Saturday, July 27, 2013


30mg Tablet
60mg Tablet
90mg Tablet
120mg Tablet

Drug Category: COX-2 Specific Inhibitor

Brand Name: Arcoxia/Arcoxia Ac

Product Description:
Etoricoxib is a member of a class arthritis/analgesia medications called, coxibs. Etoricoxib is a highly selective inhibitor of cycloxygenase-2 (COX-2). Etoricoxib tablets contain etoricoxib, which is described chemically as 5-chloro-6-methyl-3-[4-9methylsulfony)phenyl],-2,3`-bipyridine. The empirical formula is C18H15CIN2OS. The molecular weight is 358.84.

Etoricoxib is a white to off-white powder. Etoricoxib is free soluble in methanol, tetrahydrofuran, dimethyl sulfoxide, methyl ethyl ketone, dimethyl formamide, and chloroform. Etoricoxib is soluble in isopropyl acetate, ethanol and toluene, sparingly soluble in 2-propanol, and practically insoluble in water.

Orally administered etoricoxib is well absorbed. The mean oral bioavailability is approximately 100%. Following 12mg once daily dosing to steady-state, the peak plasma concentration (geometirc mean Cmax = 3.6mcg/ml) was observed at approximately 1 hour (Tmax) after administration to fasted adults. The
geometric mean AUC0-24hr was 37.8 The pharmacokinetics of etoricoxib are linear across the clinical dose range.
The standard meal had no clinically meaningful effect on the extent or rate of absorption of a dose of etoricoxib 120mg. In clinical trials, etoricoxib was administered without regard to food.
The pharmacokinetics of etoricoxib in 12 healthy subjects were similar (comparable AUC, Cmax within approximately 20%) when administered alone, with a magnesium/aluminum hydroxide antacid, or a calcium carbonated antacid (approximately 50 mEq acid-neutralizing capacity).

Etoricoxib is approximately 92% bound to human plasma protein over the range of concentration of 0.05 to 5mcg/ml. The volume of distribution at steady-state (Vdss) is approximately 120L in humans.
Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain-barrier in rats.

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 cytochrome P450 (CYP) enzymes.
Five metabolites have been identified in man. The principal metabolite in 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.

Following administration of single 25mg radio labeled intravenous dose of 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.
Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady-state concentration of etoricoxib are reached within seven days of once-daily administration of 120mg, with an accumulation ration of approximately 2, corresponding to an accumulation half-life of approximately 22 hours. The plasma clearance is estimated to be approximately 50ml/min.

Characteristic in Patients (Special Populations)
The pharmacokinetics of etoricoxib are similar between men women. (See recommended dose.)

Pharmacokinetics in elderly (65years of age and older) similar to those in the young. No dosage adjustment is necessary for elderly patients. (See recommended dose).

There is no clinically important effect of race on the pharmacokinetics of etoricoxib. (See recommended dose).

Hepatic Insufficiency
Patients with mild hepatic insufficiency (Child-Pugh score 5-6) administered etoricoxib 60mg once daily had an approximately 16% higher mean AUC as compared to healthy subjects given the same regime. Patients with moderate hepatic insufficiency (Child-Pugh score 7-9) administered etoricoxib 60m once daily; etoricoxib 30mg once daily has not been studied in this population. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9). (See recommended dose, Hepatic Insufficiency).

Renal Insufficiency
The pharmacokinetics of a single dose of etoricoxib 120mg 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 50ml/min).

Pediatric Patients
The pharmacokinetic study (N=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in adolescents weighing 40 to 60 kg given etoricoxib 60mg once daily and in adolescents >60kg given etoricoxib 90mg once daily were similar to the pharmacokinetics in adults given etoricoxib 90mg once daily. Safety and effectiveness of etoricoxib in pediatric patients have not been established.

