac epolamine (as much as 170 mg). The potential therefore exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used Flector® Patch. It is important for patients to store and dispose of Flector® Patch out of the reach of children and pets.
Information for Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed. Flector® Patch, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see ). Flector® Patch, like other NSAIDs, may cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death.
Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see ). Flector® Patch, like other NSAIDs, may cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should be instructed to promptly report signs or symptoms of unexplained weight gain or edema to their physicians (see ).
Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and 'flu-like' symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. Patients should be informed of the signs of an anaphylactoid reaction (e.g. Difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see ). In late pregnancy, as with other NSAIDs, Flector® Patch should be avoided because it may cause premature closure of the ductus arteriosus.
Patients should be advised not to use Flector® Patch if they have a aspirin-sensitive asthma. Flector® Patch, like other NSAIDs, could cause severe and even fatal bronchospasm in these patients (see ). Patients should discontinue use of Flector® Patch and should immediately seek emergency help if they experience wheezing or shortness of breath. Patients should be informed that Flector® Patch should be used only on intact skin. Patients should be advised to avoid contact of Flector® Patch with eyes and mucosa.
Patients should be instructed that if eye contact occurs, they should immediately wash out the eye with water or saline, and consult a physician if irritation persists for more than an hour. Patients and caregivers should be instructed to wash their hands after applying, handling or removing the patch. Patients should be informed that, if Flector® Patch begins to peel off, the edges of the patch may be taped down. Patients should be instructed not to wear Flector® Patch during bathing or showering. Bathing should take place in between scheduled patch removal and application (see ).
Patients should be advised to store Flector® Patch and to discard used patches out of the reach of children and pets. If a child or pet accidentally ingests Flector® Patch, medical help should be sought immediately (see ). Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically.
If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Flector® Patch should be discontinued. Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors.
This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin When Flector® Patch is administered with aspirin, the binding of diclofenac to protein is reduced, although the clearance of free diclofenac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of diclofenac and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as post marketing observations, have shown that Flector® Patch may reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see ), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.
The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of either diclofenac epolamine or Flector Patch. Mutagenesis Diclofenac epolamine is not mutagenic in Salmonella Typhimurium strains, nor does it induce an increase in metabolic aberrations in cultured human lymphocytes, or the frequency of micronucleated cells in the bone marrow micronucleus test performed in rats. Impairment of Fertility Male and female Sprague Dawley rats were administered 1, 3, or 6 mg/kg/day diclofenac epolamine via oral gavage (males treated for 60 days prior to conception and during mating period, females treated for 14 days prior to mating through day 19 of gestation).
Diclofenac epolamine treatment with 6 mg/kg/day resulted in increased early resorptions and postimplantation losses; however, no effects on the mating and fertility indices were found. The 6 mg/kg/day dose corresponds to 3-times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnancy Teratogenic Effects Pregnancy Category C. Pregnant Sprague Dawley rats were administered 1, 3, or 6 mg/kg diclofenac epolamine via oral gavage daily from gestation days 6-15. Maternal toxicity, embryotoxicity, and increased incidence of skeletal anomalies were noted with 6 mg/kg/day diclofenac epolamine, which corresponds to 3-times the maximum recommended daily exposure in humans based on a body surface area comparison. Pregnant New Zealand White rabbits were administered 1, 3, or 6 mg/kg diclofenac epolamine vial oral gavage daily from gestation days 6-18.
No maternal toxicity was noted; however, embryotoxicity was evident at 6 mg/kg/day group which corresponds to 6.5-times the maximum recommended daily exposure in humans based on a body surface area comparison. There are no adequate and well-controlled studies in pregnant women. Flector Patch should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Male rats were orally administered diclofenac epolamine (1, 3, 6 mg/kg) for 60 days prior to mating and throughout the mating period, and females were given the same doses 14 days prior to mating and through mating, gestation, and lactation.
Embryotoxicity was observed at 6 mg/kg diclofenac epolamine (3-times the maximum recommended daily exposure in humans based on a body surface area comparison), and was manifested as an increase in early resorptions, post-implantation losses, and a decrease in live fetuses. The number of live born and total born were also reduced as was F1 postnatal survival, but the physical and behavioral development of surviving F1 pups in all groups was the same as the deionized water control, nor was reproductive performance adversely affected despite a slight treatment-related reduction in body weight. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Flector® Patch on labor and delivery in pregnant women are unknown. Nursing Mothers It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human-milk and because of the potential for serious adverse reactions in nursing infants from Flector® Patch, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of Flector® Patch did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Diclofenac, as with any NSAID, is known to be substantially excreted by the kidney, and the risk of toxic reactions to Flector® Patch may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when using Flector® Patch in the elderly, and it may be useful to monitor renal function.
ADVERSE REACTIONS In controlled trials during the premarketing development of Flector® Patch, approximately 600 patients with minor sprains, strains, and contusions have been treated with Flector® Patch for up to two weeks. Adverse Events Leading to Discontinuation of Treatment In the controlled trials, 3% of patients in both the Flector® Patch and placebo patch groups discontinued treatment due to an adverse event.
The most common adverse events leading to discontinuation were application site reactions, occurring in 2% of both the Flector® Patch and placebo patch groups. Application site reactions leading to dropout included pruritus, dermatitis, and burning. Common Adverse Events Localized Reactions Overall, the most common adverse events associated with Flector® Patch treatment were skin reactions at the site of treatment.
Table 1 lists all adverse events, regardless of causality, occurring in ≥ 1% of patients in controlled trials of Flector® Patch. A majority of patients treated with Flector® Patch had adverse events with a maximum intensity of “mild” or “moderate.” Table 1.
Common Adverse Events (by body system and preferred term) in ≥1% of Patients treated with Flector® Patch or Placebo Patch 1 Diclofenac N=572 Placebo N=564 N Percent N Percent 1 The table lists adverse events occurring in placebo-treated patients because the placebo-patch was comprised of the same ingredients as Flector® Patch except for diclofenac. Adverse events in the placebo group may therefore reflect effects of the non-active ingredients. 2 Includes: application site dryness, irritation, erythema, atrophy, discoloration, hyperhidriosis, and vesicles. 3 Includes: gastritis, vomiting, diarrhea, constipation, upper abdominal pain, and dry mouth.
4 Includes: hypoaesthesia, dizziness, and hyperkinesias. Application Site Conditions 64 11 70 12 Pruritus 31 5 44 8 Dermatitis 9 2 3.