FLECTOR   - diclofenac epolamine patch 
Teikoku Seiyaku Co.. Ltd.

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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 emoved prior to topical application to the skin. Diclofenac epolamine is a non-opioid analgesic chemically designated as 2-[(2,6-dichlorophenyl) amino] benzeneacetic acid, (2-(pyrrolidin-1-yl) ethanol salt, with a molecular formula of C20H24Cl2N2O3 (molecular weight 411.3), an n-octanol/water partition coefficient of 8 at pH 8.5, and the following structure:

DICLOFENAC


EPOLAMINE

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 (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/mL 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.

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.
Figure 1: Patients Achieving Various Levels of Pain Reliefat Day 3; 14-Day Study

Figure 2: Patients Achieving Various Levels of Pain Reliefat 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

Indication 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 WARNINGS).
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 WARNINGS - Anaphylactoid Reactions, and PRECAUTIONS - Preexisting Asthma).
Flector® Patch is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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 GI 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 (see CONTRAINDICATIONS).

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 dosedependent 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.

Hepatic Effects
Elevations of one or more liver tests may occur during therapy with Flector® Patch. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.
In clinical trials, meaningful elevations (i.e., more than 3 times the ULN) of AST (GOT) (ALT was not measured in all studies) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment. In a large, open-label, controlled trial of 3,700 patients treated 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 patients and included marked elevations (i.e., more 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 (>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.
Physicians should measure transaminases 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. To minimize the possibility that hepatic injury will become severe between transaminase measurements, physicians should 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), and the appropriate action patients should take if these signs and symptoms appear.
To minimize the potential risk for an adverse liver related event in patients treated with Flector® Patch, the lowest effective dose should be used for the shortest duration possible. Caution should be exercised in prescribing Flector® Patch with concomitant drugs that are known to be potentially hepatotoxic (e.g., antibiotics, anti-epileptics).

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 CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). 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.

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.

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 (see WARNINGS, 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 (see WARNINGS, 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 orsymptoms of unexplained weight gain or edema to their physicians (see WARNINGS, 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 (see WARNINGS).
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 an aspirin-sensitive asthma. Flector® Patch, like other NSAIDs, could cause severe and even fatal bronchospasm in these patients (see PRECAUTIONS, 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 (see DOSAGE 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 (see PRECAUTIONS, Accidental Exposure in Children).

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 WARNINGS, 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, 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 via 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 antiinflammatory 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 Patch1

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.

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.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class
Flector® Patch is not a controlled substance.

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

OVERDOSAGE

There is limited experience with overdose of Flector® Patch.
In clinical studies, the maximum single dose administered was one Flector® Patch containing 180 mg of diclofenac epolamine. There were no serious adverse events.
Should systemic side effects occur due to incorrect use or accidental overdose of this product, the general measures recommended for intoxication with non-steroidal antiinflammatory drugs should be taken.

DOSAGE AND ADMINISTRATION

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 WARNINGS).
The recommended dose of Flector® Patch is one (1) patch to the most painful area twice a day.
Flector® patch should not be applied to damaged or nonintact skin.
Flector® patch should not be worn when bathing or showering.

HANDLING AND DISPOSAL

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

HOW SUPPLIED

The Flector® Patch is supplied in resealable envelopes, each containing 5 patches (10 cm x 14 cm), with 6 envelopes per box (NDC 60793-411-30). Each individual
patch is embossed with “FLECTOR PATCH DICLOFENAC EPOLAMINE TOPICAL 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.
• The ENVELOPES SHOULD BE SEALED AT ALL TIMES
• WHEN NOT IN USE.
• Store at 25ºC (77ºF); excursions permitted to 15º-30ºC

(59º-86ºF). [See USP Controlled Room Temperature].
Distributed by: King Pharmaceuticals, Inc.
501 Fifth Street
Bristol, TN 37620, USA
Telephone:1-888-840-8884
www.FlectorPatch.com
Manufactured for: IBSA Institut Biochimique SA, CH-6903
Lugano, Switzerland
Manufactured by: Teikoku Seiyaku Co., Ltd.,
Sanbonmatsu, Kagawa 769-2695 Japan
Version October 2009
FI/161 1086
Ed. V/10.09

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti- Inflammatory Drugs (NSAIDs)?
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft” (CABG).
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment.
Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding
increases with:

• aking medicines called “corticosteroids” and anticoagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

What are Non-Steroidal Anti-Inflammatory Drugs(NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine
• for pain right before or after heart bypass surgery

Tell your healthcare provider:

• about all of your medical conditions.
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effectsinclude: heart attack stroke high blood pressure heart failure from body swelling (fluid retention) kidney problems including kidney failure bleeding and ulcers in the stomach and intestine low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions liver problems including liver failure asthma attacks in people who have asthma

Other side effectsinclude: stomach pain constipation diarrhea gas heartburn nausea vomiting dizziness

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speech
• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines.
Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increasthe chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over–the–counter). Talk to your healthcare provider before using over–the–counter NSAIDs for more than 10 days.