Drug Interactions with additional pharmacokinetic data:
The main pathway of etoricoxib biotransformation is CYP-dependent oxidation to produce 6`-hydroxymethyl etoricoxib, which can undergo further metabolism to the corresponding carboxylic acid or O-glucuronide. In vitro data indicate that CYP3A4 plays a major role (approximately 60%) in the hydroxylation of etoricoxib and that the remainder of the activity (approximately 40%) is shared among CYP2C9, and 2D6. Administration of a potent inhibitor of CYP3A (ketoconazole) did not increase etoricoxib plasma concentrations to a clinically meaningful extent (approximately 43% increase in AUC). Administration of a potent inducer of CYP enzymes (rifampin) produced a 65% decrease in etoricoxib plasma AUC.

The potential for etoricoxib to inhibit or induce CYP3A4 activity was investigated in human studies using the intravenous erythromycin breath test. Compared to placebo, etoricoxib (120mg daily for 11 days) did not produce any significant effect on erythromycin N-demethylation, indicating no effect on hepatic CYP3A4 activity. Based on in vitro studies, etoricoxib does not inhibit cytochromes P4501A2, 2C9, 2C19, 2D6, or 2E1.

Etoricoxib 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 acute pain
  • Treatment of primary dysmenorrhea.
  • Treatment of moderate to sever acute post-operative pain associated with dental surgery.
  • Treatment of moderate to sever 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 (See Warnings and Precautions).

Recommended Dose:
Etoricoxib is administered orally. Etoricoxib may be taken with or without food. Etoricoxib should be administered for the shortest duration possible and the lowest effective daily dose should be used.

The recommended dose is 30mg or 60mg once daily.

Rheumatoid Arthritis
The recommended dose is 90mg once daily.

Ankylosing Spondylitis
The recommended dose is 90mg once daily.

Acute Pain
For acute pain conditions, the recommended dose is 90mg or 120mg once daily. Etoricoxib should be used only for the acute symptomatic period, limited to a maximum of 8 days treatement.

Acute Gouty Arthritis
The recommended dose is 120mg once daily.

Primary Dysmenorrhea
The recommended dose is 120mg once daily.

Post-operative Dental Pain
The recommended dose is 90mg once daily.

Post-operative Gynecological Pain
The recommended dose is 90mg once daily. The initial dose should be administered shortly before surgery. The dose can be increased to a maximum 120mg once daily.

Doses greater than those recommended for each indication have either no demonstrated additional efficacy or have not been studied. Therefore:
The dose for OA should not exceed 60mg daily.
The dose for RA should not exceed 90mg daily.
The dose for ankylosing spondylitis should not exceed 90mg daily.
The dose for acute gout should not exceed 120mg daily.
The dose for acute pain and primary dysmenorrhea should not exceed 120mg daily.
The dose for post-operative acute dental surgery pain should not exceed 90mg daily.
The dose for post-operative acute gynecological surgery pain should not exceed 120mg 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. (See Warnings and Precautions)

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 60mg 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 60mg every other day should not be exceeded, administration of 30mg once daily can also be considered. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9). (See WARNINGS AND PRECAUTIONS.)

Renal Insufficiency
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 insufficiency (creatinine clearance 30ml/min). (See WARNINGS AND PRECAUTIONS.)

Mode of Administrations:
Etoricoxib is administered orally. Etoricoxib may be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients.
Active peptic ulceration or active gastrointestinal (GI) bleeding.
Patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic edema, urticaria, or allergic-type reactions after taking acetylsalicylic acid or NSAIDS including COX-2 (cyclooxygenase-2) inhibitors.
Pregnancy and lactation.
Severe hepatic dysfunction (serum albumin <25g/l or Child-Pugh score ≥10).
Estimate renal creatinine clearance <30ml/min.
Children and adolescents under 16 years of age.
Inflammatory bowel disease.
Congestive heart failure (NYHA II-IV)
Patients with hypertension whose blood pressure has not been adequately controlled.
Established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

Warnings and Precautions:
Clinical trials suggest that the selective COX-2 inhibitors 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 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.

Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidemia, diabetes mellitus, smoking) 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, antiplatelet 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 difference in gastrointestinal safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been adequately evaluated in long-term clinical trials.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. 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 thereby impair renal function. Patients at greatest risk of this response are those with preexisting 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 preexisting edema, hypertension or heart failure. All Nonsteroidal Antiinflammatory Drugs (NSAIDs), including etoricoxib, can be associated with the new onset or recurrent congestive heart failure. (see Undesirable 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 treatment should be considered.

Physicians should be aware that individual patients may develop upper gastrointestinal (GI) ulcers/ulcer complications irrespective of treatment. Although the risk of GI toxicity is not eliminated with etoricoxib, the results of the MEDAL Program demonstrate that in patients treated with etoricoxib, the risk of GI toxicity with etoricoxib 60mg or 90mg once daily is significantly less than with diclofenac 150mg daily. In clinical studies with ibuprofen and naproxen, the risk of endoscopically detected upper GI ulcers was lower in the patients treated with etoricoxib 120mg once daily than in patients treated with non-selective NSAIDs. While the risk of endoscopically detected ulcers was low in patients treated with etoricoxib. These events can occur at any time during use and without warning symptoms. Independent of treatment, patients with a prior history of GI perforation, ulcers and bleeding (PUB) and patients greater than 65 years of age are known to be at a higher risk for a PUB.

Elevations of alanine aminotransferase (ALT) and/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, 60, and 90 mg daily. In active comparator portions of clinical trials, 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 1000mg daily, but notably less than the incidence in the diclofenac 150mg daily group. These elevations resolved in patients treated with etoricoxib, with approximately half resolving while patients remained on therapy. In controlled clinical trials of etoricoxib 30mg daily versus ibuprofen 2400mg daily or celecoxib 200mg daily, the incidence of elevations of ALT or AST was similar.

A patient 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 test (three times the upper limit of normal) are detected, etoricoxib should be discontinued.

When using etoricoxib in the elderly and in patients with renal, hepatic, or cardiac dysfunction, medically appropriate supervision should be maintained. If these patients deteriorated during treatment appropriate measures should be taken, including discontinuation of therapy.

Serious skin reactions, some of them fatal, including exfoliative dermintitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance (see Undesirable effects). These serious events may occur without warning. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib (see Undesirable effects). Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

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.

Interactions with other medicaments:
Warfarin: In subjects stabilized on chronic warfarin therapy, the administration of etoricoxib 120mg daily was associated with an approximate 13% increase in prothrombin time International Normalized Ration (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.

Rifampin: Co-administration of etoricoxib with rifampin, a potent inducer of hepatic metabolism, produced a 65% decrease in etoricoxib plasma area under the curve (AUC). This interaction should be considered when etoricoxib is co-administered with rifampin.

Methotrexate: Two studies investigated the effects of etoricoxib 60, 90, or 120mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In one study, etoricoxib 120mg had no effect on methotrexate plasma concentrations (as measured by AUC) or renal clearance. In the other study, etoricoxib 120mg increased methotrexate 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, Angiotensin Converting Enzyme (ACE) Inhibitors and Angiotensin II Antagonists (AIIAs): Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the anti-hypertensive effect of diuretics, ACE inhibitors and AIIAs. This interaction should be given consideration in patients taking etoricoxib 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.

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. At steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of low-dose aspiring with etoricoxib increased rate of GI ulceration or other complications compared to use of etoricoxib alone. (See Warnings and Precautions.)

Oral Contraceptives: Etoricoxib 60mg given concomitantly with an oral contraceptive containing 35mcg ethinyl estradiol (EE) and 0.5 to 1mg norethindrone for 21 days increased the steady sate AUC0-24hr of EE by 37%. Etoricoxib 120mg given with the same oral contraceptive concomitantly or separated by 12 hours, increased the steady state AUC0-24hr 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 thromboembolic events in women at risk).

Hormone Replacement Therapy: Administration of Etoricoxib 120mg with hormone replacement therapy consisting of conjugated estrogens (0.625mg Premarin) for 28 days, increased the mean steady state AUC0-24hr of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%).

