Locoa

Esflurbiprofen.

Each 10 × 14 cm patch contains 40mg of esflurbiprofen.
The patch consists of a colorless to light yellow transparent adhesive plaster base and has characteristic aroma, in which the adhesive plaster base is spread on a backing layer, and the surface of the adhesive plaster base is covered with a liner.
Excipients/Inactive Ingredients: Mentha oil, Liquid paraffin, Styrene-isoprene-styrene block copolymer, Polyisobutylene, Ester gum HG, Propylene glycol dicaprylate, 2-Mercaptobenzimidazole, Dibutylhydroxytoluene.

Pharmacology: Pharmacodynamics: Mechanism of action: Esflurbiprofen is an optical isomer (S isomer) of flurbiprofen, racemate.
An in vitro study demonstrated the inhibitory action of esflurbiprofen on the cyclooxygenase activity, which is probably the main source of anti-inflammatory/analgesic effects.
Pharmacodynamic effects: Analgesic effect: The analgesic effect was demonstrated in all pain models: a dog model of urate-induced knee joint arthritic pain, and rat models of carrageenan-induced inflammatory pain, silver nitrate-induced arthritic pain, and adjuvant-induced arthritic pain.
Anti-inflammatory effect: The anti-inflammatory effect was demonstrated in all acute inflammation models: rat models of carrageenan-induced footpad inflammation, traumatic oedema, and adjuvant-induced arthritis.
Clinical efficacy and safety: A randomized double-blind, placebo-controlled, parallel-group study (phase II dose-finding study) and a randomized open-label* parallel-group study with flurbiprofen patches as the control (phase III study) were performed in patients with knee osteoarthritis. The following tables show changes from baseline in VAS scores (pain felt on rising from the chair) in patients receiving esflurbiprofen 40mg, base, or flurbiprofen patches for 2 weeks.
*The study was performed with well managed information on treatment groups for study subjects and investigators.
(See Tables 1 and 2.)

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Pharmacokinetics: Plasma Levels: Single dose: The pharmacokinetic parameters and changes in plasma concentrations in healthy adults (Japanese) receiving a single 24-hour application of 40mg of esflurbiprofen are shown in Table 3 and figure. Based on the residual drug amount in the patch, the transdermal absorption was calculated to be 48.34 ± 16.70%. (See Table 3 and figure.)

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Click on icon to see table/diagram/image

Multiple doses: The pharmacokinetic parameters in healthy adults (Japanese) receiving multiple 23-hour applications of once daily doses of 80 mg of esflurbiprofen for 7 days are shown in Table 4. Based on the residual drug amount in the patch, the transdermal absorption was calculated to be 73.24 ± 11.58%. (See Table 4.)

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Distribution: Tissue penetration: In patients (Japanese) with knee osteoarthritis scheduled to undergo knee replacement arthroplasty, the levels of esflurbiprofen in the synovia, synovial fluid, and plasma after a single 12-hour application of 20 mg of esflurbiprofen were 14.8, 32.7, and 34.5 times higher, respectively, than those after the use of 40 mg flurbiprofen patch.
Protein binding: An in vitro study showed that 99.95% of esflurbiprofen was bound to human plasma protein, probably to albumin as the main binding protein.
Metabolism: Esflurbiprofen mainly undergoes oxidative metabolism by CYP2C9. A study investigating the effect of CYP2C9 polymorphism using human liver microsomes showed the 4'-hydroxylation activity (CL_int) in poor metabolizers (PMs) (with genotype CYP2C9*3/*3) was 1/69 of that in extensive metabolizers (EMs) (with genotype CYP2C9*1/*1).
Excretion: In healthy adults (Japanese) receiving a single 24-hour application of 80 mg of esflurbiprofen, little of the dose (0.253%) was excreted as unchanged compound in the urine through 72 hours after the start of application.
Major metabolites were glucuronate or sulfate conjugates of the 4'-hydroxy compound. Other metabolites were free glucuronate conjugates, 4'-hydroxy compounds, and glucuronate conjugates of the 3'-hydroxy-4'-methoxy compound.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and early development, and embryo-fetal development.
In the pre- and postnatal development study using rats in late pregnancy, maternal animal death at ≥ 0.1 mg/kg, a tendency of an increased number and percentage of stillborn pups at 0.1, 0.3, and 3 mg/kg, delayed delivery at 0.3 mg/kg, reduced live birth index at ≥ 0.3 mg/kg, and incomplete delivery and prolonged delivery at ≥ 1 mg/kg were indicated. Since the AUC_0-24h value of esflurbiprofen on Day 17 of gestation at 1 mg/kg was comparable or less than the exposure after 40 or 80 mg of esflurbiprofen was administered to humans, the AUC_0-24h values at 0.1 and 0.3 mg/kg appeared to be lower than that in humans.
After esflurbiprofen was administered to rats in the lactation period, suppression of postnatal body weight gain and delayed onset of early behavior were seen at 3 mg/kg. The AUC_0-24h value of esflurbiprofen on Day 17 of gestation at 3 mg/kg were 5.77 and 2.55 times higher than the exposure after 40 or 80 mg of esflurbiprofen was administered to humans.

