Myox

Each film-coated tablet contains: Etoricoxib 60 mg, 90 mg, or 120 mg.
Etoricoxib (Myox) 60 mg Film-coated Tablet: Slightly brownish yellow, round, biconvex, with beveled edges, engraved with mark "60" on one side of the tablet.
Etoricoxib (Myox) 90 mg Film-coated Tablet: Pink, round, biconvex, with beveled edges, engraved with mark "90" on one side of the tablet.
Etoricoxib (Myox) 120 mg Film-coated Tablet: Brownish red, round, slightly biconvex, with beveled edges, scored on one side of the tablet. The score line is not intended for breaking the tablet.

Pharmacology: Pharmacodynamics: Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities. It selectively inhibits cyclooxygenase-2 (COX-2) isoenzymes, resulting in inhibition of prostaglandin synthesis. At therapeutic doses, etoricoxib does not inhibit COX-1 isoenzyme. Thus, it does not interfere with the normal COX-1 related physiological processes in tissues, such as the gastric prostaglandin synthesis, and had no effect on platelet function. Etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily.
Pharmacokinetics: Etoricoxib is well absorbed after oral administration, with an absolute bioavailability of approximately 100%. Peak plasma concentrations occur in about 1 hour following administration in fasted adults. The pharmacokinetics of etoricoxib is linear across clinical dose range. The onset of action of etoricoxib can occur as early as 24 minutes following administration. Dosing of etoricoxib 120 mg with food (i.e., high-fat meal) decreased the peak plasma concentrations (C_max) by 36% and increased the time to reach peak plasma concentrations (t_max) by 2 hours; however, it did not alter the extent of absorption of etoricoxib.
Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 mcg/mL. The volume of distribution at steady state (V_dss) of etoricoxib was approximately 120 L in humans. It was demonstrated that etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Etoricoxib is extensively metabolized; only less than 1% of the administered drug was recovered in the urine as the parent drug. Five metabolites have been identified in man. The major route of metabolism is via cytochrome P450 (CYP) enzymes to form the 6'-hydroxymethyl derivative, which is then oxidized to the 6'-carboxylic acid derivative, the principal metabolite. These principal metabolites are both inactive or only weak COX-2 inhibitors, while none of these metabolites demonstrated COX-1 inhibition.
In vivo studies demonstrated that CYP3A4 appears to mainly contribute to the metabolism of etoricoxib, while CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can catalyze the main metabolic pathway in vitro, but their quantitative roles in vivo have not been studied.
Steady state concentrations are attained with the administration of etoricoxib 120 mg once daily for 7 days, with an accumulation ratio of approximately 2, corresponding to a half-life of about 22 hours. The plasma clearance after the intravenous administration of etoricoxib 25 mg is estimated to be approximately 50 mL/min. Etoricoxib is mainly excreted through the kidneys. Following the intravenous administration of a single 25 mg radiolabeled etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in feces, mostly as metabolites. Less than 2% was recovered as unchanged drug.
Special Populations: Hepatic Impairment: The administration of etoricoxib 60 mg once daily in patients with mild hepatic dysfunction (Child-Pugh score 5 to 6) increased the mean area under the concentration-time curve (AUC) by 16% when compared to healthy subjects. Patients with moderate hepatic dysfunction (Child-Pugh score 7 to 9) administered with etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects who received the same dose of etoricoxib once daily. There are no clinical or pharmacokinetic data performed in patients with severe hepatic dysfunction (Child-Pugh ≥10).
Renal Impairment: 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 with a dialysis clearance of approximately 50 mL/min has a negligible effect in the elimination of etoricoxib.
Elderly: The pharmacokinetics of etoricoxib in patients 65 years and older are similar to those in young patients.
Children: The pharmacokinetics of etoricoxib 60 mg administered once daily in adolescents 12 to 17 years old weighing 40 to 60 kg and of etoricoxib 90 mg given once daily in adolescents weighing >60 kg were similar to the pharmacokinetics in adults administered with etoricoxib 90 mg once daily. The pharmacokinetics of etoricoxib in children 12 years old and younger have not been studied.

For the acute and chronic treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis.
For the treatment of ankylosing spondylitis.
For the relief of acute pain.
Treatment of acute gouty arthritis.
Treatment of moderate to severe acute postoperative pain associated with dental surgery.
Treatment of primary dysmenorrhea.
Treatment of moderate to severe acute postoperative 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.

