Meicoxia

Etoricoxib.

MEICOXIA 60 MG: Green, hexagon-shaped, biconvex film-coated tablets debossed "MS E01" on one side.
Each film-coated tablet contains 60 mg of etoricoxib.
MEICOXIA 90 MG: White, hexagon-shaped, biconvex film-coated tablets debossed "MS E02" on one side.
Each film-coated tablet contains 90 mg of etoricoxib.
MEICOXIA 120 MG: Pale-green, hexagon-shaped, biconvex film-coated tablets debossed "MS E03" on one side.
Each film-coated tablet contains 120 mg of etoricoxib.

Therapeutic Class: Meicoxia is a member of a class of arthritis/analgesia medications called Coxibs. Meicoxia is a highly selective inhibitor of cyclooxygenase-2 (COX-2). ATC Code: M01AH05, Etoricoxib.
Pharmacology: Pharmacodynamics: Mechanism of Action: Etoricoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range. Across clinical pharmacology studies, Etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet function.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by proinflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.
Pharmacokinetics: Absorption: Orally administered etoricoxib is well absorbed. The absolute bioavailability is approximately 100%. Following 120 mg once-daily dosing to steady state, the peak plasma concentration (geometric mean C_max=3.6 mcg/ml) was observed at approximately 1 hours (T_max) after administration to fasted adults. The geometric mean area under the curve (AUC_0-24hr) was 37.8 mcg·hr/ml. The pharmacokinetics of etoricoxib are linearity across the clinical dose range.
Dosing with food (a high-fat meal) had no effect on the extent of absorption of etoricoxib after administration of a 120 mg dose. The rate of absorption was affected, resulting in a 36% decrease in C_max and increase in T_max by 2 hours. These data are not considered clinically significant.
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentration of 0.05 to 5 mcg/ml. The volume of distribution at steady state (V_dss) is approximately 120 L in humans.
Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Metabolism: Etoricoxib is extensively metabolized with <1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied.
Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.
Elimination: Following administration of a single 25-mg radiolabeled intravenous dose of etoricoxib to healthy subject, 70% of radioactivity was recovered in urine and 20% in feces, mostly as metabolite. Less than 2% was recovered as unchanged drug.
Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations of etoricoxib are reached within seven days of once daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. The plasma clearance after a 25 mg intravenous dose is estimated to be approximately 50 mL/min.
Characteristics in Patients: Elderly: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young.
Gender: The pharmacokinetics of etoricoxib are similar between men and women.
Hepatic insufficiency: Patients with mild hepatic insufficiency (Child-Pugh score 5-6) administered etoricoxib 60 mg once daily had an approximately 16% higher mean AUC as compared to healthy subjects given the same regimen. Patients with moderate hepatic insufficiency (Child-Pugh score 7-9) administered etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects given etoricoxib 60 mg once daily; etoricoxib 30 mg once daily has not been studied in this population. There are no clinical or pharmacokinetic data in patients with severe hepatic dysfunction (Child-Pugh score ≥10).
Renal insufficiency: The pharmacokinetics of a single dose of etoricoxib 120 mg in patients with moderate to severe renal insufficiency and patients with end-stage renal disease on hemodialysis were not significantly different from those in healthy subjects. Hemodialysis contributed negligibly to elimination (dialysis clearance approximately 50 ml/min).
Pediatric patients: The pharmacokinetics of etoricoxib in pediatric patients (<12 years old) have not been studied.
In a pharmacokinetic study (n=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in adolescents weighing 40 to 60 kg given etoricoxib 60 mg once daily and adolescents >60 kg given etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90 mg once daily. Safety and effectiveness of etoricoxib in pediatric patients have not been established.

MEICOXIA is indicated for: Acute and chronic treatment of the signs and symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA).
Treatment of ankylosing spondylitis (AS).
Treatment of acute gouty arthritis.
Relief of chronic musculo-skeletal pain, including chronic low back pain.
Relief of acute pain including dental surgery.
Treatment of primary dysmenorrhea.
Treatment of moderate to severe acute post-operative pain associated with abdominal gynecological surgery.
The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

