Etoricoxib: Uses, Interactions, Mechanism of Action

ETORICOXIB

Etoricoxib is a member of a new class of arthritis/analgesia medications called Coxibs Chemically, etoricoxib is described as, 5-Chloro-6-methyl-3-[p-(methylsulfonyl) phenyl]-2, 3'-bipyridine.

CLINICAL PHARMACOLOGY:

Mechanism of Action:

Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor. At doses as high as 150 mg per day, . Etoricoxib caused dose-dependent COX-2 inhibition without COX-1 inhibition. Etoricoxib does not inhibit gastric prostaglandin synthesis and does not affect platelet function. Selective inhibition of COX-2 by etoricoxib decreases the synthesis of prostanoid mediators of pain, inflammation, and fever with decreased potential GI toxicity and effects on platelet aggregation.

PHARMACOKINETICS:

Absorption

Following oral doses, etoricoxib is effectively absorbed from the digestive system. One hundred percent of the bioavailability is absolute. In adults who have not eaten in more than an hour, peak plasma concentrations are reached.

Distribution

In the range of concentrations from 0 to 5 mcg/mL, etoricoxib is 92 percent bound to human plasma protein. The volume of distribution at steady state (V) was approximately 120L.

Metabolism

Etoricoxib is extensively metabolized with less than 2% of a dose recovered in the urine as the parent drug. The major route of metabolism is via cytochrome P450 isoenzymes including CYP3A4 to form the 6'-hydroxymethyl derivative of etoricoxib, which is then oxidized to the 6-carboxylic acid derivative, the major metabolite.

Excretion

Excretion is mainly via the urine (70%) with only 20% of a dose appearing in the feces, mostly as metabolites. Less than 2% is recovered as an unchanged drug. Steady-state concentrations of etoricoxib are reached within seven days of the once-daily administration of 120mg. At a steady state, the half-life of etoricoxib is about 22 hours.

THERAPEUTIC INDICATIONS:

Etoricoxib is indicated for:

Symptomatic relief of osteoarthritis (OA) and rheumatoid arthritis (RA) The management of ankylosing spondylitis (AS).
Treatment of acute gouty arthritis.
Relief of acute pain.
Relief of chronic musculoskeletal pain.
Treatment of primary dysmenorrhea.
Treatment for moderate to severe acute postoperative discomfort related to dental surgery.
Abdominal gynecological surgery-related acute postoperative pain of moderate to severe severity is treated.

ADVERSE REACTIONS:

Common

Alveolar osteitis, edema/ fluid retention, dizziness, headache, palpitations, hypertension, gastrointestinal disorders (e.g., abdominal pain, flatulence, heartburn) diarrhea, dyspepsia, epigastric discomfort, nausea, ALT increased, AST increased, ecchymosis, ásthenia/fatigue and flu-like disease.

Uncommon

Gastroenteritis, upper respiratory infection, urinary tract infection, anemia, leukopenia, thrombocytopenia, increased or decreased appetite, weight gain, anxiety, depression, mental acuity decreased, dysgeusia, insomnia, paresthesia/hypoesthesia, somnolence, blurred vision, conjunctivitis, tinnitus, vertigo, atrial fibrillation, congestive heart failure, nonspecific ECG changes, angina pectoris, myocardial infarction, flushing, cerebrovascular accident, transient ischemic attack, cough, dyspnea, epistaxis, abdominal distention, acid reflux, bowel movement pattern change, constipation, dry mouth, gastroduodenal ulcer, irritable bowel syndrome, oesophagitis, oral ulcer, vomiting, gastritis, facial edema, pruritus, rash, muscular cramp/spasm, musculoskeletal pain/stiffness, proteinuria, serum creatinine increased, chest pain, blood urea nitrogen increased.

Rare

Erythema and blood sodium decreased.

Very Rare

Hypersensitivity reactions including angioedema, anaphylactic/anaphylactoid reactions including shock, confusion, hallucinations, hypertensive crisis, bronchospasm, peptic ulcers including gastrointestinal perforation and bleeding, hepatitis, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis and renal insufficiency including renal failure.