NSAID medicines that need a prescription

Generic name	Tradename
Celecoxib	Celebrex
Diclofenac	Flector, Cataflam, Voltaren, Arthrotec (combined with misoprostol)
Diflunisal	Dolobid
Etodolac	Lodine, Lodine XL
Fenoprofen	Nalfon, Nalfon 200
Flurbiprofen	Ansaid
Ibuprofen	Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone)
Indomethacin	Indocin, Indocin SR, Indo-Lemmon, Indomethagan
Ketoprofen	Oruvail
Ketorolac	Toradol
Mefenamic Acid	Ponstel
Meloxicam	Relafen
Nabumetone	Relafen
Naproxen	Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole)
Oxaprozin	Daypro
Piroxicam	Feldene
Sulindac	Clinoril
Tolmetin	Tolectin, Tolectin DS, Tolectin 600

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by: King Pharmaceuticals, Inc.
501 Fifth Street
Bristol, TN 37620, USA
Telephone:1-888-840-8884
www.FlectorPatch.com
Manufactured for: IBSA Institut Biochimique SA, CH-6903
Lugano, Switzerland
Manufactured by: Teikoku Seiyaku Co., Ltd.,
Sanbonmatsu, Kagawa 769-2695 Japan

IMPORTANT: Reseal after Opening

NDC 60793-411-05

FLECTOR PATCH
(diclofenac epolamine topical patch)
1.3%

Rx Only

5 PATCHES (10MC x 14 CM EACH)

Change patch once every 12 hours.

Fold used patches so that the adhesive side sticks to itself and safely discard used patches where children and pets cannot get to them.


FLECTOR PATCH INACTIVE INGREDIENTS: 1,3-butylene glycol, dihydroxyaluminium 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.
DOSAGE: For dosage and full prescribing information, read accompanying product information.
STORAGE: Store at 25C (77F); excursions permitted to 15-30C (59-85F).
WARNING: Envelope is not child resistant. Keep used and unused patches out of reach of children and pets. Avoid contact of FLECTOR Patch with your eyes, nose, or mouth. If contact with your eyes occurs, rinse right away with water or saline. Talk with your doctor if eye irritation continues.
DIRECTIONS FOR USE: Refer to Full Directions Before Using. Wash hands throughly after applying, handling, or removing the patch.

1. Wash and Dry site: Wash the skin where you will apply FLECTOR Patch with soap and water. Do not use a moisturizing soap, lotion, astringent, or other skin care product where you will be applying the patch. Be sure skin is completely dry before applying FLECTOR Patch.
2. Cut: Cut envelope along the dotted line, making sure not to cut the zipper seal just below it.
3. Open and Reseal: Pull apart the zipper seal. Remove the FLECTOR Patch. IMPORTANT: RESEAL ENVELOPE by squeezing the zipper seal together. The patches inside will dry out if the envelope is left open.
   
4. Remove Clear Liner: There is a clear liner covering the sticky side of the patch. To remove it, fold over one corner of the patch. Gently rub the folded corner between your finger and thumb to separate the patch and liner. Remove the entire liner before applying the patch to the skin.
   
5. Apply: FLECTOR Patch should be applied to intact skin only. Apply one FLECTOR Patch to the most painful area. Firmly press the patch in place, especially around all four edges. Change the patch every 12 hours. Remove the patch if irritation occurs. (See full prescribing information).
6. Fold and Discard: Fold used patches so that the adhesive side sticks to itself. Throw away used patches where children and pets cannot get them. Discard unused patches 3 months after opening envelope.

5 PATCHES (10CM x 14 CM EACH)

Distributed by: King Pharmaceuticals, Inc.
501 Fifth St., Bristol, TN 37620 USA
Tel.: 1-888-840-8884 www.FlectorPatch.com
Manufactured for: IBSA Institut Biochimique SA,
CH-6903 Lugano, Switzerland
Manufactured by: Teikoku Seiyaku Co., Ltd.
Sanbonmatsu, Kagawa 769-2695 Japan



IMPORTANT: Reseal after Opening

NDC 60793-411-05

FLECTOR PATCH
(diclofenac epolamine topical patch)
1.3%

PROFESSIONAL SAMPLE - NOT FOR SALE

Rx Only

2 PATCHES (10MC x 14 CM EACH)

Change patch once every 12 hours.