As with other NSAIDs, the lowest effective dose of etoricoxib should be used for the shortest possible time. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis.
Etoricoxib is administered orally and may be taken with or without food. The onset of action may be faster when etoricoxib is administered without food. This should be considered when rapid symptomatic relief is needed. (See Table 1.)

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Special Populations: Hepatic Impairment: Regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh scores 5 to 6), a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh scores 7 to 9), regardless of indication, the dose of 30 mg once daily should not be exceeded.
Clinical experience is limited particularly in patients with moderate hepatic dysfunction and caution is advised. There is no clinical experience in patients with severe hepatic dysfunction (Child-Pugh score ≥10); therefore, its use is contraindicated in these patients.
Renal Impairment: No dosage adjustment is necessary for patients with creatinine clearance ≥30 mL/min. The use of etoricoxib in patients with creatinine clearance <30 mL/min is contraindicated.
Elderly: No dosage adjustment is necessary for elderly patients. As with other drugs, caution should be exercised in elderly patients.

Clinical studies demonstrated that the administration of up to 500 mg single doses of etoricoxib and multiple doses up to 150 mg/day for 21 days did not result to significant toxicity. Cases of acute etoricoxib overdosage have been reported; however, adverse experiences were not reported in the majority of these cases. The most commonly observed adverse experiences were consistent with the safety profile for etoricoxib (e.g., gastrointestinal and cardiorenal events).
Usual supportive measures (e.g., removal of unabsorbed material from the GI tract, clinical monitoring) must be performed during overdose. Supportive therapy should be instituted, if required.
Etoricoxib is not dialyzable by hemodialysis; it is not known whether etoricoxib is dialyzable by peritoneal dialysis.

Absolute Contraindications: Not to be given to those patients who have history of: Stroke: cerebrovascular accident, CVA.
Heart attack: Myocardial infarction, MI.
Coronary artery bypass graft: CABG.
Uncontrolled hypertension.
Congestive heart failure (CHF) NYHA II-IV.
Hypersensitivity to etoricoxib, other NSAIDs, or to any component in the product.
Patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs, including other COX-2 specific inhibitors. Severe, rarely fatal, anaphylactoid reactions to NSAIDs have been reported in such patients.
Previous or active gastric, duodenal, or peptic ulceration; or active GI bleeding, or inflammatory bowel disease.
Severe renal impairment [creatinine clearance (CrCl) <30 mL/min] or deteriorating renal disease.
Severe hepatic dysfunction (serum albumin <25 g/L or Child-Pugh score ≥10).
Unstable or significant established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.
Children and adolescents under 16 years of age.
Pregnancy and breastfeeding (see Precautions and Use in Pregnancy & Lactation).
Patients who have recently undergone angioplasty.
Use in the peri-operative period in patients undergoing cardiac or major vascular surgery.

Risk of Serious Cardiovascular and Gastrointestinal Events: All NSAIDS, including etoricoxib, may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. All NSAIDs may have a similar risk. The risk may increase with higher dosage and longer duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
NSAIDs, including etoricoxib, cause an increased risk of serious GI 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 and patients with a history of peptic ulcer disease and/or GI bleeding are at greater risk for these serious GI events.

