Bupivacaine Hydrochloride

Bupivacaine Hydrochloride

5mg/ml Solution for Spinal Injection

Drug Category: Local Anesthetic

Brand Name: Sensorcaine 0.5% Heavy

Clinical Particulars

Therapeutic Indications:

Spinal anesthesia for surgery, e.g. urological surgery and surgery on the lower limbs lasting 2-3 hours, abdominal surgery lasting 45-60 minutes.

Dosage and method of administrations:

Bupivacaine hydrochloride Spinal Heavy should only be used by clinicians with experience of regional anesthesia or under their supervision. The lowest possible dose for adequate anesthesia should be used.

The doses given below are guides for adults and the dosage should be adjusted to the individual patients.

The dose should be reduced in elderly patients and patients in late stages of pregnancy.

Indication	Dose mL	Dose mg	Time to onset of effect in minutes (approx.)	Duration of effect in hours (approx.)
Urological surgery Surgery on lower limbs, including hip surgery Abdominal surgery (including cesarean section)	1.5-3 ml 2-4 ml 2-4 ml	7.5-15 mg 10-20 mg 10-20 mg	5-8 min 5-8 min 5-8 min	2-3 hours 2-3 hours 45-60 min

The recommended injection site is the L₃-L₄ intervertebral space. There is currently no experience of doses higher than 20 mg. A spinal injection is given only after the subarachnoid space has been clearly identified by means of lumbar puncture (clear cerebrospinal fluid runs out via the spinal needle or is seen on aspiration). In the event of unsuccessful anesthesia, a new attempt to administer the drug should only be made by injecting at a different level and with a smaller volume. One cause of lack of effect may be poor intrathecal distribution of the drug, and this can be helped by altering the patient's position.

Contraindications:

Hypersensitivity to local anesthetics of the amide type or to other components of the product. Diseases of the central nervous system (e.g. meningitis, poliomelitis, intracranial hemorrhage). Local pyogenic infection at or adjacent to the injection site. Spinal stenosis and active disease (e.g. spondylitis, tumor) or trauma (e.g. fracture of the spine). Septicemia, pernicious anemia with subacute degeneration of the spinal cord. Spinal anesthesia should not be given to patients in shock. Nor should spinal anesthesia be given to patients with coagulation disorders or to patients receiving ongoing anticoagulation treatment.

Special warning and precaution for use:

One should be aware that spinal anesthesia can sometimes lead to major blocks, with paralysis of intercostal muscles and the diaphragm, especially in pregnant women.

Caution should be exercised in patients with degree II or III-AV block since local anesthetics can lower the conduction capacity of the myocardium. Elderly patients and patients with severe hepatic disease, severely impaired renal function or in generally reduced general condition also require special attention.

Patients treated with class III anti-arrhythmic drugs (e.g. amiodarone) should be closely observed and ECG monitoring should be considered, since the cardiac effects of bupivacaine and class III anti-arrhythmic drugs can be addictive.

Like all local anesthetic drugs, bupivacaine can cause acute central nervous and cardiovascular toxic effects in cases of use leading to high concentrations in the blood. This applies particularly after inadvertent intravascular administration.

Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in association with high systemic concentrations of bupivacaine. However, with doses normally used for spinal anesthesia high systemic concentrations are uncommon.

An uncommon, but dangerous, side effect in spinal anesthesia is extensive or total spinal blockade, which results in cardiovascular depression and respiratory depression. The cardiovascular depression is caused by extensive sympathetic blockade, which can result in hypotension and bradycardia, or even cardiac arrest. Respiratory depression can be caused by blockade of the innervation of the respiratory muscles, including the diaphragm. There is an increased risk of extensive or total spinal blockade in elderly patients and patients in late stages of pregnancy. The dose should therefore be reduced for these patients.

Spinal anesthesia can lead to a fall in blood pressure and bradycardia. The risk can be reduced by means of intravenous administration of crystalloid or colloid solution. A fall in blood pressure should be treated immediately, for example with ephedrine 5-10mg intravenously, repeated as required.

