Etoricoxib

Ketoconazole, a potent inhibitor of CYP3A4, dosed at 400 mg once a day for 11 days to healthy volunteers, did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib (43% increase in AUC).

Co-administration of either oral voriconazole or topical miconazole oral gel, strong CYP3A4 inhibitors, with etoricoxib caused a slight increase in exposure to etoricoxib, but is not considered to be clinically meaningful based on published data.

Regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh score 5-6) a dose of 60 mg once daily should not be exceeded.

In patients with moderate hepatic dysfunction (Child-Pugh score 7-9), regardless of indication, the dose of 30 mg once daily should not be exceeded.

Clinical experience is limited particularly in patients with moderate hepatic dysfunction and caution is advised.

In subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed.

NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or Angiotensin II antagonist and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

Etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC_0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive concomitantly or separated by 12 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 thrombo-embolic events in women at risk).

Administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated estrogens (0.625 mg estrogens conjugated) for 28 days, increased the mean steady state AUC_0-24hr of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%). The effect of the recommended chronic doses of etoricoxib (30, 60, and 90 mg) has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC_0-24hr) to these estrogenic components of estrogens conjugated were less than half of those observed when estrogens conjugated was administered alone and the dose was increased from 0.625 to 1.25 mg. The clinical significance of these increases is unknown, and higher doses of estrogens conjugated were not studied in combination with etoricoxib. These increases in estrogenic concentration should be taken into consideration when selecting post-menopausal hormone therapy for use with etoricoxib because the increase in oestrogen exposure might increase the risk of adverse events associated with HRT.

The use of etoricoxib, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

In a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the anti-platelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose acetylsalicylic acid). However, concomitant administration of low-dose acetylsalicylic acid with etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.

Although this interaction has not been studied with etoricoxib, coadministration of cyclosporin or tacrolimus with any NSAID may increase the nephrotoxic effect of cyclosporin or tacrolimus. Renal function should be monitored when etoricoxib and either of these drugs is used in combination.

Etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC_0-24hr or renal elimination of digoxin. There was an increase in digoxin C_max (approximately 33%). This increase is not generally important for most patients. However, patients at high risk of digoxin toxicity should be monitored for this when etoricoxib and digoxin are administered concomitantly.

NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.

Two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate monitoring for methotrexate-related toxicity is recommended when etoricoxib and methotrexate are administered concomitantly.

Co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction may result in recurrence of symptoms when etoricoxib is co-administered with rifampicin. While this information may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended.

Etoricoxib is an inhibitor of human sulfotransferase activity, particularly SULT1E1, and has been shown to increase the serum concentrations of ethinyl estradiol. While knowledge about effects of multiple sulfotransferases is presently limited and the clinical consequences for many drugs are still being examined, it may be prudent to exercise care when administering etoricoxib concurrently with other drugs primarily metabolised by human sulfotransferases (e.g. oral salbutamol and minoxidil).

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

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

Fertility

The use of etoricoxib, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

Patients who experience dizziness, vertigo or somnolence while taking etoricoxib should refrain from driving or operating machinery.

Summary of the safety profile

In clinical trials, etoricoxib was evaluated for safety in 9,295 individuals, including 6,757 patients with OA, RA, chronic low back pain or ankylosing spondylitis (approximately 600 patients with OA or RA were treated for one year or longer).

In clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with etoricoxib for one year or longer.

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

In a cardiovascular safety outcomes programme of pooled data from three active comparator controlled trials, 17, 412 patients with OA or RA were treated with etoricoxib (60 mg or 90 mg) for a mean duration of approximately 18 months.

In clinical studies for acute postoperative dental pain following surgery including 614 patients treated with etoricoxib (90 mg or 120 mg), the adverse experience profile in these studies was generally similar to that reported in the combined OA, RA, and chronic low back pain studies.