Fold used patches so that the adhesive side sticks to itself and safely discard used patches where children and pets cannot get to them.


FLECTOR PATCH INACTIVE INGREDIENTS: 1,3-butylene glycol, dihydroxyaluminium 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.
DOSAGE: For dosage and full prescribing information, read accompanying product information.
STORAGE: Store at 25C (77F); excursions permitted to 15-30C (59-85F).
WARNING: Envelope is not child resistant. Keep used and unused patches out of reach of children and pets. Avoid contact of FLECTOR Patch with your eyes, nose, or mouth. If contact with your eyes occurs, rinse right away with water or saline. Talk with your doctor if eye irritation continues.
DIRECTIONS FOR USE: Refer to Full Directions Before Using. Wash hands throughly after applying, handling, or removing the patch.

1. Wash and Dry site: Wash the skin where you will apply FLECTOR Patch with soap and water. Do not use a moisturizing soap, lotion, astringent, or other skin care product where you will be applying the patch. Be sure skin is completely dry before applying FLECTOR Patch.
2. Cut: Cut envelope along the dotted line, making sure not to cut the zipper seal just below it.
3. Open and Reseal: Pull apart the zipper seal. Remove the FLECTOR Patch. IMPORTANT: RESEAL ENVELOPE by squeezing the zipper seal together. The patches inside will dry out if the envelope is left open.
   
4. Remove Clear Liner: There is a clear liner covering the sticky side of the patch. To remove it, fold over one corner of the patch. Gently rub the folded corner between your finger and thumb to separate the patch and liner. Remove the entire liner before applying the patch to the skin.
   
5. Apply: FLECTOR Patch should be applied to intact skin only. Apply one FLECTOR Patch to the most painful area. Firmly press the patch in place, especially around all four edges. Change the patch every 12 hours. Remove the patch if irritation occurs. (See full prescribing information).
6. Fold and Discard: Fold used patches so that the adhesive side sticks to itself. Throw away used patches where children and pets cannot get them. Discard unused patches 3 months after opening envelope.

2 PATCHES (10CM x 14 CM EACH)

Distributed by: King Pharmaceuticals, Inc.
501 Fifth St., Bristol, TN 37620 USA
Tel.: 1-888-840-8884 www.FlectorPatch.com
Manufactured for: IBSA Institut Biochimique SA,
CH-6903 Lugano, Switzerland
Manufactured by: Teikoku Seiyaku Co., Ltd.
Sanbonmatsu, Kagawa 769-2695 Japan

FLECTOR   diclofenac epolamine   patch

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64032-0005 Route of Administration TOPICAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Diclofenac epolamine (Diclofenac ) Diclofenac epolamine 180 mg  in 14 g

Inactive Ingredients Ingredient Name Strength Gelatin 280 mg  in 14 g POVIDONE K30 280 mg  in 14 g SORBITOL 5.6 g  in 14 g Kaolin 420 mg  in 14 g Titanium dioxide 70 mg  in 14 g PROPYLENE GLYCOL 420 mg  in 14 g Methylparaben 14 mg  in 14 g Propylparaben 7 mg  in 14 g EDETATE DISODIUM 17 mg  in 14 g Tartaric acid 70 mg  in 14 g CARBOXYMETHYLCELLULOSE SODIUM 450 mg  in 14 g DIHYDROXYALUMINUM AMINOACETATE 42 mg  in 14 g BUTYLENE GLYCOL 1.4 mg  in 14 g Polysorbate 80 28 mg  in 14 g Water 4.2 g  in 14 g

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 64032-0005-5 5 PATCH In 1 POUCH contains a PATCH (64032-0005-0) 1 64032-0005-0 14 g In 1 PATCH This package is contained within the POUCH (64032-0005-5) 2 64032-0005-2 2 PATCH In 1 POUCH contains a PATCH (64032-0005-0) 2 64032-0005-0 14 g In 1 PATCH This package is contained within the POUCH (64032-0005-2)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021234	01/01/2008

Labeler - Teikoku Seiyaku Co.. Ltd. (690849997)

Registrant - Teikoku Pharma USA, Inc. (045643751)

Establishment
Name	Address	ID/FEI	Operations
Teikoku Seiyaku Co., Ltd.		690849997	manufacture

Revised: 10/2009Teikoku Seiyaku Co.. Ltd.