Etoricoxib

Registered South African indications:

• Symptomatic relief of osteoarthritis (OA)
• Symptomatic relief of rheumatoid arthritis (RA)
• Ankylosing spondylitis (AS)
• Acute gouty arthritis
• Short-term relief of acute pain
• Primary dysmenorrhoea
• Acute postoperative pain associated with dental surgery - moderate to severe

Etoricoxib may predispose patients to cardiovascular events, gastrointestinal events or cutaneous reactions which may be fatal.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy (avoid prescribing non-steroidal anti-inflammatory drugs (NSAIDs) such as etoricoxib after 20 weeks as it may cause rare kidney problems in unborn babies)
• Breastfeeding
• Severe renal impairment (CrCl<30ml/min)
• Severe hepatic impairment (Child-Pugh score >9 or serum albumin <25g/l)
• Active peptic or gastrointestinal (GI) bleeding
• Patients who have developed signs of asthma, acute rhinitis, nasal polyps, angioedema or urticaria following the administration of aspirin or other NSAIDs including etoricoxib
• Uncontrolled hypertension
• Children and adolescents under 16 years of age
• Inflammatory bowel disease
• Congestive heart failure (NYHA II-IV)
• Established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease
• Peri-operative analgesia in the setting of coronary artery bypass surgery (CABG)
• Coadministration with lithium may lead to toxic blood concentrations of lithium
• Coadministration with digoxin: there was an approximate increase of 33% in digoxin C_max in healthy volunteers

South African recommendations

Caution in the following patient groups

• Women of childbearing potential
• Mild to moderate hepatic impairment
• Elderly

Long term administration

• Long-term administration of NSAIDs such as etoricoxib, 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 liver cirrhosis. Monitoring of renal and hepatic function in such patients is indicated

Dehydration

• Caution should be used when initiating treatment with etoricoxib in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with etoricoxib

Inhibition of prostaglandin synthesis

• Fluid retention, oedema and hypertension have been reported in patients taking etoricoxib. All nonsteroidal anti-inflammatory drugs (NSAIDs), including etoricoxib, can be associated with new onset or recurrent congestive heart failure
• Caution should be exercised in patients with a history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures including discontinuation of etoricoxib should be taken

Blood pressure

• Etoricoxib may be associated with more frequent and severe hypertension than 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

Cardiovascular thrombotic events

• Clinical trials suggest that the selective COX-2 inhibitor class of medicines, such as etoricoxib, are associated with an increased risk of arterial thrombotic events (especially myocardial infarction (MI)) and stroke)
• Risk increases with higher doses and longer 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

Cardiovascular risk factors

• Use only after careful consideration in patients with significant cardiovascular risk factors, including hypertension, hyperlipidaemia, diabetes mellitus, or smoking

Aspirin and antiplatelet therapy

• Etoricoxib is not a substitute for aspirin for cardiovascular prophylaxis because of its lack of effect on platelets. Because etoricoxib does not inhibit platelet aggregation, anti-platelet therapies should not be discontinued and if indicated, should be considered in patients at risk for or with a history of cardiovascular or other thrombotic events
• There is no evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic events associated with etoricoxib

Serious skin and hypersensitivity reactions

• Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in association with the use of selective COX-2 inhibitors such as etoricoxib during post-marketing surveillance
• Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib
• Selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity

Elderly and organ dysfunction

• Intensified medical supervision is required when treating the elderly or patients with renal, hepatic, or cardiac dysfunction due to increased risk of deterioration
• If these patients show deterioration during treatment, appropriate measures should be taken, including discontinuation

Gastrointestinal complications

• Increased risk of serious upper gastrointestinal perforations, ulcers, or bleeding, especially in the elderly, those with prior gastrointestinal disease, or those using concomitant NSAIDs/aspirin

Hepatic dysfunction

• Elevations of liver enzymes (ALT/AST) may occur; therapy should be discontinued if persistently abnormal liver function tests (3 times the upper limit of normal) are detected

Masking of infection

• Etoricoxib may mask fever and other clinical signs of inflammation or underlying infection

Fertility

• Use is not recommended in fertile women attempting to conceive due to potential effects on female fertility