General: If any organ system functions deteriorate during treatment with etoricoxib, discontinuation of treatment should be considered and appropriate measures should be taken.
Cardiovascular Effects: Cardiovascular Thrombotic Events: Clinical trials using selective COX-2 inhibitors such as etoricoxib have shown an increased risk of serious cardiovascular (CV) thrombotic events, especially MI and stroke, compared to placebo and some NSAIDs. The lowest effective daily dose of etoricoxib should be used for the shortest duration possible to minimize the potential risk for an adverse CV event. Patients receiving long term treatment with etoricoxib should be reviewed regularly (e.g., every three months) with regards to efficacy, risk factors, and need for treatment, especially in patients with osteoarthritis.
Patients with known CV disease, history of atherosclerotic CV disease, or significant risk factors for CV events (e.g., hypertension, hyperlipidemia, diabetes mellitus, a first-degree relative with ischemic heart disease, cardiac failure, smoking) should be treated with etoricoxib with caution only after careful consideration of the patient's overall risk and potential risks and benefits of alternative analgesic therapies. Physicians and patients should be alert throughout the entire treatment course to observe the development of such events, even in the absence of previous CV symptoms. Patients should be informed on the signs and/or symptoms of serious CV events and the steps to take if they occur. Medically appropriate supervision should be maintained when using etoricoxib in patients with heart failure.
Two large, controlled, clinical trials of different COX-2 selective inhibitors for the treatment of pain found an increased incidence of MI and stroke in the first 10 to 14 days following CABG surgery. In the absence of comparable data with etoricoxib, it may be assumed that patients at high risk of cardiovascular disease (including patients with diabetes, hyperlipidemia, hypertension, or smokers) who are undergoing any major surgery may face an increased risk of developing a cardiovascular event.
Etoricoxib is not a substitute for aspirin for cardiovascular prophylaxis because of its lack of antiplatelet effect. Antiplatelet therapies should not be discontinued.
Fluid retention and Edema: As with other NSAIDs, etoricoxib is associated with new onset or recurrent congestive heart failure. Fluid retention and edema have been also observed in etoricoxib-treated patients due to its prostaglandin synthesis inhibition.
Etoricoxib should be used with caution in patients with a history of cardiac failure, left ventricular dysfunction, or hypertension, and in patients with pre-existing edema due to other reasons. These high-risk patients should be closely monitored during etoricoxib therapy. If there is a clinical evidence of deterioration in the condition of these patients, appropriate measures should be taken, including treatment discontinuation.
Hypertension: Etoricoxib is associated with more frequent and severe hypertension compared to some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore, hypertension should be controlled before starting treatment with etoricoxib. Blood pressure should be strictly monitored two weeks after treatment initiation and periodically thereafter. If blood pressure increases significantly, alternative treatment should be considered.
Gastrointestinal Effects: Etoricoxib may cause upper gastrointestinal (GI) complications (such as perforations, ulcers, or bleeding), some of which are fatal. These events can occur any time of the treatment, even without warning symptoms. Although the likelihood of developing a serious GI event increases during the course of treatment, short-term etoricoxib therapy is not without risk. In addition, the risk of GI adverse effects is further increased when etoricoxib is coadministered with aspirin, even at low doses. NSAIDs are also known to exacerbate inflammatory bowel disease associated with spondyloarthropathies.
Etoricoxib should be used with caution in the elderly, patients with concomitant NSAID or aspirin therapy, or patients with a prior history of GI diseases, since they are at higher risk of developing a GI complication. Patients should be informed of the signs and/or symptoms of serious GI toxicity and the steps to take if they occur.
Renal Effects: Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal prostaglandins may play a compensatory role in the maintaining renal perfusion. Therefore, under conditions of compromised renal blood perfusion, etoricoxib may cause a reduction in prostaglandin formation and, subsequently, renal blood flow and thereby impair renal function. Patients at highest risk of this response are those with pre-existing significant renal function impairment, uncompensated renal failure, or cirrhosis. Monitoring of renal function should be considered in these patients.