The effects o the recommended chronic doses of etoricoxib (30, 60, and 90mg) has not been studied. The effects of etoricoxib 120mg on the exposure ( AUC0-24hr) 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 1.25mg. The clinical significance of these increases is unknown, and higher doses of Premarin were not studied in combination with etoricoxib. These increases in estrogenic concentration should be taken into consideration when selecting prost-menopausal hormone therapy for use with etoricoxib.

Other:In drug-interaction studies etoricoxib did not have clinical 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.

Pregnancy and Lactation:
The use of etoricoxib, as with any drug substances known to inhibit COX-2, is not recommended in women attempting to conceive.

No clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have shown reproductive toxicity. The potential for human risk in pregnancy in unknown. Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure o the ductus arteriosus during the last trimester. Etoricoxib is contraindicated in pregnancy. If a woman becomes pregnant during treatment, etoricoxib must be discontinued.

Reproductive studies conducted in rats have demonstrated no evidence of developmental abnormalities at doses up to 15mg/kg/day (approximately 1.5 times the human dose [90mg] based on systemic exposure). At doses approximately 2 times the adult human exposure (90mg) based on systemic exposure, a low incidence of cardiovascular malformations and increases in post implantation loss were observed in etoricoxib-treated rabbits. No developmental effects were seen at systemic exposure of approximately equal to or less than the daily human dosage (90mg). However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.

It is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of lactating rats. Women who use etoricoxib should not breast feed.

Pediatric Use:
Safety and effectiveness of etoricoxib in pediatric patients have not been established.

Use in the Elderly:
Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young. In clinical 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.

Undesirable Effects:
In clinical trials, etoricoxib was evaluated for safety in 7152 individuals, including 4488 patients with OA, RA or chronic low back pain (approximately 600 patients with OA or RA were treated for one year or longer).

The following drug-related adverse experiences were reported in clinical 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 one year or longer.

In the MEDAL Study, an endpoint driven CV outcomes trial involving 23,504 patients, the safety of etoricoxib 60 or 90 mg daily was compared to diclofenac 150mg daily in patients with OA or RA (mean duration of treatment was 20 months). In this large trial, only serious adverse events and discontinuations due to any adverse events were recorded. The rates of confirmed thrombotic cardiovascular serious adverse events were similar between etoricoxib and diclofenac. The incidence of discontinuations for hypertension-related adverse events was less than 3% in each treatment group; however, etoricoxib 60 and 90mg demonstrated significantly higher rates of discontinuations for these events than diclofenac. The incidence of congestive heart failure adverse event (discontinuations and serious events) and the incidence of discontinuations due to edema occurred at similar rate on etoricoxib 60mg compared to diclofenac; however, the incidences for these events were higher for etoricoxib 90mg compared to diclofenac. The incidence of discontinuations due to atrial fibrillation was higher for etoricoxib compared to diclofenac.

The EDGE and EDGE II studies compared the GI tolerability of etoricoxib 90mg daily (1.g to 3 times the doses recommended for OA) and diclofenac 150mg daily in 7111 patients with OA (EDGE Study; mean duration of treatment 9 months) and 4086 patients with RA (EDGE II; mean duration of treatment 19 months). In each of these studies, the adverse experience profile of etoricoxib was generally similar to that reported in the phase IIb/III placebo-controlled clinical studies; however, hypertension and edema-related adverse experiences occurred at a higher rate on etoricoxib 90 mg than on diclofenac 150 mg daily. The rate of confirmed thrombotic cardiovascular serious adverse events occurring in the two treatment groups was similar.

In combined analysis of phase IIb to V clinical studies 4 weeks duration or longer (excluding the MEDAL Program Studies), there was no discernible difference in the rate of confirmed thrombotic cardiovascular serious adverse events between patients receiving etoricoxib ≥30mg or non-naproxen NSAIDs. The rate of these events was higher in patients receiving etoricoxib compared with those receiving with those of naproxen 500mg twice daily.