Relief of pain and inflammation associated with osteoarthritis.

Posology: LOCOA should be applied to the affected area once daily in adults. Do not use more than 2 patches at once.
Do not use more than 2 patches per day, since LOCOA is a topical patch with improved transdermal absorption and enhanced penetration of esflurbiprofen, the active ingredient, into the affected tissue. Also, the safety of LOCOA has been examined for up to 2 patches per day in clinical studies. The use of LOCOA with any other anti-inflammatory agent with expected systemic effects should be avoided wherever possible. If such use is deemed necessary, it should be limited to a minimal level and the condition of the patient should be carefully monitored.
Elderly: Since elderly patients are more susceptible to adverse reactions, their condition should be carefully monitored during treatment.
Paediatric population: Safety has not been established in low-birth-weight babies, neonates, nursing infants, infants and children. [Clinical studies have only been performed in adults and there is no experience in the use for the previously mentioned patients.]
Method of administration: LOCOA is administered topically by attaching the patch to the skin of the affected area.
LOCOA cannot be applied to the skin wounds, open injuries, mucous membrane or to the area of eczema or rash. If 2 patches are used at a time, the entire sticky side needs to be in direct contact with the skin. The patches should not be placed overlap or on top of another. LOCOA should be applied to clean and dry skin. Careful administration is required with attention to the skin condition of the application site. LOCOA should be detached slowly and carefully to prevent any damage to the skin.

Symptoms: Symptoms of overdose may include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting and occasionally convulsions. In cases of significant poisoning, acute renal failure and liver damage are possible.
Therapeutic measures: Patients should be treated symptomatically as required.
Patients should be advised to immediately remove the patches and wash the skin with water, then contact the doctor, pharmacist, or nearest hospital immediately.

Patients with peptic ulcer (See Precautions.)
Patients with severe blood abnormality.
Patients with severe liver disorder.
Patients with severe renal disorder.
Patients with severe cardiac dysfunction.
Patients with severe hypertension.
Patients with a history of hypersensitivity to the components of LOCOA or flurbiprofen.
Patients with current or previous aspirin-induced asthma (asthmatic attacks induced by nonsteroidal anti-inflammatory analgesics and other relevant drugs.)
Patients on enoxacin hydrate, lomefloxacin, norfloxacin, or prulifloxacin (See Interactions.)
Women in late pregnancy (See Use in Pregnancy & Lactation.)

