Nosmen

Etoricoxib.

Each tablet contains Etoricoxib 120 mg.

PHARMACOLOGY: Pharmacodynamics: Etoricoxib is a member of a class of Non-Steroid Anti-Inflammatory Drugs which is highly selective cyclo-oxygenase-2 (COX-2) inhibitor with anti-inflammatory and analgesic properties.
Pharmacokinetics: Absorption: Etoricoxib is well absorbed from the gastrointestinal tract after oral doses. The bioavailability is approximately 100%. Peak plasma concentrations are reached in about 1 hour in fasted adults. Dosing with food has no effect on the extent of absorption of etoricoxib. Food delays absorption, resulting peak plasma concentrations by about 2 hours.
Distribution: Etoricoxib is approximately 92% bound to plasma protein. At steady state the half-life of etoricoxib is about 22 hours. The volume of distribution (V_d) is approximately 120 l.
Metabolism: The major route of metabolism is via cytochrome P450 isoenzymes including CYP3A4 to from the 6'-hydroxymethyl derivative of etoricoxib, which is then oxidized to the 6'-carboxylic acid derivative, the major metabolite. Both are inactive or only weak cyclo-oxygenase-2 (COX-2) inhibitors.
Excretion: Etoricoxib is excretion mainly via the urine 70% with only 20% of a dose appearing in the faeces. Less than 2% was recovered as unchanged drug.

NOSMEN 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.

NOSMEN is administered orally. NOSMEN may be taken with or without food. NOSMEN should be administered for the shorted duration possible and the lowest effective daily dose should be used.
Osteoarthritis: The recommended dose is 60 mg once daily.
Rheumatoid Arthritis: The recommended dose is 60 mg or 90 mg once daily.
Ankylosing Spondylitis: The recommended dose is 60 mg or 90 mg once daily.
Chronic musculo-skeletal pain, including chronic low back pain: The recommended dose is 60 mg once daily.
Acute pain: For acute pain conditions, NOSMEN 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.
Post-operative Dental pain: The recommended dose is 90 mg once daily should be used a maximum of 3 days.
Primary Dysmenorrhea: The recommended dose is 120 mg once daily should be used a maximum of 8 days.
Post-operative abdominal gynecological pain: The recommended dose is 90 mg or 120 mg once daily.
Elderly, Gender, Race: No dosage adjustment in etoricoxib is necessary for the elderly or based on gender or race.
Hepatic Impairment: Etoricoxib should not be given to patients with severe hepatic impairment (Child-Pugh 10 or more), maximum 60 mg daily in mild hepatic impairment (Child-Pugh score 5 to 6), maximum 60 mg on alternate days or 30 mg once daily in moderate hepatic impairment (Child-Pugh score 7 to 9).
Renal Impairment: In patients with advanced renal disease (creatinine clearance < 30 mL/min), treatment with etoricoxib is not recommended. No dosage adjustment is necessary for patients with lesser degrees of renal impairment (creatinine clearance ≥ 30 mL/min).

Symptoms: In clinical studies of originator product, administration of etoricoxib at single doses up to 500 mg and multiple doses up to 150 mg/day for 21 days did not result in significant toxicity. There have been reports of acute overdosage with etoricoxib, although adverse experiences were not reported in the majority of cases. The most frequently observed adverse experiences were consistent with the safety profile for etoricoxib (e.g. gastrointestinal events, renovascular events).
Treatment: Treatment of NSAID toxicity is primarily supportive and symptomatic. In addition to supportive measures, the use of oral activated charcoal may help to reduce the absorption of the NSAID. However, hemodialysis may be necessary in cases of NSAID-induced prolonged or severe renal failure.

NOSMEN is contraindicated in: Patients with known hypersensitivity to any component of this product.
Patients with congestive heart failure (NYHA II-IV).
Patients with renal impairment associated with a creatinine clearance < 30 ml/min.
Patients with ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (including patients who have recently undergone coronary artery bypass graft surgery or angioplasty).
Patients with severe hepatic impairment (Child-Pugh score of 10 or more).
Patients with hypertension whose blood pressure has not been adequately controlled.
Patients with active peptic ulceration or gastro-intestinal (GI) bleeding.
Patients with inflammatory bowel disease.
Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioneurotic oedema or urticaria following the administration of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
Pregnancy and lactation.
Children under 16 years of age.