In a clinical study for ankylosing spondilitis, patients were treated with etoricoxib 90mg once daily for up to 1 year (N=126). The adverse experience profile in this study was generally similar to that reported in chronic studies in OA, RA and chronic low back pain.

In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120mg once daily for eight days. The adverse experience profile in these studies was generally similar to that reported in chronic studies in OA, RA and chronic low back pain.

In initial clinical studies for acute analgesia, patients were treated with etoricoxib 120mg once daily for one to sever days. The adverse experience profile in these studies was generally similar to that reported in chronic studies in OA, RA and chronic low back pain.

In the additional clinical studies for acute post-operative pain associated with dental and abdominal gynecological surgeries including 1222 patients treated with etoricoxib (90 or 120mg), the adverse experience profile was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

In the combined studies for acute post-operative dental pain, the incidence of post-dental extraction alveolitis (dry socket) reported in patients treated with etoricoxib was similar to that of patients treated with active comparators.

Post-marketing experiences
The following adverse reactions have been reported in post-marketing experience.
Blood and lymphatic systems disorders: 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.
Nervousness system disorders: dysgeusia, somnolence.
Eye disorders: blurred vision.
Cardiac disorders: congestive heart failure, palpitation, angina, arrhythmia.
Vascular disorders: hypersensitive 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 subcutaneous tissue disorders: angioedema, pruritus, erythema, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, fixed drug eruption.
Renal and urinary disorders: renal insufficiency, including renal failure (see Warnings and precautions).

Overdosage and Treatment:
In clinical studies, administration of etoricoxib at single doses up to 500mg and multiple doses up to 150mg/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).

In the event of overdosage, 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.

Storage Condition:
Store ate temperatures not exceeding 30oC. Protect from light. Store in the original package.

Thursday, July 4, 2013

Ketorolac Trometamol

Ketorolac Trometamol
30mg/ml Solution for Injection (IM/IV)

Drug Category: Non-Opioid Analgesic

Mode of Actions:
Ketorolac Trometamol is a non-narcotic analgesic. It inhibits synthesis of prostaglandins and is considered a peripherally acting analgesic since it does not have any known effects on opiate receptors. No evidence of respiratory depression has been observed after administration of Ketorolac Trometamol. It did not cause pupil constriction. It caused no more drowsiness than placebo and less drowsiness than morphine in postoperative patients. It is a non-steroidal anti-inflammatory agent that exhibits anti-inflammatory and antipyretic activity.

Ketorolac Trometamol is rapidly and completely absorbed following intramuscular administration with a mean peak plasma concentration of 2.2mcg/ml occurring an average 50minute after a single 30 mg dose. The terminal plasma half-life is 5.3 hours in young adults and 7 hours in elderly subjects (mean age 72). Intravenous administration of a single 10 mg dose of ketorolac trometamol results in a terminal plasma elimination intravenous administration of a single 10 mg dose of ketorolac trometamol results in a terminal plasma elimination half-life of 5.1 hours, an average volume of distribution of 0.15L/kg and a total plasma clearance of 0.35 ml/min/kg. More than 99% of the ketorolac in plasma is protein-bound over a wide concentration range. The pharmacokinetics of ketorolac in a man following single or multiple intramuscular (IM) doses are linear. Steady-state plasma levels are achieved after dosing every 6 hours of 1 day. No changes in clearances occur with chronic dosing. The primary route of excretion of ketorolac and its metabolites (conjugates and a para-hydroxyl metabolites) is in the urine (mean 91.4%) and the remainder (mean 6.1%) is excreted in the feces (see table).

Influence of Age Liver and Kidney Function on the Clearance
and Terminal Half-life of Ketorolac Trometamol
Type Of Subjects
Total clearance (L/Hr/Kg)
Mean (range)
Terminal Half-life (hrs)
Mean (range)
Normal subjects (n=54)
Patients with hepatic dysfunction (n=7)
Patients with renal impairment (n=10) (serum creatinine) (1.9-5mg/dl)
Renal dialysis (n=9)
Healthy elderly subjects (n=13)
(mean age 72)
Estimated from 30mg single doses of Ketorolac Trometamol IM/IV
Hemodynamics of patients are not altered by parenteral administration of Ketorolac Trometamol.