Neonatal renal impairment and oligohydramnios

• The use of NSAIDs such as etoricoxib around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment
• Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some reported post marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required
• If NSAID treatment is determined necessary, limit use to the lowest effective dose and shortest duration possible. Avoid prescribing NSAIDs at 20 weeks and later in pregnancy because of the additional risk of premature closure of the fetal ductus arteriosus
• Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs

Drug Reaction with Eosinophillia and Systemic Symptoms (DRESS)

• DRESS has been reported in patients taking NSAIDs such as etoricoxib. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling
• Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophillia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved
• It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue etoricoxib and evaluate the patient immediately

Lactose intolerance

• Avoid use in patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption or fructose intolerance

Effects on ability to drive and use machinery

• Patients experiencing dizziness, vertigo, or somnolence should refrain from driving or operating machinery

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Symptomatic relief of osteoarthritis (OA)

• Oral (fct): Recommended dose: 30mg, once daily; If insufficient relief from symptoms is experienced in some patients; Increase to: 60mg, once daily; Max: 60mg/24hrs

Symptomatic relief of rheumatoid arthritis (RA)
Ankylosing spondylitis (AS)

• Oral (fct): Recommended dose: 90mg, dly; In some patients: 60mg, once daily may provide adequate therapeutic benefit; Max: 90mg/24hrs

Short-term relief of acute pain

• Oral (fct): Recommended dose: 90-120mg, dly; Max. treatment duration: 8 days; Max: 120mg/24hrs

Acute gouty arthritis

• Oral (fct): Recommended dose: 120mg, dly; Max. treatment duration: 8 days; Max: 120mg/24hrs

Primary dysmenorrhoea

• Oral (fct): Recommended dose: 120mg, dly; Max: 120mg/24hrs

Acute postoperative pain associated with dental surgery - moderate to severe

• Oral (fct): Recommended dose: 90mg, dly; Max: 90mg/24hrs

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The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual overall risks

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Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied

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As the cardiovascular risks of etoricoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The need for symptomatic relief and response to therapy should be re-evaluated periodically

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Etoricoxib is administered orally and may be taken with or without food

Paed. forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Symptomatic relief of osteoarthritis (OA)
Symptomatic relief of rheumatoid arthritis (RA)
Ankylosing spondylitis (AS)
Acute gouty arthritis
Short-term relief of acute pain
Primary dysmenorrhoea
Acute postoperative pain associated with dental surgery - moderate to severe

Younger than 16 years

• Contraindicated

Older than 16 years

• See adult dosage

Pregnancy

South African recommendations

• Contraindicated
• Etoricoxib is contraindicated in pregnancy
• Etoricoxib, as in other medicines inhibiting prostaglandin synthesis may cause uterine inertia and premature ductus arteriosis during the last trimester of pregnancy. Pregnant women should not use etoricoxib at 20 weeks or later unless specifically advised to do so by health care professional because these medicines may cause foetal renal dysfunction

Breastfeeding  

South African recommendations

• Contraindicated 
• Mothers on etoricoxib should not breastfeed their infants 

Fertility 

South African recommendations

• The use of etoricoxib is not recommended in fertile women attempting to conceive

South African recommendations

• CrCl≥30ml/min: No dose adjustment recommended 
• CrCl<30ml/min: Contraindicated

South African recommendations

• Mild (Child-Pugh A score 5-6): Caution; dose adjustment recommended 
  Regardless of indication: Oral (fct): Max: 60mg/24hrs
• Moderate (Child-Pugh B score 7-9): Caution; dose adjustment recommended 
  Regardless of indication: Oral (fct): Max: 30mg/24hrs OR 60mg, every other day
  Clinical experience is limited
• Severe (Child-Pugh C score>9): Contraindicated 

South African recommendations

• Caution; no dose adjustment recommended 
  No dosage adjustment is necessary for elderly patients although the elderly may be more susceptible to renal, gastrointestinal and cardiovascular adverse effects
  When using etoricoxib in the elderly and in patients with renal, hepatic or cardiac dysfunction, medically appropriate supervision should be intensified. If these patients show deterioration during treatment, appropriate measures should be taken, including discontinuation of etoricoxib