Cardiovascular: NSAIDs are associated with an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events including MI and stroke. Risk may be increased with long-term use or preexisting cardiac risk factors (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking). Carefully evaluate individual cardiovascular profiles prior to prescribing and periodically reevaluate the need for symptomatic relief and response to therapy.
The cardiovascular safety of etoricoxib has been assessed in the MEDAL program which pooled data from 3 studies involving over 30,000 patients with either osteoarthritis or rheumatoid arthritis. Patients with osteoarthritis were given etoricoxib 60 or 90 mg daily; those with rheumatoid arthritis received 90 mg daily. In all studies, diclofenac 150 mg daily was given as the comparator. After an average treatment duration of 18 months, the rate of thrombotic events such as myocardial infarction, stroke, and sudden or unexplained death with etoricoxib were similar to those for diclofenac. One of the 3 studies showed that there was a non-significant increase in the rate of heart failure with etoricoxib 90 mg daily compared to diclofenac.
In another study that pooled pre-licensing data, the risk of thrombotic events with etoricoxib, given at a dose of at least 60 mg daily, was also found to be similar to that for placebo treatment, ibuprofen 2.4 g daily, diclofenac 150 mg daily and naproxen 1 g daily, although there was a trend towards more events with etoricoxib than with naproxen. The EMEA's Committee for Medicinal Product for Human Use (CHMP) has recommended the inclusion of a warning in the labelling of etoricoxib that it must not be given to patients whose blood pressure is persistently above 140/90 mmHg and inadequately controlled; in addition, high blood pressure should be controlled before starting treatment and monitored for 2 weeks afterwards then regularly thereafter. Etoricoxib should be used the shortest duration possible and lowest effective daily dose. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically.
New onset or worsening edema and heart failure may occur. Use caution with preexisting edema (any cause), left ventricular dysfunction, or NYHA class I heart failure. Use is contraindicated with NYHA class II-IV heart failure. Discontinue use if worsening heart failure, edema, or uncontrolled/severe hypertension occurs.
Hepatic: Elevations in transaminases (three or more times the upper limit of normal) may occur; monitor hepatic function closely in patients with previous abnormal hepatic function test or signs/symptoms of hepatic dysfunction. Severe hepatic reactions (e.g. hepatitis, jaundice, liver failure) have (rarely) occurred with use, discontinue if signs or symptoms of hepatic disease develop, if systemic manifestations occur, or with persistent or worsening abnormal hepatic function test.
Renal: Long-term administration of NSAIDs has resulted in renal papillary necrosis. NSAIDs use may compromise existing renal function through a dose-dependent decrease in prostaglandin synthesis, resulting in a reduction in renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction; those taking diuretics, ACE inhibitors, angiotensin II receptor blockers and elderly are at greater risk for renal toxicity.
Etoricoxib should be used with caution in patients with renal impairment; the lowest effective dose should be used for the shortest possible duration, and renal function should be monitored. Sodium and water retention may occur and renal function may deteriorate, possibly leading to renal failure; deterioration in renal function has also been reported after topical use. Avoid if eGFR less than 30 ml/minute/1.73 m².
Gastro-intestinal: It is generally accepted that the inhibition of cyclo-oxygenase-1 (COX-1) plays a role in the adverse gastrointestinal effects of the NSAIDs, and COX-2 by NSAIDs such as etoricoxib may cause less gastrotoxicity than that seen with the non-selective inhibition of the traditional NSAIDs. In addition, etoricoxib should not be used in patients with active gastrointestinal ulceration or bleeding. In a study of the pooled data from 3 randomised clinical studies, etoricoxib (in doses of 60 or 90 mg daily) was associated with significantly less frequent upper gastrointestinal clinical events than diclofenac (150 mg daily).
Use caution with history of GI disease (bleeding or ulcer), concurrent therapy with aspirin or other NSAIDs, anticoagulants and/or corticosteroids, smoking, alcohol, and the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; consider alternate therapies for high-risk patients. When used concomitantly with aspirin (even at low doses), gastroprotective therapy (e.g. proton pump inhibitors, misoprostol) is recommended.
Skin: Serious hypersensitivity reactions, including anaphylaxis, angioedema, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been (rarely) reported with etoricoxib; discontinue use at first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Do not use in patients who experience bronchospasm, asthma, rhinitis, or urticarial with NSAIDs or aspirin therapy.
Use in Patients with Infection: Etoricoxib may mask the signs and symptoms of infection resulting in delayed diagnosis.

Pregnancy: NSAIDs should be avoiding during pregnancy or avoiding them unless the potential benefit outweighs the risk. NSAIDs should be avoided during the third trimester because use is associated with a risk of closure of fetal ductus arteriosus in utero and possibly persistent pulmonary hypertension of the newborn. In addition, the onset of labour may be delayed and its duration may be increased.
No clinical data are available on the use of etoricoxib in pregnant woman. In animal studies, reproductive toxicity was shown. Therefore NOSMEN is contraindicated in pregnancy. If a women becomes pregnant during treatment, NOSMEN must be discontinued.
Lactation: It is unknown whether etoricoxib is excreted into human breast milk. However, etoricoxib is excreted into the milk of lactating rats. Women who use etoricoxib must not breast feed.