For short term management of moderate to severe acute post-operative pain following surgical procedures associated with low risk of hemorrhage.

Ketorolac Trometamol should not be used:
  1. In patients who have previously exhibited allergy to it.
  2. In suspected or confirmed cerebrovascular bleeding or hemophilia in other bleeding problems including coagulation or platelet function disorders due to increased risk of bleeding because ketorolac inhibits platelet aggregation and may also cause gastrointestinal ulceration or hemorrhage.
  3. In active, recent or history of gastrointestinal bleeding or recent gastrointestinal perforation or active or history of peptic ulceration, ulceration colitis or other ulcerative gastrointestinal disease due to increased risk of gastrointestinal ulceration, perforation and/or hemorrhage.
  4. In aspirin induced nasal polyps associated with bronchospasm, or angioedema, anaphylaxis or history of other severe allergic reactions of cross-sensitivity.
  5. In severe renal function impairment, due to increased risk of renal failure.
  6. During pregnancy labor, delivery or lactation.
  7. A history of asthma.
  8. Hypovolemia or dehydration from any cause.

Adverse Effects:
The following adverse reactions were reported to be probably related to patients who receive up to 20 doses for 5 days of intramuscular administered Ketorolac Trometamol and in patients who receive up to 8 doses for 2 days, of intravenously administered ketorolac trometamol.

Incidence between 3 and 9%:
Gastrointestinal: Nausea, dyspepsia, gastrointestinal pain.
Central nervous system: Drowsiness

Incidence between 1 and 3%:
Gastrointestinal: Diarrhea
Central Nervous system: Dizziness, headache, sweating
Body as a whole: Edema
Injection site pain was reported by 2% of patient

Incidence 1% or less:
Gastrointestinal: Constipation, flatulence, gastrointestinal fullness, liver function abnormalities, melena, peptic ulcer, rectal bleeding, stomatitis, vomiting.
Body as a whole: Asthenia, myalgia
Cardiovascular: flushing, pallor
Hemic and lymphatic: purpura
Nervous system: Dry mouth, nervousness, paresthesia, abnormal thinking, depression, euphoria, excessive thirst, inability to concentrate, insonmia, stimulation, vertigo
Respiratory: Dyspnea, asthma
Urogenital: Increased urinary frequency, oliguria
Dermatologic: Pruritus, urticaria
Special senses: Abnormal taste, abnormal vision

As with other non-steroidal anti-inflammatory analgesic agents, ketorolac trometamol can cause gastrointestinal irritation, ulcers or bleeding with or without previous symptoms and should be given under close supervision to patients with history of gastrointestinal tract disease. Elderly and debilitated individuals are most susceptible to these complications, the incidence of which increased with dose and duration of treatment.

Renal Effects: As with other non-steroidal anti-inflammatory drugs that inhibits prostaglandin biosynthesis, elevations of serum urea nitrogen and creatinine have been reported with ketorolac trometamol. Since ketorolac trometamol and its metabolites are excreted primarily by the kidney, patients with significance impairment or renal functions should not receive ketorolac trometamol unless the expected benefits out weight the risks. If used in patients with impaired renal function, ketorolac trometamol dosage should be reduced and renal status should be closely monitored. In patients with serum creatinine values ranging from 1.9-5mg/dl, the rate of ketorolac clearance was reduced to approximately half of normal. The total daily dose of ketorolac should be reduced by half in such patients. With more severe degrees of renal impairment, ketorolac is not recommended for patients with serum creatinine serum levels above 5 mg/dl. Patients who are volume-depleted because of blood loss or severe dehydration may be dependent on renal prostaglandin production to maintain renal perfusion and therefore, glomerular filtration rate. In such situation, the use of drugs which inhibit prostaglandin synthesis might be expected to further decrease renal blood flow. Caution is advised if ketorolac trometamol is used in such circumstances. Close monitoring of urine output, serum urea and serum creatinine is recommended until the patient is normo-volemic. As with other drugs that inhibit prostaglandin biosynthesis, the following renal abnormalities may be associated with the use of ketorolac trometamol: Glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. Other renal disease is possible.