CONTRAINDICATIONS:

Etoricoxib is contraindicated in:

Hypersensitivity to active substances or any of the excipients.
Active gastrointestinal (GI) bleeding or peptic ulcer disease.
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. Severe hepatic dysfunction (serum albumin <25 g/L or Child-Pugh score ≥10). - Estimated 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 is persistently elevated above 140/90mmHg and has not been adequately controlled.
Established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease.

PRECAUTIONS:

Gastrointestinal Effects

The elderly, those taking another NSAID or acetylsalicylic acid concurrently, patients using any other NSAID, or patients with a history of gastrointestinal diseases like ulceration and GI bleeding should all be treated with caution when using NSAIDs.

Cardiovascular Effects

Patients with substantial cardiovascular event risk factors (e.g. hyperlipidemia, diabetes, smoking, hypertension, and hyperlipidemia) should only be treated with etoricoxib after careful consideration.

Aspirin substitution

Because they lack an antiplatelet effect, COX-2 selective inhibitors cannot replace acetylsalicylic acid in the prophylaxis of cardiovascular thrombo-embolic diseases. Consequently, antiplatelet treatments shouldn't be stopped.

Renal Effects

Etoricoxib administration may result in a decrease in prostaglandin synthesis and, subsequently, renal blood flow, which would impair renal function in patients with compromised renal perfusion. Such patients should think about monitoring their renal function. When starting etoricoxib treatment with patients who have significant dehydration, caution should be exercised. Rehydrating patients is advised before beginning etoricoxib therapy.

Hepatic Effects

Patients should be closely watched for symptoms of liver dysfunction and abnormal liver function tests. Etoricoxib should be stopped taking if symptoms of hepatic insufficiency appear or if persistently abnormal liver function tests are found (three times the upper limit of normal).

Hypersensitivity

Patients who have previously experienced acute asthmatic attacks, urticaria, or rhinitis brought on by salicylates or non-selective cyclooxygenase inhibitors should use etoricoxib with caution.

DRUG INTERACTIONS:

Oral Anticoagulants

The daily administration of 120 mg of etoricoxib to patients taking chronic warfarin therapy is linked to an increase in the prothrombin time International Normalized Ratio (INR). Because of this, patients taking oral anticoagulants need to have their prothrombin time INR closely monitored.

Angiotensin II antagonists, ACE inhibitors, and diuretics

Co-administration of ACE inhibitors or Angiotensin II antagonists and cyclo-oxygenase inhibitors may cause patients with compromised renal function to experience further deterioration of their renal function, including possible acute renal failure, which is typically reversible. As a result, the combination should be used with care, especially in the case of the elderly.

Acetylsalicylic Acid

A higher rate of Gl ulceration or other complications may occur when low-dose acetylsalicylic acid is administered concurrently with etoricoxib than when etoricoxib is used alone.

Methotrexate

When etoricoxib and methotrexate are administered concurrently, adequate monitoring for methotrexate-related toxicity is advised.

Oral contraceptives

When etoricoxib is used concurrently with an oral contraceptive pill that contains ethinyl estradiol and norethindrone, ethinyl estradiol's steady-state AUC is increased. When choosing a suitable oral contraceptive to use with etoricoxib, one should take this increase in concentration into account.

Hormones Replacment Therapy (HRT)

The mean steady-state AUC of unconjugated estrone, equilin, and 17-B-estradiol is elevated by the administration of etoricoxib along with hormone replacement therapy. The choice of post-menopausal hormone therapy for use with etoricoxib should take into account these increases in oestrogenic concentration.

Digoxin.

Etoricoxib increases digoxin Cm when given together with digoxin. Therefore, when etoricoxib and digoxin are administered simultaneously, patients who are at a high risk of digoxin toxicity should be closely watched.

Rifampicin.

Toroxifin plasma concentrations are lowered when the two drugs are administered together. When etoricoxib and rifampicin are administered together, this interaction could cause symptoms to return.