Etoricoxib should be used with caution in patients with considerable dehydration. Patients should be rehydrated prior to starting therapy with etoricoxib.
Advanced renal disease: Since the clinical experience in patients with advanced renal disease (CrCl <30 mL/min) is very limited, the use of etoricoxib in these patients is not recommended.
Hepatic Effects: Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials treated for up to one year with etoricoxib 30 mg, 60 mg, and 90 mg daily.
There have been rare reports of jaundice during post-marketing experience. While there are limited reports of hepatic failure, it was not clear if these reactions were associated with etoricoxib.
Physician and patients must be alert for hepatotoxicity. Physicians must inform their patients on the warning signs and symptoms of hepatotoxicity. Patients with symptoms and/or signs indicating liver dysfunction (e.g., nausea, fatigue, pruritus, jaundice, abdominal tenderness in the right upper quadrant, and "flu-like" symptoms), or in whom an abnormal liver function test has occurred, should be monitored and evaluated.
If clinical signs and symptoms consistent with hepatic insufficiency develop, or if abnormal liver enzyme tests persist (approximately three or more times the upper limit of normal), treatment with etoricoxib should be discontinued immediately.
Hypersensitivity Reactions: Serious hypersensitivity reactions such as anaphylaxis and angioedema have been reported in patients treated with etoricoxib. Etoricoxib therapy should be discontinued at the first appearance of signs of hypersensitivity.
Etoricoxib should be used with caution in patients who have previous acute asthmatic attacks, urticaria, or rhinitis precipitated by salicylates or non-selective COX inhibitors. Since the pathophysiology of these reactions is unknown, physicians must weigh the potential benefits and risks of prescribing etoricoxib in these patients.
Serious Skin Reactions: Serious skin reactions, some of which are fatal, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), have been very rarely reported with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance. These serious events may occur without warning. Some selective COX-2 inhibitors have been associated with increased risk of skin reactions in patients with history of any drug allergy. Patients appear to be at a higher risk during the early phase of treatment; majority of the cases have an onset within the first month of treatment. Etoricoxib therapy should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Hematologic Effects: NSAIDs may increase the risk of bleeding events. Etoricoxib should be used with caution in patients with co-morbid conditions such as coagulation disorders or concomitant use of drugs that increase the risk of bleeding (see Interactions). Signs of bleeding should be monitored during treatment.
Masking of Fever and Inflammation: Due to its anti-inflammatory and antipyretic effects, etoricoxib may mask fever and other usual signs and symptoms of infection. The physician should be aware of this when using etoricoxib in patients being treated for infection.
Patients with Renal or Hepatic Impairment: Etoricoxib should be used with caution in patients with renal and/or hepatic impairment. Medically appropriate supervision should be conducted during treatment. If these patients deteriorate during treatment, appropriate measures should be taken, including treatment discontinuation.
Effects on Ability to Drive and Use Machines: Although there are no studies have been conducted on the effect of etoricoxib on the ability to drive or use machines, patients who experience dizziness, vertigo, or somnolence while taking etoricoxib should not drive or operate machinery.
Use in Pregnancy & Lactation: Effects on Sexual Function and Fertility: As with any medicinal product that inhibits COX/prostaglandin synthesis, the use of etoricoxib is not recommended in women attempting to conceive.
Use in Children: The safety and effectiveness of etoricoxib in pediatric patients have not been established. Etoricoxib is contraindicated in children and adolescents under 16 years of age.
Use in the Elderly: A higher incidence of adverse experiences was observed in older patients compared to younger patients receiving etoricoxib. Greater sensitivity of some patients cannot be ruled out. Elderly patients should be treated with caution and should be medically supervised during etoricoxib treatment.