Fluid retention and edema: Fluid retention and edema have been reported with use of ketorolac trometamol; therefore ketorolac trometamol should be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

Hematological Effects: Ketorolac trometamol inhibits platelet aggregation and may prolong bleeding time. Patients on full anticoagulation therapy (e.g. Heparin or dicumarol derivatives) may be at increased risk of bleeding, if given ketorolac trometamol concurrently. Thus, the benefits should be weighed against the risk. Low-dose heparin (5000 units SC 2 times a day) appears to be associated with less risk. Patients who have coagulation disorders or are receiving drug therapy that interferes with homeostasis should be carefully observed if ketorolac trometamol is administered. Unlike the prolonged effects from aspirin, the inhibition of platelet function by ketorolac disappears within 24-48 hours after the drug is discontinued. Ketorolac does not affect platelet count, prothrombin time (PT) or partial thromboplastin similar to control groups i.e. 5/11750 (0.4%) with ketorolac trometamol compared to 1/570 (0.2%) with opiates. Postoperative wound hemorrhage has been reported rarely in association with the immediate perioperative use of ketorolac trometamol. Therefore caution should be used where strict homeostasis is critical. Specifically in cosmetic plastic surgery, hematomas and other other signs of wound hemorrhage have been reported with the use of ketorolac trometamol. Physicians should be alert to the pharmacologic similarity of ketorolac to other non-steroidal anti-inflammatory drugs that inhibits cyclooxygenase.

Hepatic effects: Borderline elevation of one or more liver tests may occur. These abnormalities may progress, may remain unchanged or may be transient with continued therapy. Meaningful elevations (>3 times normal) of serum glutamic oxaloacetic transaminase (SGOT or AST) occurred in <1% of patients. If clinical signs and symptoms consistent with liver disease develop or if systemic manifestation occur (e.g. eosinophilia, rash, etc.) ketorolac trometamol should be discontinued. Patients with impaired hepatic functions from cirrhosis do not have any clinical important changes in ketorolac clearance.

Ketorolac trometamol is not an anesthetic agent and possesses no sedative or anxiolytic properties: therefore it is not recommended as an preoperative medication when these effects are required. Ketorolac is not recommended in obstetric analgesia.

Carcinogenicity, mutagenicity, and impairment of fertility: In animal ketorolac was not associated with tumourigenicity or mutagenicity and did not demonstrate teratogenic potential.

Use in pregnancy and lactation: Ketorolac trometamol is not recommended during pregnancy, labor or delivery. Ketorolac trometamol is not recommended for treatment of nursing mothers. Secretion of ketorolac in human milk after ingestion of ketorolac trometamol is limited. The milk to plasma ration of ketorolac concentrations ranged between 0.015 and 0.037.

Use in children: Safety and efficacy in children have not been established. Therefore, it is not recommended for use in children under 16 years.

Use in the Elderly: Because ketorolac is cleared somewhat more slowly by the elderly who are also more sensitive to the renal effects of NSAIDs (see Renal effects), extra caution and the lowest effective dose should be given when treating the elderly with ketorolac trometamol.

Drug abuse and Physical dependence: Ketorolac is not a narcotic agonist or antagonist. No subjective symptoms or objective signs of drug withdrawal upon abrupt discontinuation of IV or IM dosing. Patients receiving Ketorolac Trometamol for 6 months or longer have not developed tolerance to the drug and there is no pharmacological basis to expect addition. Ketorolac Trometamol did not exhibit activity in classical animal which are reasonable predictors of opiate analgesic action (hot plate and tail withdrawal test). In vitro, ketorolac does not bind to opiate receptors. These demonstrate that ketorolac trometamol does not have opiate-like activity.