In rare cases spinal anesthesia can cause neurological damage, resulting in paresthesia, anesthesia, motor weakness and paralysis. Neurological disorders, such as multiple sclerosis, hemiplegia, paraplegia and neuromuscular disturbances are not thought to be adversely affected by spinal anesthesia, but caution should be exercised.

Interactions with other medical products and other forms of interactions:

Bupivacaine should be use with caution with other local anesthesia or drugs that are structurally similar to local anesthetics, i.e. class IB anti-arrhythmic drugs, as the toxic effects are additive.

No specific interaction studies with local anesthesia and class III anti-arrhythmic drugs (e.g. amiodarone) have been carried out, but caution is recommended (see Special warning and special precautions for use).

Pregnancy and Lactation:

Pregnancy

No known risks for the fetus from use during pregnancy. However, note that the dose should be reduced for patients in late stages of pregnancy (see Special warning and special precautions for use).

Lactation

Bupivacaine passes into breast milk, but the risk of this affecting the child appears unlikely with therapeutic doses.

Effects on ability to drive and use machines:

Depending on the dose and method of administration, bupivacaine can have a transient effect on movement and coordination.

Undesirable effects:

Undesirable effects caused by the product itself can be difficult to distinguish form the physiological effects of the nerve block (e.g. fall in blood pressure, bradycardia, temporary urinary retention), events caused directly by the needle puncture (e.g. spinal hematoma) or caused indirectly by the needle puncture (e.g. meningitis, epidural abscess) or events associated with leakage of cerebrospinal fluid ( e.g. post lumbar puncture headache).

Very common (>1/10)	General: Nausea Circ.: Hypotension, bradycardia
Common (>1/100)	CNS: Post lumbar puncture headache GI: Vomiting Genitourinary: Urinary retention, urinary incontinence
Uncommon (1/100-1/1000)	CNS: Paresthesia, paresia, dysesthesia Musculoskel.: Muscle weakness, back pain
Rare (<1/1000)	Circ.: Cardiac arrest General: Allergic reactions, anaphylactic shock CNS: Accidental total spinal blockade, paraplegia, paralysis, neurophathy, arachnoiditis Airways: Respiratory depression

Overdose:

Bupivacaine can cause acute toxic effects of a central nervous and cardiovascular nature if it is given in high doses, especially if it is administered intravascularly. However, the dose used in spinal anesthesia is low (≤ 20% of the dose used for epidural anesthesia) and thus the risk of overdosage is unlikely. In cases of concomitantly administration with other local anesthetics, however, systemic toxic effects may occur, ass the toxic effects are additive.

Treatment of complications

In cases of total spinal blockade adequate ventilation must be ensured (patent airways, oxygen, intubation and controlled ventialtion if necessary). If there is a fall in blood pressure a vasopressor (preferably with an inotropic effect) should be given, e.g. ephedrine 5-10mg intravenously.

If signs of acute systemic toxicity occur the administration of local anesthesia must be stopped immediately. Treatment must be given to maintain good ventilation, oxygenation and circulation. Oxygen must always be given, and assisted ventilation if necessary. If convulsions do not cease spontaneously within 15-20 seconds, theopentone sodium 1-3 mg/kg should be given intravenously to facilitate ventilation or diazepam 0.1 mg/kg intravenously ( acts rather more slowly). Prolonged seizures jeopardize the patient's respiration and oxygenation. Injection of muscle relaxants (e.g. suxamethonium 1mg/kg) creates more favourable conditions for ventilation and oxygenation of the patient, but requires experience of tracheal intubation and controlled ventilation. In cases of a fall in blood pressure/bradycardia, a vasopressor should be given (e.g. ephedrine 5-10 mg intravenously, which may be repeated after 2-3 minutes). In the event of circulatory arrest, cardiopulmonary resuscitation should be instituted immediately. It is important to maintain good oxygenation, respiration and circulation, and to treat acidosis.

Children must be given doses in proportion to their age and body weight for treatment of systemic toxicity.