List of adverse reactions

The following undesirable effects were reported at an incidence greater than placebo in clinical trials in patients with OA, RA, chronic low back pain or ankylosing spondylitis treated with etoricoxib 30 mg, 60 mg or 90 mg up to the recommended dose for up to 12 weeks; in the MEDAL Programme studies for up to 3½ years; in short term acute pain studies for up to 7 days; or in post-marketing experience:

Frequency Category: Defined for each Adverse Experience Term by the incidence reported in the clinical trials data base: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), Very Rare (<1/10,000).

Infections and infestations

Common: alveolar osteitis

Uncommon: gastroenteritis, upper respiratory infection, urinary tract infection

Blood and lymphatic system disorders

Uncommon: anaemia (primarily associated with gastrointestinal bleeding), leukopenia, thrombocytopenia

Immune system disorders

Uncommon: hypersensitivity‡,ß

Rare: angioedema/anaphylactic /anaphylactoid reactions including shock‡

Metabolism and nutrition disorders

Common: oedema/fluid retention

Uncommon: appetite increase or decrease, weight gain

Psychiatric disorders

Uncommon: anxiety, depression, mental acuity decreased, hallucinations‡

Rare: confusion‡, restlessness‡

Nervous system disorders

Common: dizziness, headache

Uncommon: dysgeusia, insomnia, paresthaesia/hypaesthesia, somnolence

Eye disorders

Uncommon: blurred vision, conjunctivitis

Ear and labyrinth disorders

Uncommon: tinnitus, vertigo

Cardiac disorders

Common: palpitations, arrhythmia‡

Uncommon: atrial fibrillation, tachycardia‡, congestive heart failure, non-specific ECG changes, angina pectoris‡, myocardial infarction§

Vascular disorders

Common: hypertension

Uncommon: flushing, cerebrovascular accident§, transient ischaemic attack, hypertensive crisis‡, vasculitis‡

Respiratory, thoracic and mediastinal disorders

Common: bronchospasm‡

Uncommon: cough, dyspnoea, epistaxis

Gastrointestinal disorders

Very common: abdominal pain

Common: Constipation, flatulence, gastritis, heartburn/acid reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, oesophagitis, oral ulcer

Uncommon: abdominal distention, bowel movement pattern change, dry mouth, gastroduodenal ulcer, peptic ulcers including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis‡

Hepatobiliary disorders

Common: ALT increased, AST increased

Rare: hepatitis‡

Rare†: hepatic failure‡, jaundice‡

Skin and subcutaneous tissue disorders

Common: ecchymosis

Uncommon: facial oedema, pruritus, rash, erythema‡, urticaria‡

Rare†: Stevens-Johnson syndrome‡, toxic epidermal necrolysis‡, fixed drug eruption‡

Musculoskeletal and connective tissue disorders

Uncommon: muscular cramp/spasm, musculoskeletal pain/stiffness

Renal and urinary disorders

Uncommon: proteinuria, serum creatinine increased, renal failure/renal insufficiency‡

General disorders and administration site conditions

Common: asthenia/fatigue, flu-like disease

Uncommon: chest pain

Investigations

Uncommon: blood urea nitrogen increased, creatine phosphokinase increased, hyperkalaemia, uric acid increased

Rare: blood sodium decreased

^‡ This adverse reaction was identified through post-marketing surveillance. Its reported frequency has been estimated based upon the highest frequency observed across clinical trial data pooled by indication and approved dose.
^† The frequency category of “Rare” was defined per the Summary of Product Characteristics (SmPC) guidance (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of subjects treated with etoricoxib in the analysis of the Phase III data pooled by dose and indication (n=15,470).
^ß Hypersensitivity includes the terms “allergy”, “drug allergy”, “drug hypersensitivity”, “hypersensitivity”, “hypersensitivity NOS”, “hypersensitivity reaction” and “nonspecific allergy”.
^§ Based on analyses of long-term placebo and active controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of serious thrombotic arterial events, including myocardial infarction and stroke. The absolute risk increase for such events is unlikely to exceed 1% per year based on existing data (uncommon).

The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity including interstitial nephritis and nephrotic syndrome.