Risk of GI ulceration, bleeding and perforation with NSAID
Serious GI toxicity such bleeding, ulceration and perforation can occur at any time, with or without 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 NSAID 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 adverse 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 then other individuals and account for most spontaneous for fatal GI events.

Drug Interactions:
Given 10 mg orally for 6 days prior to coadministration of single dose of warfarin 25mg, no significant changes in pharmacokinetics of the warfarin enantiomers were detected. Ketorolac is highly bound to plasma proteins (mean 99.2%) and binding is independent of concentration. The in-vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac. Ketorolac does not alter digoxin, protein binding. In vitro at therapeutic concentration of salicylate (300mcg/ml). The binding of ketorolac was reduced from approximately 99.2%-97.5%. Therapeutic concentrations of digoxin, warfarin, acetaminophen, phenytoin and tolbutamine did not alter ketorolac protein-binding. Because ketorolac is highly potent drug and present in low concentrations in plasma, it would be expected to displace other protein bound drugs significantly. There is no evidence that ketorolac induces or inhibits the hepatic enzymes capable of metabolizing itself or other drugs. Hence ketorolac would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction of inhibition mechanisms. Concomitant administration of ketorolac trometamol and probenecid results in the decreased clearance of ketorolac and a significant increase in ketorolac plasma levels and terminal half-life of ketorolac. Ketorolac trometamol reduces the diuretic response to furosemide in normo-volemic healthy subjects by approximately 20%. Inhibition of renal lithium clearance leading to an increase in plasma lithium concentrations and potential lithium toxicity has been reported with some prostaglandin synthesis inhibiting drugs. Concomitant administration of ketorolac trometamol and methotrexate should be done with caution, since some prostaglandin synthesis inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance the toxicity of methotrexate. Ketorolac trometamol has been administered concurrently with morphine in postoperative pain without evidence of adverse interactions. There are no clinical data available dealing with the safety or efficacy of concomitant use with other non-steroidal anti-inflammatory drugs. It is not recommended that ketorolac trometamol be routinely used with other non-steroidal anti-inflammatory drugs because of potential for additive side effects.

Cautions for Usage:
Incompatibilities: This product should not be mixed in a small volume (e.g. in a syringe) with Morphine Sulfate, Pethidine hydrochloride, Promethazine hydrochloride or Hydroxyzine hydrochloride as precipitation of ketorolac trometamol will occur. It is compatible with normal saline, 5% dextrose, Ringer's solution, Ringer's Lactate Solution or Plasmalyte solution.

Recommended Dosage, Dosage Schedule and Route of Administration:
Dosage and Administration: Dosage should be adjusted according to the severity of the pain and the patient response. The recommended usual initial dose of ketorolac trometamol is 30mg followed by 10-30 mg every 4-6 hours as needed to control pain. A lower initial dose is recommended for patients under 50kg for patients over 65 years and for patients with reduced renal function. In the initial postoperative period, ketorolac trometamol may be given as often as every 2 hours if needed. A total daily dose >120mg/day is not recommended. Intravenous injections should be administered over at least 15 seconds.

Opiates analgesic (e.g. Morphine, Pethidine) may be concomitantly used if further pain relief, anxiolytic effects and/or sedative effects of opiates are desired. Supplemental opiates may be most appropriate in the early postoperative period when pain is most severe. The administration of continuous multiple daily intramuscular doses of ketorolac trometamol should not exceed 2 days because adverse events may increase with prolonged usage.

Symptoms and treatment for overdosage and antidotes:
Overdosage: The absence of experience with acute overdosage precludes characterization of sequalae and assessment of antidotal efficacy at this time. In gastroscopic uses, daily doses of 360mg given over an 8 hour interval for each of 5 consecutive days (3 times the highest recommended dose) caused abdominal pain and peptic ulcers which healed after discontinuation of dosing.

Storage Conditions:
Store at temperatures not exceeding 30oC. Protect from light.
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