Pharmacological Properties

Pharmacodynamic Properties

Bupivacaine hydrochloride spinal heavy contains bupivacaine, which is a long-acting local anesthetic of the amide type. Bupivacaine reversibly blocks impulse conduction in the nerves by inhibiting the transport of sodium ions through the nerve membrane. Similar effects can also be seen on excitatory membranes in the brain and myocardium.

Bupivacaine hydrochloride spinal heavy is intended for hyperbaric spinal anesthesia. The relative density of the solution for injection is 1.026 at 20^oC (equivalent to 1.021 at 37^oC) and the initial distribution into the subarachnoid space is markedly influenced by gravity.

For administration into the spine, a small dose is given, which gives a relatively low concentration and short duration of effects. Bupivacaine hydrochloride spinal (without glucose) produces a less predictable block, but with a longer duration of effects than bupivacaine hydrochloride spinal heavy (with glucose).

Pharmacokinetic Properties:

Bupivacaine is very liposoluble with an oil/water distribution coefficient of 27.5.

Bupivacaine displays complete and bi-phasic absorption from the subarachnoid space, with half-lives for the two phases of approx. 50 and approx. 400 minutes, with large variations. The slow absorption phase is the rate-determining factor in the elimination of bupivacaine, which explains why the apparent half-life is longer than after intravenous administration.

Absorption form the subarachnoid space is relatively slow, which, in combination with the low dose required a spinal anesthesia, gives relatively low plasma concentration (approx. 0.4 mg/mL per 100 mg injected).

After intravenous administration, total plasma clearances is approx. 0.58 L/min, the volume of distribution in steady state is approx. 73 L, the elimination half-life is 2.7 hours, and the hepatic extraction ration is approx. 0.40. Bupivacaine is metabolized almost completely in the liver, predominantly through aromatic hydroxylation to 4-hydorxybupivacaine and N-dealkylation to PPX, both of which are mediated by cytochrome P450 3A4. Clearance is thus depended on hepatic perfusion and the activity of the metabolizing enzyme.

Bupivacaine crosses the placenta and the concentration of free bupivacaine is the same in the the mother and the fetus. However, the total plasma concentration is lower in the fetus, which has a lower degree of protein binding.

Pharmaceutical Particulars

Incompatibilities:

Additions to spinal solutions are not recommended.

Shelf-Life:

Please refer to the expiration date.

The solution must be used as soon as possible after the container has been opened.

Storage:

Store at a temperature not exceeding above 25^oC. Do not freeze.

MEFENAMIC ACID

MEFENAMIC ACID

500mg Capsule

250mg Capsule

50mg/5ml Suspension

DRUG CATEGORY: Analgesic/Antipyretic, Non Steroidal Anti-inflammatory

BRAND NAME: Ponstan®

DESCRIPTION:

Mefenamic acid is N-(2,3,-xylyl)-anthranilic acid. It is an orally active analgesic agent. It is a white powder with a melting point of 230-231^oC, molecular weight of 241.28, and water solubility of 0.0004% at pH 7.1.

THERAPEUTIC INDICATIONS

Mefenamic acid is indicated for:

1. The symptomatic relief of rheumatoid arthritis (including Still's Disease), osteoarthritis, and pain including muscular, traumatic and dental pain, headaches of most etiology, post-operative and postpartum pain.
2. The symptomatic relief of primary dysmenorrhea.
3. Menorrhagia due to dysfunctional causes or the presence of an intrauterine device (IUD) when organic pelvic pathology has been excluded.
4. Premenstrual syndrome.
5. The relief of pyrexia in pediatric patients over 6 months of age.

DOSAGE AND METHOD OF ADMINISTRATION

Undesirable effects may be minimized by using the minimum effective dose for shortest duration necessary to control symptoms.

The oral dosage form of mefenamic acid may be taken with food if gastrointestinal upset occurs.

Mild to moderate pain/rheumatoid arthritis/osteoarthritis in adults and adolescents over 14 years of age: 500mg three times daily.

Dysmenorrhea: 500mg three times daily, to be administered at the onset of menstrual pain and continued while symptoms persist according to the judgment of the physician.

Menorrhagia: 500mg three times daily, starting with the onset of bleeding and associated symptoms and continued according to the judgment of the physician.