Blood and lymphatic system: thrombocytopenia.
Infections and infestation: gastroenteritis, upper respiratory infection, urinary tract infection.
Immune system: hypersensitivity reactions, including angioedema, anaphylactic/anaphylactoid reactions including shock.
Metabolism and nutrition: appetite increase or decrease, weight gain.
Psychiatric: anxiety, depression, mental acuity decreased, confusion, hallucinations, restlessness.
Nervous system: dysgeusia, insomnia, paresthaesia/hypaesthesia, somnolence, asthenia/fatigue, dizziness, headache.
Eye: blurred vision.
Ear and labyrinth: tinnitus.
Cardiac: congestive heart failure, non-specific ECG changes, myocardial infarction, palpitations, angina, arrhythmia, atrial fibrillation.
Vascular: flushing, cerebrovascular accident, hypertensive crisis, hypertension, edema.
Respiratory, thoracic and mediastinal: cough, dyspnea, epistaxis, bronchospasm.
Gastrointestinal: 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, abdominal pain, flatulence, diarrhea, dyspepsia, heartburn, epigastric discomfort, nausea.
Hepatobiliary: hepatitis, jaundice, hepatic failure, ALT increased, AST increased.
Skin and subcutaneous tissue: ecchymosis, facial oedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, fixed drug eruption, oedema/fluid retention, lower extremity edema.
Musculoskeletal, connective tissue and bone: muscular cramp/spasm, musculoskeletal pain/stiffness.
Renal and urinary: proteinuria, renal insufficiency, including renal failure.
General disorders and administration site conditions: chest pain.
Investigations: blood urea nitrogen increased, creatine phosphokinase increased, haematocrit decreased, haemoglobin decreased, hyperkalaemia, leukocytes decreased, platelets decreased, serum creatinine increased, uric acid increased.
Miscellaneous: flu-like disease, post-dental extraction alveolitis (dry socket).
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.

Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin II Antagonists (AIIAs): NSAIDs may decrease the antihypertensive of ACEI and/or AIIAs. The co-administration medication may be the risk of nephrotoxicity increased. Consider discontinuation of NOSMEN if patient is uncontrolled blood pressure. Periodically measure renal function during concomitant use.
Azole antifungals (Fluconazole, Ketoconazole): Increase in NOSMEN plasma concentration may occur, increasing the pharmacologic effect and adverse reactions.
Corticosteroid oral (Prednisone): The risk of GI bleeding may be increased. Use corticosteroid oral and NOSMEN with caution.
Antiplatelet therapy (Clopidogrel, Prasugrel): The risk of bleeding may be increased. Use antiplatelet and NOSMEN with caution.
Anticoagulant (Warfarin): Co-administration with NOSMEN may increase the risk of anticoagulant-induced bleeding (eg. GI bleeding). Monitor prothrombin time and International Normalized Ratio (INR) and patients closely, especially the first few days.
Beta-blockers: The antihypertensive effect of beta-blockers with NOSMEN may be impaired, possibly because of NOSMEN as the NSAIDs inhibition of renal prostaglandin synthesis, thereby allowing unopposed pressure systems. Monitor blood pressure and adjust beta-blocker dose as needed to treat.
Cyclosporin and tacrolimus: Co-administration with NOSMEN may increase nephrotoxicity. Monitor renal function frequently and consider avoiding concurrent use.
Diuretics (Thiazides, Potassium-sparing diuretics, Loop diuretics): The effects of diuretics may be decreased, the risk of acute renal failure may be increased when coadministration. Closely monitor renal function if coadministration cannot be avoided. If renal function decreases, consider stopping one or both drugs.
Lithium: Concomitant administration with NOSMEN may increase plasma lithium levels. This interaction should be given consideration in patients taking NOSMEN concomitantly with lithium.
Methotrexate: Concomitant administration with NOSMEN may increase risk of methotrexate toxicity (eg. stomatitis, bone marrow suppression, nephrotoxicity). This interaction should be given low-dose methotrexate in patients taking NOSMEN concomitantly.
Rifampin: Rifampin, a potent CYP3A4 inducer, resulted in a 65% reduction in etoricoxib blood concentrations. The co-administration of etoricoxib and rifampin may require etoricoxib dose increases beyond current recommendations for each indication, and therefore is not recommended.
Oral Contraceptives: Clinical studies showed that concomitant use of ethinyl estradiol (EE)/norethindrone, an oral contraceptive, and etoricoxib, a COX-2 inhibitor, increased the steady-state AUC _{(0 to 24 hours)} of ethinyl estradiol between 37% and 60%, depending on the etoricoxib dosage. Consider the increased risk for adverse effects (e.g. venous thromboembolic events) with higher ethinyl estradiol exposure in at-risk patients when selecting an oral contraceptive to be used concurrently with etoricoxib.
Hormone Replacement Therapy: Clinical studies showed that concomitant use of conjugated estrogens and etoricoxib 120 mg/day increased the mean steady-state AUC of several estrogenic components. While the clinical significance of these AUC increases is unknown, consider the increased risk of adverse effects associated with higher exposures to conjugated estrogens with hormone replacement therapy during postmenopausal hormone therapy selection.
Digoxin: Co-administration of digoxin and NSAIDs may increase digoxin plasma concentrations and prolong the half-life of digoxin. If concurrent use is required, monitoring of serum digoxin levels is recommended.

Do not store above 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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