MEICOXIA should be administered for the shortest duration possible and the lowest effective daily dose should be used.
Osteoarthritis: The recommended dose is 30 mg or 60 mg once daily.
Rheumatoid Arthritis: The recommended dose is 60 mg or 90 mg once daily. The minimum effective daily dose is 60 mg once daily. In some patients, 90 mg once daily may provide increased therapeutic benefit.
Ankylosing Spondylitis: The recommended dose is 60 mg or 90 mg once daily. The minimum effective daily dose is 60 mg once daily. In some patients, 90 mg once daily may provide increased therapeutic benefit.
Chronic musculo-skeletal pain, including chronic low back pain: The recommended dose is 60 mg once daily.
Acute Pain: For acute pain conditions, the recommended dose is 90 mg or 120 mg once daily. Meicoxia should be used only for the acute symptomatic period limited to a maximum of 8 days.
Acute Gouty Arthritis: The recommended dose is 120 mg once daily.
Primary Dysmenorrhea: The recommended dose is 120 mg once daily.
Post-operative Dental Pain: The recommended dose is 90 mg once daily.
Post-operative Gynecological Pain: The recommended dose is 90 mg once daily. The initial dose should be administered shortly before surgery. The dose can be increased to a maximum 120 mg daily.
Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Therefore: The dose for OA and chronic pain should not exceed 60 mg daily.
The dose for RA, ankylosing spondylitis and post-operative acute dental surgery pain should not exceed 90 mg daily.
The dose for acute gout, acute pain, primary dysmenorrhea and post-operative acute gynecological surgery pain should not exceed 120 mg daily.
As the cardiovascular risks of selective COX-2 inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.
Elderly, Gender, Race: No dosage adjustment in Meicoxia is necessary for the elderly or based on gender or race.
Hepatic Insufficiency: In patients with mild hepatic insufficiency (Child-Pugh score 5-6) a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic insufficiency (Child-Pugh score 7-9), the dose should be reduced; a dose of 60 mg every other day should not be exceeded, administration of 30 mg once daily can also be considered. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9).
Renal Insufficiency: In patients with advance renal disease (creatinine clearance <30 mL/min), treatment with Meicoxia is not recommended. No dosage adjustment is necessary for patients with lesser degrees of renal insufficiency (creatinine clearance ≥30 mL/min).
Pediatric Use: Safety and effectiveness of etoricoxib in pediatric patients have not been established, and should not be given to them.
Geriatric Use: Pharmacokinetics in elderly (65 years of age and older) are similar to those in theyoung. In clinical studies, a higher incidence of adverse experiences was seen in older patients compared to younger patients; the relative difference between etoricoxib and control groups were similar in the elderly and the young. Greater sensitivity of some older individuals cannot be ruled out.
MODE OF ADMINISTRATION: MEICOXIA is administered orally and may be taken with or without food.

In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
Etoricoxib is not dialyzable by hemodialysis; it is not known whether etoricoxib is dialyzable by peritoneal dialysis.

MEICOXIA is contraindicated in: Patients with known hypersensitivity to any component of this product.
Patients with active peptic ulceration or gastro-intestinal (GI) bleeding.
Patients with severe hepatic dysfunction (Child-Pugh score >9).
Patients with estimated creatinine clearance <30 ml/min.
Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioneurotic oedema or urticarial following the administration of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
Pregnancy and lactation.
Children under 16 years of age.
Patients with inflammatory bowel disease.
Patients with congestive heart failure (NYHA II-IV).
Patients with hypertension whose blood pressure has not been adequately controlled.
Patients with established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (including patients who have recently undergone coronary artery bypass graft surgery or angioplasty).

Contraindicated in patients with known hypersensitivity to any component of this product, pregnancy and lactation.
Contraindicated in patients who have recently undergone coronary artery bypass graft surgery (immediately postoperative period).
Contraindicated in patients with cardiovascular or cerebrovascular disease.
Contraindicated in patients with un-controlled hypertension.
Contraindicated in patients with myocardial infraction or congestive heart failure NYHA II-IV.
Contraindicated in patients with history of ischemic heart disease or history of paralysis from cerebrovascular disease.
Caution should be used in patients with risk factors for cardiovascular events e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking, elderly.
Caution should be used in patients with liver or renal disease.

Hypersensitivity reactions including anaphylaxis and angioedema have occurred in patients receiving etorixocib; it should be stopped at the first signs of hypersensitivity.
Etoricoxib should not be used in patients with ischemic heart disease, peripheral arterial disease, or cerebrovascular disease. It should be used with caution in patients with significant risk factors for cardiovascular disease such as hypertension, hyperlipidemia, and diabetes mellitus.
Etoricoxib particularly at high doses, may be associated with more frequent and severe hypertension compared with other NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors; blood pressure monitoring during etoricoxib treatment is recommended. Etoricoxib should not be used in patients with hypertension whose blood pressure is not controlled.
Etoricoxib is also contraindicated in patients with inflammatory bowel disease, moderate to severe heart failure (NYHA class II to IV), and renal impairment associated with a creatinine clearance of less than 30 mL/min. It should be avoided in patients with severe hepatic impairment (Child-Pugh score of 10 or more). Therapy should be stopped if persistently abnormal liver enzyme values are seen.
Caution is recommended when using etoricoxib in dehydrated patients; it may be advisable to hydrate patients before giving etoricoxib.
Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs, the elderly patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding.

Pregnancy: The use of Meicoxia, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.
No clinical data on exposed pregnancies are available for Meicoxia. Studies in animals have shown reproductive toxicity. The potential for human risk in pregnancy is unknown. Meicoxia, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Meicoxia is contraindicated in pregnancy. If woman becomes pregnant during treatment, Meicoxia must be discontinued.
Lactation: It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of lactating rats. Women who use etoricoxib must not breast feed.