Premenstrual syndrome: 500mg three times daily, starting with the onset of symptoms and continued until the anticipated cessation of symptoms according to the judgment of the physician.

For Still's Disease or antipyretic action in infants and children over 6 months to 14 years: 19.5mg/kg to 25mg/kg of body weight daily in divided doses three times daily.

Pediatric Use

Mefenamic acid is reported to be effective for pyrexia in pediatric patients over 6 months of age, and for pain in adolescents over 14 years of age.

Use in the Elderly

Impairment of renal function, sometimes leading to acute renal failure, has been reported. Elderly or debilitated patients seem unable to tolerate ulceration of bleeding as well as some other individuals; most spontaneous reports of fatal gastrointestinal events are in this patient population. (See Special Warnings and Special Precautions for Use – Gastrointestinal Effects)

CONTRAINDICATIONS

Because the potential exists for cross-sensitivity to aspirin or other nonsteroidal anti-inflammatory drugs, mefenamic acid should not be given to patients in whom these drugs induce symptoms of bronchospasm, allergic rhinitis, or urticaria.

Mefenamic acid is contraindicated in patients with active ulceration or chronic inflammation of either the upper or lower gastrointestinal tract and should be avoided in patients with pre-existing renal disease.

Mefenamic acid should not be used in patients with known hypersensitivity or any of the components of this drug.

Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

Patients with severe renal and hepatic failure.

Patients with severe heart failure.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE

The use of mefenamic acid with concomitant NSAIDs including COX-2 inhibitors should be avoided.

Cardiovascular Effects

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocadial infarction, and stroke which can be fatal. This risk may increase with duration risk. Patients with known cardiovascular disease may be at greater risk. To minimize the potential risk for an adverse cardiovascular event in patients treated with mefenamic acid, 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 cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur (see Contraindications).

Hypertension

As with all NSAIDs, mefenamic acid can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. NSAIDs, including mefenamic acid, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of therapy with mefenamic acid and throughout the course of therapy.

Fluid Retention and Edema

As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking NSAIDs, including mefenamic acid. Therefore, mefenamic acid should be used with caution in patients with compromised cardiac function and other conditions predisposing to, or worsened by, fluid retention. Patients with pre-existing congestive heart failure or hypertension should be closely monitored.

Gastrointestinal Effects

If diarrhea occurs, the dosage should be reduced or temporarily suspended. Symptoms may recur in certain patients following subsequent exposure. NSAIDs including mefenamic acid, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of stomach, small intestine, or large intestine, which can be fatal. When GI bleeding or ulceration occurs in patients receiving mefenamic acid, the treatment should be withdrawn. Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with cardiovascular disease, patients using concomitant aspirin, or patients with a prior history of, or active gastrointestinal disease, such as ulceration, GI bleeding or inflammatory conditions. Therefore, mefenamic acid should be used with caution in the patients (see Contraindications)

Skin Reaction

Serious skin reactions, some of them fatal including exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs including mefenamic acid. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Mefenamic acid should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Laboratory Tests

A false-positive reaction for urinary bile, using the diazo tablet test, may result following mefenamic acid administration. If biliuria is suspected, other diagnostic procedures, such as the Harrison spot test, should be performed.

Renal Effects

In rare cases, NSAIDs, including mefenamic acid, may cause interstitial nephritis, glomerulitis, papillary necrosis and the nephrotic syndrome. NSAIDs inhibit the synthesis of renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. In these patients, administration of an NSAID may precipitate overt renal decompensation, which is typically followed by recovery to pretreatment state upon discontinuation of NSAID therapy. Patients at greatest risk of such a reaction are those with congestive heart failure, liver cirrhosis, nephrotic syndrome, overt renal disease and the elderly. Such patients should be carefully monitored while receiving NSAID therapy.

Discontinuation of nonsteroidal anti-inflammatory drug (NSAID) therapy is typically followed by recovery to the pretreatment state. Since mefenamic acid metabolites are eliminated primarily by the kidneys, the drug should not be administered to patients with significantly impaired renal function.