General: A thorough health interview should be performed to predict hypersensitivity reactions.
For long term use, periodic laboratory tests (urine analysis, blood test, liver function test, etc.) should be performed. If any abnormality is observed, appropriate measures such as dose interruption should be taken.
Patients should be monitored closely for adverse reactions. Symptoms such as an excessive decrease in body temperature, collapse and coldness of limbs may occur and hence, this drug should be administered with great care while monitoring their condition in the elderly with hyperthermia or patients with debilitating diseases.
LOCOA must not be used with enoxacin hydrate, lomefloxacin, norfloxacin or prulifloxacin since convulsions have been reported in a few patients after receiving flurbiprofen axetil with these new quinolone antibiotics. The use of LOCOA with other new quinolone antibiotics should be avoided wherever possible.
If cutaneous symptoms are observed with the use of LOCOA, appropriate measures such as drug interruption or discontinuation should be taken according to symptoms.
Temporary infertility has been reported in women after long term use of nonsteroidal anti-inflammatory analgesics.
Careful administration: LOCOA should be administered with care in the following patients.
Patients with peptic ulcer induced by long term use of nonsteroidal anti-inflammatory analgesics who need long term use of LOCOA and are being treated with agents such as misoprostol: Since some patients may have peptic ulcer resistant to agents such as misoprostol, adequate monitoring and careful administration is required, when the use of LOCOA is continued.
Patients with a history of peptic ulcer: Gastric mucosal barrier decreased by inhibition of prostaglandin synthesis may cause a relapse of peptic ulcer.
Patients with current or previous blood abnormality: Blood abnormality may be aggravated or recur by development of blood disorder.
Patients with bleeding tendency: Platelet function may decrease, increasing bleeding tendency.
Patients with current or previous liver disorder: Liver disorder may be aggravated or recur by hepatic function abnormality.
Patients with current or previous renal disorder, or reduced renal blood flow: Renal disorder may be aggravated or recur, or may be induced by reduced renal blood flow via inhibition of prostaglandin synthesis.
Patients with abnormal cardiac function: Water and sodium retention induced by inhibition of prostaglandin synthesis may aggravate cardiac dysfunction.
Patients with hypertension: Water and sodium retention induced by inhibition of prostaglandin synthesis may further increase blood pressure.
Patients with a history of hypersensitivity to esflurbiprofen or flurbiprofen, or any of the other excipients: For the full list of excipients, see Description.
Patients with bronchial asthma: Some patients with bronchial asthma may actually have aspirin-induced asthma, with which asthmatic attacks may be induced.
Patients with ulcerative colitis: Symptoms aggravated by other nonsteroidal anti-inflammatory analgesics have been reported.
Patients with Crohn's disease: Symptoms aggravated by other nonsteroidal anti-inflammatory analgesics have been reported.
Risk of GI ulceration, bleeding and perforation with NSAID: Serious GI toxicity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated with NSAID therapy. Although minor upper GI problems (e.g. dyspepsia) are common, usually developing early in therapy, prescribers should remain alert for ulceration and bleeding in patients treated with NSAIDs even in the absence of previous GI tract symptoms.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Patients with prior history of serious GI events and other risk factors associated with peptic ulcer disease (e.g. alcoholism, smoking, and corticosteroid therapy) are at increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less than other individuals and account for most spontaneous reports for fatal GI events.
Use this medication by prescription only.
Effects on ability to drive and use machines: It is considered that application of LOCOA at recommended doses has no influence on the ability to drive and use machines.
Use in the elderly: Elderly patients are more susceptible to adverse reactions. Care should be taken in administering LOCOA to elderly patients, for example, limiting the use to a minimal level, while special attention should be paid to possible adverse reactions.
Use in Children: Safety has not been established in low birth weight babies, neonates, babies, infants and children. [There is no experience in the use for the previously mentioned patients.]

LOCOA cannot be used in women in late pregnancy. A study in rats in late pregnancy showed deaths of dams, delayed delivery, reduced fertility rates, and increased stillbirths with less than the plasma esflurbiprofen level (AUC) equivalent to that yielded by the use of 2 patches of LOCOA in humans (See Pharmacology: Toxicology: Preclinical safety data under Actions.)
LOCOA should be used in pregnant women (other than those in late pregnancy) or potentially pregnant women, only if therapeutic benefits are deemed to outweigh risks. [Safety has not been established in pregnant women.]
The use of LOCOA should be avoided in lactating women. If such use is deemed necessary, they should use it after the patient has stopped lactating. [An animal study (rats) showed excretion of esflurbiprofen into the milk and restricted increase in body weight in offspring of dams with approximately 3 times the plasma level (AUC) yielded by the use of 2 patches of LOCOA in humans (See Pharmacology: Toxicology: Preclinical safety data under Actions.)]
Constriction of the fetal ductus arteriosus has been reported in women in late pregnancy using other topical nonsteroidal anti-inflammatory analgesics.
Temporary infertility has been reported in women after long term use of nonsteroidal anti-inflammatory analgesics.

Summary of the safety profile: In the clinical studies performed in a total of 1,391 patients, 415 adverse reactions were reported in 269 patients (19.3%), including application site dermatitis in 111 patients (8.0%), application site erythema in 44 patients (3.2%), and application site eczema in 32 patients (2.3%).
Tabulated list of adverse reactions reported in the clinical studies and from post-marketing experience: The following adverse reactions have been reported in all the clinical trials and from post-marketing experience with LOCOA. Adverse reactions listed as follows are classified according to frequency and system organ class (SOC). (See Table 5.)

