Sikstop

Etoricoxib.

Sikstop 60: Each film coated tablet contains Etoricoxib 60 mg.
Sikstop 90: Each film coated tablet contains Etoricoxib 90 mg.
Sikstop 120: Each film coated tablet contains Etoricoxib 120 mg.

Pharmacology: Mechanism of action: Etoricoxib is a nonsteroidal anti inflammatory drug (NSAID) that exhibits anti inflammatory, analgesic, and antipyretic activities in animal models. Etoricoxib is a potent, orally active highly selective cyclooxygenase-2 (COX-2) inhibitor within and above the clinical dose range. Two isoforms of cyclooxygenase have been identified: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is responsible for prostaglandin-mediated normal physiologic functions such as gastric cytoprotection and platelet aggregation. Inhibition of COX-1 by nonselective NSAIDs has been associated with gastric damage and platelet inhibition. COX-2 has been shown to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. Selective inhibition of COX- by etoricoxib decreases these clinical signs and symptoms with decreased GI toxicity and without effects on platelet function.
Etoricoxib produced dose - dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily.
Platelet Function: Multiple doses of etoricoxib up to 150 mg administered daily up to nine days had no effect on bleeding time relative to placebo. Similarly, bleeding time was not altered in a single-dose study with etoricoxib 250 or 500 mg. There was no inhibition of ex vivo arachidonic acid-or collagen-induced platelet aggregation at steady state with doses of Etoricoxib up to 150 mg. These findings are consistent with the COX-2 selectivity of Etoricoxib.

Sikstop is indicated for: Symptomatic relief in the treatment of ostheoarthritis (OA) and rheumatoid arthritis (RA).
Symptomatic relief in the treatment of ankylosing spondylitis (AS).
Treatment of pain and signs of inflammation associated with acute gouty arthritis. Etoricoxib should be used only for the acute symptomatic period limited to a maximum of 8 days.
Relief of chronic musculoskeletal pain.
Relief of acute pain associate with dental surgery.

Sikstop is administered orally. Sikstop may be taken with or without food.
Arthritis: Osteoarthritis: The recommended dose is 60 mg once daily.
Rheumatoid Arthritis: The recommended dose is 90 mg once daily.
Ankylosing Spondylitis: The recommended dose is 90 mg once daily. Duration of treatment should not be longer than (one) years.
Chronic Musculoskeletal Pain: The recommended dose is 60 mg once daily.
Acute Gouty Arthritis: The recommended dose 120 mg once daily. Etoricoxib should be used only for the acute symptomatic period limited to a maximum of 8 days.
Post-operative Dental Pain: The recommended dose is 90 mg once daily.
Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Therefore, the dose for each indication is the maximum recommended dose.
Elderly, Gender, Race: No dosage adjustment in Etoricoxib 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. There are pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score > 9) (See PRECAUTIONS).
Renal Insufficiency: In patients with advanced renal disease (Creatinine clearance < 30mL/min), treatment with ETORICOXIB is not recommended. No dosage adjustment is necessary for patients with lesser degrees of renal insufficiency (creatinine clearance < 30mL/min) (See PRECAUTIONS).

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 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).
In the event of overdoses it is reasonable to employ the usual supportive measure 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.

Sikstop is contraindicated in patients with: Hypersensitivity to any component of this product.
Congestive heart failure (NYHA II-IV).
Established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease (including patients who have recently undergone coronary artery bypass graft surgery or angioplasty).

Cardiovascular Risk: NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Elderly patients and patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See as follows).
Sikstop is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see as follows).
Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal 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 are at greater risk for serious gastrointestinal events. (See as follows).
Asthma and Skin Reaction: Sikstop is contraindicated to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAID (See PRECAUTIONS).
Congestive Heart Failure and Edema: Sikstop should be used with caution in patients with fluid retention or heart failure (See as follows).
Hepatic Effects: A patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Sikstop (See PRECAUTIONS).
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 (See PRECAUTIONS).
Cardiovascular Effects: Cardiovascular Thrombotic Events: Use 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 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 NSAIDs 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 the 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 Gastrointestinal Effects as follows).
Use 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 Etoricoxib, 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. Patiens taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Etoricoxib, 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 Etoricoxib should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects-Risk of Ulceration, Bleeding and Perforation: NSAIDs, including Etoricoxib, 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 like lihood 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 development GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding who use 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 reduce the risk of gastrointestinal effect on NSAID therapy, the lowest effective dose must be given in short term therapy. Doctor and patient must be caution on sign and symptoms of ulceration and gastrointestinal bleeding during NSAID therapy. If there is serious gastrointestinal effects suspected, evaluate immediately and give additional treatment. For high risk patient, alternative therapy that does not include NSAID can be considered.