Hematologic Effects

Mefenamic acid, like other nonsteroidal anti-inflammatory agents, can inhibit platelet aggregation and may prolong prothrombin time in patients on warfarin therapy. (see Interactions with other Medicinal Products and Other Forms of Interaction)

Hepatic effects

Borderline elevations of one or more liver function tests may occur in some patients receiving mefenamic acid therapy. These elevations may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient 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 more severe hepatic reaction while on therapy with mefenamic acid. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systematic manifestations occur, mefenamic acid should be discontinued.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Anticoagulants: Mefenamic acid has been shown to displace warfarin from protein binding sites, and may enhance the response to oral anticoagulants. Therefore, concurrent administration of mefenamic acid with oral anticoagulant drugs requires frequents prothrombin time monitoring.

Anti-hypertensives including diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonist (AII): NSAIDs can reduce the efficacy of diuretics and other antihypertensive drugs.

In patients with impaired renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the co-administration of an ACE inhibitor or an AIIA with a cyclo-oxygenase inhibitor can increase the deterioration of the renal function, including the possibility of acute renal failure, which is usually reversible. The occurrence of these interactions should be considered in patients taking mefenamic acid with an ACE inhibitor or an AIIA.

Therefore, the concomitant administration of these drugs should be done with caution, especially in elderly patients. Patients should be adequately hydrated and the need to monitor the renal function should be assessed in the beginning of the concomitant treatment and periodically thereafter.

Corticosteroids: Increased risk of gastrointestinal ulceration or bleeding.

Cyclosporine: Because of their effect on renal prostaglandins, cyclo-oxygenase inhibitors such as diclofenac can increase the risk of nephrotoxicity with cyclosporine.

Hypoglycemic agents: There have been reports of changes in the effects of oral hypoglycemic agents in the presence of NSAIDs. Therefore, mefenamic acid should be administered with caution in patients receiving insulin or oral hypoglycemic agents.

Lithium: Nonsteroidal anti-inflammatory drugs (NSAIDs), including mefenamic acid have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. Thus, when mefenamic acid and lithium are administered concurrently, patients should be observed carefully for signs of lithium toxicity.

Methotrexate: Caution is advised when methotrexate is administered concurrently with NSAIDs, including mefenamic acid, because NSAID administration may result in increased plasma levels of methotrexate.

Tacrolimus: Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

PREGNANCY AND LACTATION

Pregnancy

(see Preclinical Safety)

Since there are no adequate and well-controlled studies in pregnant women, this drug should be used only if the potential benefits to the mother justify the possible risk to the fetus. It is known if mefenamic acid or its metabolites cross the placenta. However, because of the effects of drugs in this class (i.e., inhibitors of prostaglandin synthesis) on the fetal cardiovascular system (e.g., premature closure of the ductus arteriosus), the use of mefenamic acid in pregnant women is not recommended. Mefenamic acid inhibits prostaglandin synthesis which may result in prolongation of pregnancy and interference with labor when administered late in the pregnancy. Women on mefenamic acid therapy should consult their physician if they decide to become pregnant.

Lactation

Trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant.

Therefore, mefenamic acid should not be taken by nursing mothers.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINE

The effects of mefenamic acid on the ability to drive or use machinery has not been systematically evaluated.

UNDESIRABLE EFFECTS

Blood and lymphatic system disorders: agranulocytosis, aplastic anemia, autoimmune hemolytic anemia, bone marrow hypoplasia, decreased hematocrit, eosinophilia, leukopenia, pancytopenia, and thrombocytopenic purpura.

Immune system disorders: anaphylaxis

Metabolism and nutrition disorder: glucose intolerance in diabetic patients, hyponatremia

Psychiatric disorders: nervousness

Nervous system disorders: aseptic meningitis, blurred vision, convulsions, dizziness, drowsiness, headache, and insomnia.

Eye disorders: eye irritation, reversible loss of color vision

Ear and labyrinth disorders: ear pain

Cardiac disorders: palpitation

Vascular disorders: hypotension

Respiratory, thoracic and mediastinal disorders: asthma, dyspnea

Gastrointestinal disorders:

The most frequently reported side effects associated with mefenamic acid involve the gastrointestinal tract. Diarrhea appears to be the most common side effect and is usually dose-related. It generally subsides on dosage reduction, and rapidly disappears on termination of therapy. Some patients may not be able to continue therapy.

