^ Pharmacodynamics
DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% applied to intact skin provides local analgesia by releasing diclofenac epolamine from the topical system into the skin.
^ Drug Reaction With Eosinophilia And Systemic Symptoms (dress)
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% . Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved.
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and evaluate the patient immediately
^ Anaphylactic Reactions
Diclofenac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8) ]. Seek emergency help if an anaphylactic reaction occurs.
^ 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 DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and periodically during the course of ongoing therapy.
^ Description
DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is a nonsteroidal anti-inflammatory drug for topical application. DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is a 10 cm × 14 cm topical system 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.
The chemical name of diclofenac epolamine is 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, (2-(pyrrolidin-1-yl) ethanol salt, with a molecular formula of C 20H 24Cl 2N 2O 3, and molecular weight 411.3, an n-octanol/water partition coefficient of 8 at pH 8.5, and the following chemical structure:
Each adhesive topical system contains 180 mg of diclofenac epolamine (13 mg per gram adhesive) in an aqueous base. It also contains the following inactive ingredients: butylene glycol, carboxymethylcellulose sodium, dihydroxyaluminum aminoacetate, edetate disodium, fragrance (Dalin PH), gelatin, kaolin, methylparaben, polysorbate 80, povidone, propylene glycol, propylparaben, sodium polyacrylate, sorbitol solution, tartaric acid, titanium dioxide, and purified water.
^ Accidental Exposure In Children
Even a used DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%. It is important for patients to store and dispose of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% out of the reach of children and pets.
^ Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
^ Overdosage
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions (5.1, 5.2, 5.4, 5.6) ].
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1-800-222-1222).
^ Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions (7) ].
^3 Dosage Forms And Strengths
Diclofenac Epolamine Topical System is a 10 cm × 14 cm topical system that contains 1.3% diclofenac epolamine, and is debossed with YARAL
^ Heart Failure And Edema
The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions (7) ].
Avoid the use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
^ Masking Of Inflammation And Fever
The pharmacological activity of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
^ Pediatric Use
The safety and effectiveness of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% have been established in pediatric patients 6 years and older based on evidence from adequate and well-controlled studies with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % in adults, as well as an open-label study in pediatric patients 6 years and older. The pediatric study enrolled 104 patients, 6 years of age and older with minor soft tissue injuries. One DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % was applied to the injury site twice daily for a maximum of 14 days or until treatment was no longer required for pain management, whichever occurred first. Based on the available data from the pediatric study, the safety profile of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % topical system in pediatric patients is similar to that in adults. The safety and effectiveness of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3 % has not been investigated in pediatric patients less than 6 years old. [ see Clinical Trials Experience (6.1), Clinical Pharmacology (12.3) ].
^4 Contraindications
DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is contraindicated in the following patients:
^ Postmarketing Experience
The following adverse reactions have been identified during post-approval use of diclofenac. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).
^ How Supplied/storage And Handling
The DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is supplied in resealable envelopes, each containing 5 topical systems (10 cm × 14 cm), with 6 envelopes per box (NDC 82347-0405-5). Each individual topical system is debossed with "YARAL < DICLOFENAC EPOLAMINE TOPICAL SYSTEM > 1.3%".
^Principal Display Panel - Topical System Pouch Carton
NDC 82347-0405-5
diclofenac epolamine topical system 1.3%
30 TOPICAL SYSTEMS (10 CM X 14 CM EACH)
Dispense with enclosed Medication Guide
Change diclofenac epolamine topical system once every 12 hours
Fold used topical systems so that the adhesive side sticks to itself and safely discard used topical systems where children and pets cannot get them.
Rx only
YARAL Pharma
^ Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].
Clinical studies of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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.
^ Eye Exposure
Avoid contact of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% and an oral NSAID unless the benefit outweighs the risk.
^ Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions (5.2, 5.3, 5.6) ].
^ General Dosing Instructions
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions (5) ].
The recommended dose of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is one (1) topical system to the most painful area twice a day both in adults and pediatric patients 6 years of age and older.
^6 Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
^ Strains, Sprains, And Contusions
Efficacy of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% was demonstrated in two of four studies of patients with minor strains, sprains, and contusions. Patients were randomly assigned to treatment with the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, or a placebo identical to the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% 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 strains, sprains and contusions were treated twice daily for up to two weeks. Pain was assessed over the period of treatment. Patients treated with the DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% experienced a greater reduction in pain as compared to patients randomized to placebo 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
Figure 2: Patients Achieving Various Levels of Pain Relief at End of Study; 14-Day Study
Figure 3: Patients Achieving Various Levels of Pain Relief at Day 3; 7-Day Study
Figure 4: Patients Achieving Various Levels of Pain Relief at End of Study; 7-Day Study
^ Special Precautions
^7 Drug Interactions
See Table 2 for clinically significant drug interactions with diclofenac.
^ 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.), DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% should be discontinued immediately.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver related event in patients treated with DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).
^ 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.NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% at the first appearance of skin rash or any other sign of hypersensitivity. DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications (4) ].
^ 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.
^ 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 EPOLAMINE TOPICAL SYSTEM 1.3% is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications (4) ]. When DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
^1 Indications And Usage
DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3% is indicated for the topical treatment of acute pain due to minor strains, sprains, and contusions in adults and pediatric patients 6 years and older.
^ 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 Warnings and Precautions (5.2) ].
^ 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.
^ Hypertension
NSAIDs, including DICLOFENAC EPOLAMINE TOPICAL SYSTEM 1.3%, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions (7) ].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.