The selective COX-2 inhibitor class of drugs may be associated with an increased risk of thrombotic events (especially MI and stroke), relative to placebo and some NSAIDs (naproxen). As the cardiovascular risk of selective COX-2 inhibitors may increase with dose and duration possible and the lowest effective daily dose should be used. The patients need for symptomatic relief and response to therapy should be re-evaluated periodically.
Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking) or peripheral arterial disease should only be treated with etoricoxib after careful consideration.
Selective COX-2 inhibitors are not a substitute for aspirin for cardiovascular prophylaxis because of their lack of effect on platelets. Because etoricoxib, a member of this class, does not inhibit platelet aggregation, anti platelet therapies should not be discontinued.
There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) for etoricoxib, other selective COX-2 inhibitors and NSAIDs, when taken concomitantly with acetylsalicylic acid (even at low doses). The relative differences in gastrointestinal safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been adequately evaluated in long term.
In patiens with advenced renal disease, treatment with Etoricoxib is not recommended. Study experience in patients with estimated creatinine clearance of <30 mL/min is very limited. If therapy with Etoricoxib must be initiated in such patients, close monitoring of the patient’s renal function is advisable.
Renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of Etoricoxib may cause a reduction in prostaglandin formation and, secondarily, in renal blood flow, and there by impair renal function. Patients at greatest risk of this response are those with pre-existing significantly impaired renal function, uncompensated heart failure, or cirrhosis. Monitoring of renal function in such patients should be considered.
Caution should be used when initiating treatment with Etoricoxib in patients with considerable dehydration. It is advisable to rehydrate patients prior to starting therapy with Etoricoxib.
As with other drugs known to inhibit prostaglandin synthesis, fluid retention, edema and hypertension have been observed in some patients taking Etoricoxib. The possibility of fluid retention, edema or hypertension should be taken into consideration when Etoricoxib is used in patients with pre-existing edema hypertension, or heart failure. All Nonsteriodal Antiinflammatory Drugs (NSAIDs), including Etoricoxib, can be associated with new onset or recurrent congestive heart failure (See SIDE EFFECTS). Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore, special attention should be paid to blood pressure monitoring during treatment with Etoricoxib. If blood pressure rises significantly, alternative should be considered.
Physician should be aware that individual patients may develop upper gastrointestinal (GI) ulcers/ulcer complications irrespective of treatment. Upper gastrointestinal complications [perforations, ulcers or bleeding (PUBs)], some of them resulting in fatal outcame, have occurred in patients treated with 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. There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when Etoricoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitory + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term.
Elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (approximately three or more times the upper limit of normal) have been reported rarely in patient treated for up to one year with Etoricoxib 60 and 90 mg daily. The incidence of elevated AST and/or ALT in patients treated with Etoricoxib 60 and 90 mg daily was similar to that of patients treated with naproxen, but notably less than the incidence in the diclofenac group. These elevations resolved in patients treated with Etoricoxib, with approximately half resolving while patients remained on therapy.
A patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for persistently abnormal liver function tests. If persistently abnormal liver function tests (three times the upper limit of normal) are detected, Etoricoxib should be discontinued.
Etoricoxib should be used with caution in patients who have previously experienced acute asthmatic attacks, urticaria, or rhinitis, which were precipitated by salicylates or non selective cyclooxygenase inhibitors. Since the pathophysiology of these reactions is unknown, physicians should weigh the potential benefits of prescribing Etoricoxib versus the potential risks.
When using Etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction, medically appropriate supervision should be maintained. If these patients deteriorate during treatment, appropriate measures should be taken, including discontinuation of therapy.
Etoricoxib may mask fever, which is a sign of infection. The physician should be aware of this when using Etoricoxib in patients being treated for infection.
Effects on Ability to Drive and Use Machines: There is no information to suggest that Etoricoxib affects a patient's ability to drive or operate machinery.
Use in Pregnancy: As with other drugs known to inhibit prostaglandin synthesis, use of Etoricoxib should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.
There are no adequate and well-controlled studies in pregnant women. Etoricoxib should be used during the first two trimesters of pregnancy only if the potential benefits justified the potential risk to the fetus.
Use in Lactation: Etoricoxib excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the possible adverse effects of drugs that inhibit prostaglandin synthesis on nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into taking account the importance of the drug to the mother.
Use in Children: Safety and effectiveness of Etoricoxib in pediatric patients have not been established.
Use in Elderly: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young. In studies, a higher incidence of adverse experiences was seen in older patients compared to younger patients; the relative differences between Etoricoxib and control groups were similar in the elderly and the young. Greater sensitivity of some older individuals cannot be ruled out.