The following are the most common gastrointestinal side effects: abdominal pain, diarrhea and nausea with or without vomiting.

Less frequently reported gastrointestinal/hepatobiliary side effects include: anorexia, cholestatic jaundice, colitis, constipation, enterocolitis, flatulence, gastric ulceration with and without hemorrhage, mild hepatic toxicity, hepatitis, hepatorenal syndrome, pyrosis, pancreatitis and steatorrhea.

Skin and subcutaneous tissue disorders: angioedema, edema of the larynx, erythema multiforme, facial edema, Lyell's syndrome (toxic epidermal necrolysis), perspiration, pruritus, rash, Stevens-Johnson syndrome and urticaria.

Renal and urinary disorders: dysuria, hematuria, renal failure including papillary necrosis.

OVERDOSE

Following accidental overdosage, the stomach should be emptied immediately by inducing emesis, or by gastric lavage, followed by administration of activated charcoal. Vital functions should be monitored and supported. Hemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins.

Seizures, acute renal failure, and coma have been reported with mefenamic acid overdoses. Overdose has led to fatalities.

PHARMACODYNAMIC PROPERTIES

Mechanism of Action

Mefenamic acid is a nonsteroidal agent with demonstrated anti-inflammatory, analgesic, and antipyretic activity in laboratory animals. It is not a narcotic. Mefenamic acid was found to inhibit prostaglandin synthesis and to compete for binding at the prostaglandin receptor sites in animal models.

PHARMACOKINETICS PROPERTIES

Absorption

Mefenamic acid is rapidly absorbed from the gastrointestinal tract. Following administration of a one gram dose to adult, peak plasma levels of 10mcg/ml occur in 1 to 4 hours, with a half-life of 2 hours. Plasma levels are proportional to dose, following multiple doses, with no drug accumulation. One gram of mefenamic acid administered four times daily produces peak blood levels of 20mcg/ml by the second day of administration.

Distribution

Mefenamic acid is extensively bound to plasma proteins.

Metabolism

Mefenamic acid metabolism is predominantly mediated via cytochrome P450 CYP 2C9 in the liver. Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates should be administered mefenamic acid with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Elimination

Following a single oral dose, 52-67% of the dose was recovered from the urine as unchanged drug or one of two metabolites. Assay of stools over 3 days accounted for 20-25% of the dose, chiefly as unconjugated metabolite II.

PRECLINICAL SAFETY

Rats given up to 10 times the human dose showed decreased fertility delay in parturition, and a decreased rate of survival to weaning. No fetal abnormalities were observed in this study and in another study in dogs receiving 10 times the human dose.

SPECIAL PRECAUTIONS FOR STORAGE

Store at temperature not exceeding 30^oC.

Etoricoxib

Etoricoxib

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.

Pharmacokinetics:

Absorption

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 C_max = 3.6mcg/ml) was observed at approximately 1 hour (T_max) after administration to fasted adults. The

geometric mean AUC_0-24hr was 37.8 mcg.hr/ml. 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, C_max within approximately 20%) when administered alone, with a magnesium/aluminum hydroxide antacid, or a calcium carbonated antacid (approximately 50 mEq acid-neutralizing capacity).

Distribution

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 (V_dss) is approximately 120L in humans.

Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain-barrier in rats.

Metabolism

Etoricoxib is extensively metabolized with <1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6`-hydroxymethyl derivative is catalyzed by 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.

Elimination

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)

Gender

The pharmacokinetics of etoricoxib are similar between men women. (See recommended dose.)

Elderly

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).

Race

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.

Indications:

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.

Arthritis

Osteoarthritis

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.

Contraindications:

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 AUC_0-24hr of EE by 37%. Etoricoxib 120mg given with the same oral contraceptive concomitantly or separated by 12 hours, 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 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 AUC_0-24hr 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 ( 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 1.25mg. 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 30^oC. Protect from light. Store in the original package.