Flector® Patch (diclofenac epolamine topical patch) 1.3%

• 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. (SeeWARNINGS).

¹ Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug.

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.

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 (<1%) than after a single oral 50 mg diclofenac sodium tablet.

The pharmacokinetics of Flector® Patch has been tested in healthy volunteers at rest or undergoing moderate exercise (cycling 20 min/h for 12 h at a mean HR of 100.3 bpm).  No clinically relevant differences in systemic absorption were observed, with peak plasma concentrations in the range of 2.2 – 8.1 ng/m while resting, and 2.7 – 7.2 ng/mL during exercise.

Distribution

Diclofenac has a very high affinity (>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.

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.

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 (seeGI WARNINGS).

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 (seeCONTRAINDICATIONS).

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.

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.

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.

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.

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.

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 (seeCONTRAINDICATIONS andPRECAUTIONS - Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

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.

In late pregnancy, as with other NSAIDs, Flector® Patch should be avoided because it may cause premature closure of the ductus arteriosus.

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.

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.

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.

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.

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.

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.

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.

1. 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 (seeWARNINGS, Cardiovascular Effects).

2. 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 (seeWARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).

3. 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.

4. Patients should be instructed to promptly report signs or symptoms of unexplained weight gain or edema to their physicians (seeWARNINGS, Cardiovascular Effects).

5. 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.

6. 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 (seeWARNINGS).

7. In late pregnancy, as with other NSAIDs, Flector® Patch should be avoided because it may cause premature closure of the ductus arteriosus.

8. 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 (seePRECAUTIONS, Preexisting asthma).  Patients should discontinue use of Flector® Patch and should immediately seek emergency help if they experience wheezing or shortness of breath.

9. Patients should be informed that Flector® Patch should be used only on intact skin.

10. 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.

11. Patients and caregivers should be instructed to wash their hands after applying, handling or removing the patch.

12. Patients should be informed that, if Flector® Patch begins to peel off, the edges of the patch may be taped down.

13. Patients should be instructed not to wear Flector® Patch during bathing or showering.  Bathing should take place in between scheduled patch removal and application (seeDOSAGE AND ADMINISTRATION).

14. 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 (seePRECAUTIONS, Accidental Exposure in Children).

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.

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 (seeWARNINGS, Renal Effects), 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

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.

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.

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.

Safety and effectiveness in pediatric patients have not been established.

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.

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.

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.”

Foreign labeling describes that dermal allergic reactions may occur with Flector® Patch treatment.  Additionally, the treated area may become irritated or develop itching, erythema, edema, vesicles, or abnormal sensation.

Flector® Patch is not a controlled substance.

Diclofenac, the active ingredient in Flector® Patch, is an NSAID that does not lead to physical or psychological dependence.

Patients and caregivers should wash their hands after applying, handling or removing the patch.  Eye contact should be avoided.