Pregnancy: There are no clinical data on exposed pregnancy for etoricoxib. Animal studies have shown reproductive toxicity. The potential for human risk is unknown.
Etoricoxib is a prostaglandin synthesis inhibitor, and may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Data from epidemiological studies demonstrate an increased risk of miscarriage after using a prostaglandin synthesis inhibitor during early pregnancy. Etoricoxib is contraindicated in pregnant women and should be discontinued if the patient becomes pregnant.
Lactation: It is not known if etoricoxib is excreted in human milk. Because of the potential risk to breastfed infants, a decision should be made whether to discontinue breastfeeding or to discontinue etoricoxib, taking into consideration the importance of the drug to the mother. Etoricoxib is contraindicated in breastfeeding women.
Effects on Sexual Function and Fertility: As with any medicinal product that inhibits COX/prostaglandin synthesis, the use of etoricoxib is not recommended in women attempting to conceive.

The most common adverse reactions associated with etoricoxib are abdominal pain, hypertension, dizziness, headache, ecchymosis, alveolar osteitis, edema, fluid retention, palpitations, arrhythmia, bronchospasm, constipation, flatulence, gastritis, dyspepsia, gastroesophageal reflux disorder, diarrhea, epigastric discomfort, nausea, vomiting, esophagitis, pharyngitis, oral ulcer, asthenia, fatigue, influenza-like illness, and increased ALT and/or AST.
Infections and infestations: Abscess, bacterial infection, bronchitis, cellulitis, fungal infection, herpes simplex, herpes zoster infection, nasopharyngitis, pneumonia, post-operative wound infection, staphylococcal infection, tinea pedis.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma, bladder malignant neoplasm, breast malignant neoplasm, malignant melanoma, non-Hodgkin's lymphoma, uterine leiomyoma.
Blood and lymphatic system disorders: Anemia, leukopenia, thrombocytopenia.
Immune system disorders: Angioedema, anaphylactic/anaphylactoid reaction, anaphylactic/anaphylactoid shock, hypersensitivity, seasonal allergy, urticaria.
Endocrine disorders: Diabetes mellitus.
Metabolism and nutrition disorders: Anorexia, decreased appetite, hyperglycemia, hyperkalemia, increased appetite, peripheral edema, thirst, weight gain.
Psychiatric disorders: Anxiety, confusion, decreased mental acuity, depression, dream abnormality, hallucination, insomnia, somnolence.
Nervous system disorders: Carpal tunnel syndrome, cerebrovascular accident, generalized tonic-clonic seizure, hypoesthesia, hyporeflexia, intracranial hemorrhage, lacunar infarction, lumbar radiculopathy, median nerve neuropathy, memory impairment, paresthesia, restlessness, sciatica, spinal stenosis, syncope, tremor, vertigo.
Eye disorders: Blepharitis, blurred vision, cataract, conjunctivitis, eye pain, Sicca syndrome, visual impairment.
Ear and labyrinth disorders: Ear pain, tinnitus.
Cardiac disorders: Angina pectoris, angina unstable, atrial fibrillation, atrial flutter, cardiac arrest, chest discomfort, chest pain, congestive heart failure, coronary artery disease, dyspnea exertional, mitral valve regurgitation, myocardial infarction, myocardial ischemia, tachycardia.
Vascular disorders: Deep vein thrombosis, diastolic hypertension, flushing, hemorrhoids, hot flush, hypertensive crisis, hypovolemic shock, orthostatic hypotension, transient ischemic attack, vasculitis.
Respiratory, thoracic, and mediastinal disorders: Cough, dyspnea, epistaxis, laryngitis, pulmonary embolism, rales, respiratory failure, sinus congestion, sinusitis, upper respiratory tract infection, wheezing.
Gastrointestinal disorders: Abdominal distention, aphthous ulcer, bowel movement pattern change, dental pain, dry mouth, dysgeusia, esophagitis, frequent bowel movements, gastritis, gastroduodenal ulcers, gastroenteritis, gastrointestinal sounds abnormal, gastrointestinal disorder, gastrointestinal distress, gastrointestinal hemorrhage, gastrointestinal perforation, gingival disorder, glossitis, irritable bowel syndrome, melena, mouth ulceration, oral lesion, oral pain, pancreatitis, peptic ulcer, retching, tongue edema, toothache.
Hepatic and hepatobiliary disorders: Cholelithiasis, cholecystitis, hepatic failure, hepatic steatosis, hepatitis, jaundice.
Skin and subcutaneous tissue disorders: Alopecia, blister, dermal cyst, dermatitis, eczema, erythema, fixed drug eruption, folliculitis, maculopapular rash, non-specific skin disorder, onychomycosis, pruritus, rash, rosacea, skin infection, skin nodule, skin ulcer, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disorders: Ankle pain, arthralgia, bursitis, costochondritis, finger pain, foot pain, gout, hip osteoarthritis, hip pain, knee osteoarthritis, muscle spasms, muscular weakness, musculoskeletal pain, musculoskeletal stiffness, neck pain, osteoporosis, periarthritis, rheumatoid arthritis, rotator cuff syndrome, shoulder pain, tendonitis, tenosynovitis, toe deformity.
Renal and urinary disorders: Cystitis, erythrocyturia, glycosuria, hematuria, interstitial nephritis, nephrolithiasis, nephrotic syndrome, nephrotoxicity, nocturia, polyuria, proteinuria, pyelonephritis, renal colic, renal failure, renal insufficiency, urinary calculus, urinary tract infection.
Pregnancy, puerperium and perinatal conditions: Pregnancy.
Reproductive system and breast disorders: Erectile dysfunction, ovarian cyst, vaginal hemorrhage, vaginal infection.
General disorders and administration site conditions: Face edema, feeling hot, fever, hyperhidrosis, pain, prolapse.
Investigations: Decreased bicarbonate, decreased blood sodium, decreased hematocrit, decreased hemoglobin, decreased leukocytes, decreased platelets, fecal occult blood, increased alkaline phosphatase, increased blood pressure, increased blood urea nitrogen, increased creatine phosphokinase, increased erythrocytes, increased gamma-glutamyl transpeptidase, increased monocytes, increased serum creatinine, increased urine nitrite, increased uric acid, non-specific electrocardiogram changes.
Injury, poisoning and procedural complications: Back strain, burn, contusion, corneal abrasion, femoral fracture, hip fracture, humeral fracture, joint sprain, knee sprain, laceration, motor vehicle accident, overdose, strain, subarachnoid hemorrhage, sunburn, tendon rupture, trauma, traumatic arthropathy, wrist fracture.

See Table 2.

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Store at temperatures not exceeding 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

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

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