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Clinically significant adverse reactions: Shock, anaphylaxis: Since shock and anaphylaxis have been reported (with an unknown incidence for both) with the use of esflurbiprofen, the condition of patients, should be carefully monitored, and treatment should be discontinued while taking appropriate actions if symptoms such as chest discomfort, chills, cold sweat, dyspnea, numbness in extremities, decreased blood pressure, angioedema, and urticaria are observed.
Acute kidney injury, nephrotic syndrome: Since acute kidney injury has been reported (with an unknown incidence) with the use of esflurbiprofen, this medicine may cause serious renal disorders including acute kidney injury and nephrotic syndrome. So the condition of patients should be carefully monitored, for example, with periodic tests, and appropriate actions should be taken such as discontinued treatment, if signs such as oliguria, hematuria, protein urine, increases in BUN and blood creatinine, hyperkalaemia, and hypoalbuminaemia are observed.
Gastrointestinal bleeding: Since gastrointestinal bleeding has been reported (with an unknown incidence) with the use of esflurbiprofen, the condition of patients should be carefully monitored, and treatment should be discontinued while taking appropriate treatment, if any abnormality is observed.
Aplastic anaemia: Since aplastic anaemia has been reported (with an unknown incidence) with the use of oral flurbiprofen, the condition of patients should be carefully monitored, and appropriate actions should be taken such as discontinued treatment.
Induced asthma attacks (aspirin-induced asthma): Since asthma attacks have been induced by the use of esflurbiprofen, treatment should be discontinued if initial symptoms such as dry rales, wheezing, and dyspnea are observed.
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, exfoliative dermatitis: Since Stevens-Johnson syndrome has been reported (with an unknown incidence) with the use of esflurbiprofen, this medicine may cause toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis. So the condition of patients should be carefully monitored and treatment should be discontinued while taking appropriate treatment, if any abnormality is observed.
Impaired consciousness, convulsions with impaired consciousness: Since impaired consciousness and convulsions with impaired consciousness have been reported as a rare incidence (< 0.1%) with the use of flurbiprofen axetil [injections], the condition of patients should be carefully monitored, and treatment should be discontinued while taking appropriate treatment, if any abnormality is observed.

Contraindications for concomitant administration: Enoxacin hydrate, Lomefloxacin, Norfloxacin, Prulifloxacin: Concomitant use may induce convulsions due to enhancing GABA inhibition by new quinolone antibiotics.
Precautions for concomitant administration: New quinolone antibiotics (Ofloxacin, etc.) [Note that enoxacin hydrate, lomefloxacin, norfloxacin and prulifloxacin are contraindicated for concomitant administration]: Concomitant use may induce convulsions due to enhancing GABA inhibition by new quinolone antibiotics.
Coumarin anticoagulants (Warfarin): Care such as dose adjustment should be taken to avoid possible increase in effect of coumarin anticoagulants (warfarin). Esflurbiprofen may compete with warfarin in plasma protein binding, increasing free warfarin.
Methotrexate: Care such as dose adjustment should be taken to avoid possible poisoning symptoms (e.g., anaemia and thrombocytopenia) due to increase in the effect of methotrexate.
Inhibition of prostaglandin synthesis by esflurbiprofen may reduce renal blood flow, resulting in decreased renal excretion and thus increased blood levels of methotrexate.
Lithium products (Lithium carbonate): Careful measures such as adequate monitoring of lithium blood levels should be taken during the use of lithium products, since concomitant use may increase blood levels of lithium, which may cause lithium poisoning symptoms. Inhibition of prostaglandin synthesis by esflurbiprofen may reduce renal excretion of sodium and lithium clearance, thus increasing lithium blood levels.
Thiazide diuretics (Hydrochlorothiazide, etc.) and loop diuretics (Furosemide, etc.): The effect of these diuretics may decrease. Inhibition of prostaglandin synthesis by esflurbiprofen may produce water and salt retention in the body.
Corticosteroids (Methylprednisolone, etc.): Concomitant use may mutually increase gastrointestinal reactions (peptic ulcer, gastrointestinal bleeding, etc.). Concomitant use may increase gastrointestinal reactions to both drugs.
Pharmacokinetic interaction with CYP2C9 inhibitors (Fluconazole, etc.): Esflurbiprofen is mainly metabolized by hepatic enzyme CYP2C9. Esflurbiprofen blood levels may increase, since metabolism of esflurbiprofen is inhibited by concomitant use of CYP2C9 inhibitors.

Special precautions for disposal: LOCOA should not be disposed via wastewater or household waste.

Store away from direct sunlight, heat and moisture. Store below 25°C.
Shelf life: 2 years.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M02AA29 - esflurbiprofen ; Belongs to the class of non-steroidal antiinflammatory preparations for topical use. Used in the treatment of joint and muscular pains.

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