Blood and lymphatic system disorders: thrombocytopenia.
Infections and infestation: gastroenteritis, upper respiratory infection, urinary tract infection.
Immune system disorders: hypersensitivity reactions, including angioedema, anaphylactic/anaphylactoid reactions including shock.
Metabolism and nutrition disorders: appetite increase or decrease, weight gain, hyperkalemia.
Psychiatric disorders: anxiety, depression, mental acuity decreased, confusion, hallucinations, restlessness.
Nervous system disorders: dysgeusia, insomnia, paresthesia/hypaesthesia, somnolence.
Eye disorders: blurred vision.
Ear and labyrinth disorders: tinnitus.
Cardiac disorders: congestive heart failure, non-specific ECG changes, myocardial infarction, palpitations, angina, arrhythmia.
Vascular disorders: flushing, cerebrovascular accident, hypertensive crisis.
Respiratory, thoracic and mediastinal disorders: cough, dyspnea, epistaxis, bronchospasm.
Gastrointestinal disorders: abdominal distention, acid reflux, bowel movement pattern change, constipation, dry mouth, gastroduodenal ulcer, irritable bowel syndrome. Oesophagitis, oral ulcers, peptic ulcers including perforation and bleeding (mainly in elderly patients), vomiting, gastritis.
Hepatobiliary disorders: hepatitis, jaundice, hepatic failure.
Skin and subcutaneous tissue disorders: ecchymosis facial oedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticarial, fixed drug eruption.
Musculoskeletal, connective tissue and bone disorder: muscular cramp/spasm, musculoskeletal pain/stiffness.
Renal and urinary disorders: proteinuria, renal insufficiency, including renal failure.
General disorder and administration site conditions: chest pain.
Investigation: blood urea nitrogen increased, creatine phosphokinase increased, haematocrit decreased, haemoglobin decreased, hyperkalaemia, leukocytes decreased, platelets decreased, serum creatinine increased, uric acid increased.
The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity including interstitial nephritis and nephrotic syndrome; hepatotoxicity, including hepatic failure.

Warfarin: Standard monitoring of International Normalized Ratio (INR) values should be conducted when therapy with Meicoxia is initiated or changed, particularly in the first few days, in patients receiving warfarin or similar agent.
Rifampin: Co-administration of Meicoxia with rifampin, a potent inducer of hepatic metabolism, produced a 65% decreased in etoricoxib plasma area under the curve (AUC). This interaction should be considered when Meicoxia is co-administered with rifampin.
Methotrexate: Monitoring for methrotrexate-related toxicity should be considered when Meicoxia at dose greater than 90 mg daily and methrotrexate are administered concomitantly.
Diuretics, Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin II Antagonists (AIIAs): Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive effect of diuretics, ACE inhibitors and AIIAs. This interaction should be given consideration in patients taking Meicoxia concomitantly with these products.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors, the co-administration of ACE inhibitors or AIIAs may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.
Lithium: Reports suggest that non-selective NSAIDs and selective COX-2 inhibitors may increase plasma lithium levels. This interaction should be given consideration in patients taking Meicoxia concomitantly with lithium.
Aspirin: Meicoxia can be used concomitantly with low-doses for cardiovascular prophylaxis. At steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of low-dose aspirin (81 mg once daily). However, concomitant administration of low-dose aspirin with Meicoxia increases the rate of GI ulceration or other complication compared to use of Meicoxia alone. Concomitant administration of etoricoxib with doses of aspirin above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.
Cyclosporin and tacrolimus: co-administration of cyclosporine or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporine or tacrolimus. Renal function should be monitored when etoricoxib and either of these drugs are used in combination.
Oral Contraceptives: Etoricoxib 60 mg and 120 mg given concomitantly with an oral contraceptive increased the steady state AUC_0-24hr of EE by 37% and 50-60% respectively. The increase in EE concentration should be considered when selecting an oral contraceptive for use with etoricoxib. An increase in Ethinyl estradiol (EE) exposure can increase the incidence of adverse events associated with oral contraceptives (e.g., venous thrombo-embolic events in woman at risk).
Hormone Replacement Therapy: Administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg PREMARIN), increased the mean steady state AUC_{0-24 hr} of unconjugated estrone (41%), equilin (76%) and 17ß-estradiol (22%). These increases in estrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with Meicoxia because the increase in estrogen exposure might increase the risk of adverse events associated with HRT.
Prednisone/prednisolone: In drug-interaction studies, etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone.
Digoxin: Patients at high risk of digoxin toxicity should be monitored for this when etoricoxib and digoxin are administered concomitantly.
Effect of etoricoxib on drugs metabolized by sulfotransferases: Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SLUT1E1 and has been shown to increase the serum concentrations of ethinyl estradiol. It may be prudent to exercise care when administering etoricoxib concurrently with other drugs primarily metabolized by human sulfotransferases (e.g., oral salbutamol and minoxidil).
Ketoconazole: Ketoconazole, a potent inhibitor of CYP3A4. Dosed at 400 mg once a day for 11 days to healthy volunteers did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).

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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AH05 - etoricoxib ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, coxibs.

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