Pregnancy: As with other drugs known to inhibit prostaglandin synthesis, use of Etoricoxib should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.
There are no adequate and well-controlled studies in pregnant women. Etoricoxib should be used during the first two trimesters of pregnancy only if the potential benefits justified the potential risk to the fetus.
Nursing Mother: Etoricoxib excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the possible adverse effects of drugs that inhibit prostaglandin synthesis on nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into taking account the importance of the drug to the mother.

The following drug-related adverse experiences were reported in studies in patients with OA, RA, or chronic low back pain treated for up to 12 weeks. These occurred in ≥1% of patients treated with Etoricoxib and at an incidence greater than placebo: asthenia/fatigue, dizziness, lower extremity edema, hypertension, dyspepsia, heartburn, nausea, headache, ALT increased, AST increased.
The Adverse experience profile was similar in patients with OA or RA treated with Etoricoxib for year or longer.
The following adverse reaction have been reported in post-marketing Experience: Blood and lymphatic system disorder: thrombocytopenia.
Immune system disorders: hypersensitivity reactions, including anaphylactic/anaphylactoid reactions including shock.
Metabolism and nutrition disorders: hyperkalemia.
Psychiatric disorders: anxiety, insomnia, confusion, hallucinations, depression, restlessness.
Nervous system disorders: dysgeusia, somnolence.
Eye disorder: blurred vision.
Cardiac disorder: congestive heart failure, palpitations, angina, arrhythmia.
Vascular disorders: hypertensive crisis.
Respiratory, thoracic and mediastinal disorders: bronchospasm.
Gastrointestinal disorders: abdominal pain, oral ulcers, peptic ulcers including perforation and bleeding (mainly in elderly patients), vomiting, diarrhea.
Hepatobiliary disorders: Hepatitis, jaundice, hepatic failure.
Skin and subcutaneus tissue disorders: angioedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, fixed drug eruption.
Renal and urinary disorders: renal insuffciency, including renal failure (see PRECAUTIONS).

Warfarin: in subjects stabilized on chronic warfarin therapy, the administration of Etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalized Ratio (INR). Standard monitoring of INR values should be conducted when therapy with Etoricoxib is initiated or changed, particularly in the first few days, in patients receiving warfarin or similar agents.
Rifampicin: Co-administration of Etoricoxib with rifampicin, a potent inducer of hepatic metabolism, produced a 65 % decrease in Etoricoxib plasma area under the curva (AUC). This interaction should be considered when Etoricoxib is co-administered with rifampicin.
Methotrexate: Investigated the effects of Etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In study, Etoricoxib 120 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearence. In other study, Etoricoxib 120 mg increased methorexate plasma concentrations by 28 % (as measured by AUC) and reduced renal clearance of methotrexate by 13%. Monitoring for methotrexate - related toxicity should be considered when Etoricoxib at doses greater than 90 mg daily and methotrexate are administered concomitantly.
Diuretics, Agiotensin 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 Etoricoxib concomitantly with these products.
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 Etoricoxib concomitantly with lithium.
Aspirin: Etoricoxib can be used concomitantly with low-dose aspirin at doses for cardiovascular prophylaxis. However, concomitant administration of low-dose aspirin with Etoricoxib results in an increased rate of GI ulceration or other complications compared to use of Etoricoxib alone. At steady state, Etoricoxib 120 mg once daily had no effect on the anti-platelet activity of low-dose aspirin (81 mg once daily) (see PRECAUTION).
Oral Contraceptives: Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 mcg ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC_0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive concomitantly or separated by 12 hour, increased the steady state AUC_0-24hr of EE by 50 to 60 %. This increase in EE concentration should be considered when selecting an oral contraceptive for use with Etoricoxib. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g. venous thrombo-embolic events in women at risk).
Hormone Replacement Therapy: Administration of Etoricoxib 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg Premarin) for 28 days, increased the mean steady state AUC_0-24hr of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22 %). The effect of the recommended chronic doses of Etoricoxib (60 and 90 mg) has not been studied. The effects of Etoricoxib 120 mg on the exposure (AUC_0-24hr) to these estrogenic components of Premarin were less than half of those observed when Premarin was administered alone and the dose was increased from 0.625 to 1.25 mg. These increases in estrogenic concetration should be taken into consideration when selecting post-menopausal hormone therapy for use with Etoricoxib.
Other: In the drug-interaction studies, Etoricoxib did not have clinically important effects on the pharmacokinetics of prednisone/prednisolone or digoxin.
Antacids and ketoconazole (a potent inhibitor of CYP3A4) did not have clinically important effects on the pharmacokinetics of Etoricoxib.

Store below 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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