Infections and Infestations

Frequent

• Alveolar osteitis

Less frequent

• Gastroenteritis
• Upper respiratory infection
• Urinary tract infection

Blood and Lymphatic System Disorders

Less frequent

• Anaemia (primarily associated with gastrointestinal bleeding)
• Leukopenia

Frequency unknown

• Thrombocytopenia

Immune System Disorders

Less frequent

• Hypersensitivity reactions
• Angioedema

Frequency unknown

• Anaphylactic/anaphylactoid reactions including shock

Metabolism and Nutrition Disorders

Frequent

• Oedema/fluid retention

Less frequent

• Appetite increase or decrease
• Weight gain

Psychiatric Disorders

Less frequent

• Anxiety
• Depression
• Mental acuity decreased

Frequency unknown

• Confusion
• Hallucinations
• Restlessness

Nervous System Disorders

Frequent

• Dizziness
• Headache

Less frequent

• Insomnia
• Paraesthesia/hypaesthesia

Frequency unknown

• Dysgeusia
• Somnolence

Eye Disorders

Less frequent

• Conjunctivitis

Frequency unknown

• Blurred vision

Ear and Labyrinth Disorders

Less frequent

• Tinnitus
• Vertigo

Cardiac Disorders

Frequent

• Palpitations

Less frequent

• Atrial fibrillation
• Congestive heart failure
• Non-specific EGG changes
• Myocardial infarction
• Angina

Frequency unknown

• Aggravated hypertension
• Dysrhythmia
• Cardiovascular thrombotic events
• Tachycardia

Vascular Disorders

Frequent

• Hypertension

Less frequent

• Flushing
• Cerebrovascular incidents (stroke)
• Transient ischaemic attack
• Vasculitis

Frequency unknown

• Hypertensive crisis
• Peripheral oedema

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Cough
• Dyspnoea
• Epistaxis

Frequency unknown

• Bronchospasm

Gastrointestinal Disorders

Frequent

• Gastrointestinal disorders (e.g. abdominal pain, flatulence, heartburn)
• Diarrhoea
• Dyspepsia
• Epigastric discomfort
• Nausea

Less frequent

• Abdominal distension
• Acid reflux
• Bowel movement pattern change
• Constipation
• Dry mouth
• Gastroduodenal ulcer
• Irritable bowel syndrome
• Oesophagitis
• Oral ulcer
• Vomiting
• Gastritis
• Pancreatitis

Frequency unknown

• Peptic ulcers including gastrointestinal perforation and bleeding (mainly in the elderly)

Hepato-biliary Disorders

Frequent

• Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 

Frequency unknown

• Hepatitis
• Jaundice
• Hepatic failure

Skin and Subcutaneous Tissue Disorders

Frequent

• Ecchymosis

Less frequent

• Facial oedema
• Pruritus
• Rash
• Erythema

Frequency unknown

• Urticaria
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Fixed drug eruption
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Musculoskeletal, Connective Tissue and Bone Disorders

Less frequent

• Muscular cramp/spasm
• Musculoskeletal pain/stiffness

Renal and Urinary Disorders

Less frequent

• Proteinuria
• Increased serum creatinine

Frequency unknown

• Renal insufficiency, including renal failure
• Nephrotoxicity including interstitial nephritis and nephrotic syndrome

General Disorders and Administration Site Conditions

Frequent

• Asthenia/fatigue
• Flu like disease
• Chest pain

Investigations

Less frequent

• Increased blood urea
• Increased creatine phosphokinase
• Decreased haematocrit
• Decreased haemoglobin
• Hyperkalaemia
• Decreased leukocytes
• Decreased platelets
• Increased uric acid
• Decreased blood sodium

• Lithium
• Digoxin
• Ciclosporin
• Tacrolimus
• Warfarin
• Rifampicin
• Methotrexate
• Diuretics
• Angiotensin converting enzyme (ACE) inhibitors
• Angiotensin receptor blockers (ARBs)
• Aspirin
• Oral contraceptives
• Furosemide
• Hormone replacement therapy
• Medicines primarily metabolised by human sulfotransferases
• Oral salbutamol
• Minoxidil

None routine. Specific cases may require

• Renal function
• Hepatic function
• Blood pressure
• International normalised ratio (INR) (when coadministered with warfarin)

Additional observations

• Methotrexate-related toxicity (when coadministered with etoricoxib at doses >90mg daily)

Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. Etoricoxib is an orally active, selective cyclooxygenase-2 (COX-2) inhibitor.