Dolocox^® (Tablets) Instructions for Use

Marketing Authorization Holder

Hetero Labs, Limited (India)

Manufactured By

Hetero Labs, Limited (India)

Or

Makiz-Pharma, LLC (Russia)

Contact Information

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

M01AH05 (Etoricoxib)

Active Substance

Etoricoxib (Rec.INN WHO registered)

Dosage Forms

	Dolocox®	Film-coated tablets, 30 mg: 7, 10, 14, 20, 21, 28, 30, 40, 42, 56, 90 or 100 pcs.
		Film-coated tablets, 60 mg: 7, 10, 14, 20, 21, 28, 30, 40, 42, 56, 90 or 100 pcs.
		Film-coated tablets, 90 mg: 7, 10, 14, 20, 21, 28, 30, 40, 42, 56, 90 or 100 pcs.
		Film-coated tablets, 120 mg: 7, 10, 14, 20, 21, 28, 30, 40, 42, 56, 90 or 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets of gray-blue color, biconvex, apple-shaped, engraved with “96” on one side and “J” on the other; the cross-section shows two layers: an almost white core and a gray-blue coating.

Excipients: anhydrous calcium hydrogen phosphate – 26.25 mg, microcrystalline cellulose (type 102) – 37.75 mg, croscarmellose sodium – 1.5 mg, magnesium stearate – 4.5 mg.

Coating composition Opadry II green 32K510001 (hypromellose – 40%, lactose monohydrate – 28%, titanium dioxide (E171) – 23.1%, triacetin – 8%, indigo carmine aluminum lake (FD&C Blue No.2) (E132) (11%-14%) – 0.6%, yellow iron oxide (E172) – 0.3%) – 2 mg; Opadry clear 02K19253 (hypromellose – 90%, triacetin – 10%) – 0.51 mg.

7 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
14 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – aluminum blisters (3,10) – cardboard packs.
30 pcs. – polyethylene jars (1) – cardboard packs.
90 pcs. – polyethylene jars (1) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.
90 pcs. – polyethylene bottles (1) – cardboard packs.

Film-coated tablets of gray-blue color, biconvex, apple-shaped, engraved with “97” on one side and “J” on the other; the cross-section shows two layers: an almost white core and a gray-blue coating.

Excipients: anhydrous calcium hydrogen phosphate – 52.5 mg, microcrystalline cellulose (type 102) – 75.5 mg, croscarmellose sodium – 3 mg, magnesium stearate – 9 mg.

Coating composition Opadry II green 32K510001 (hypromellose – 40%, lactose monohydrate – 28%, titanium dioxide (E171) – 23.1%, triacetin – 8%, indigo carmine aluminum lake (FD&C Blue No.2) (E132) (11%-14%) – 0.6%, yellow iron oxide (E172) – 0.3%) – 4 mg; Opadry clear 02K19253 (hypromellose – 90%, triacetin – 10%) – 1.02 mg.

7 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
14 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – aluminum blisters (3,10) – cardboard packs.
30 pcs. – polyethylene jars (1) – cardboard packs.
90 pcs. – polyethylene jars (1) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.
90 pcs. – polyethylene bottles (1) – cardboard packs.

Film-coated tablets white, biconvex, apple-shaped, engraved with “98” on one side and “J” on the other; the cross-section shows two layers: an almost white core and a white coating.

Excipients: anhydrous calcium hydrogen phosphate – 78.75 mg, microcrystalline cellulose (type 102) – 113.25 mg, croscarmellose sodium – 4.5 mg, magnesium stearate – 13.5 mg.

Coating composition Opadry II white 32K580000 (hypromellose – 40%, lactose monohydrate – 28%, titanium dioxide (E171) – 24%, triacetin – 8%) – 6 mg; Opadry clear 02K19253 (hypromellose – 90%, triacetin – 10%) – 1.53 mg.

7 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
14 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – aluminum blisters (3,10) – cardboard packs.
30 pcs. – polyethylene jars (1) – cardboard packs.
90 pcs. – polyethylene jars (1) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.
90 pcs. – polyethylene bottles (1) – cardboard packs.

Film-coated tablets of gray-blue color, biconvex, apple-shaped, engraved with “99” on one side and “J” on the other; the cross-section shows two layers: an almost white core and a gray-blue coating.

Excipients: anhydrous calcium hydrogen phosphate – 105 mg, microcrystalline cellulose (type 102) – 151 mg, croscarmellose sodium – 6 mg, magnesium stearate – 18 mg.

Coating composition Opadry II green 32K510001 (hypromellose – 40%, lactose monohydrate – 28%, titanium dioxide (E171) – 23.1%, triacetin – 8%, indigo carmine aluminum lake (FD&C Blue No.2) (E132) (11%-14%) – 0.6%, yellow iron oxide (E172) – 0.3%) – 8 mg; Opadry clear 02K19253 (hypromellose – 90%, triacetin – 10%) – 2.04 mg.

7 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
14 pcs. – contour cell blisters (1,2,3,4) – cardboard packs.
10 pcs. – aluminum blisters (3,10) – cardboard packs.
30 pcs. – polyethylene jars (1) – cardboard packs.
90 pcs. – polyethylene jars (1) – cardboard packs.
30 pcs. – polyethylene bottles (1) – cardboard packs.
90 pcs. – polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

NSAID. Highly selective COX-2 inhibitor

Pharmacotherapeutic Group

NSAID

Pharmacological Action

Etoricoxib, when taken orally at therapeutic concentrations, is a selective inhibitor of cyclooxygenase-2 (COX-2). In clinical pharmacological studies, Etoricoxib dose-dependently inhibited COX-2 without affecting COX-1 when used at daily doses up to 150 mg. Etoricoxib does not inhibit prostaglandin synthesis in the gastric mucosa and does not affect platelet function.

Cyclooxygenase is responsible for the formation of prostaglandins. Two isoforms of cyclooxygenase have been identified – COX-1 and COX-2. COX-2 is an isoenzyme that is induced by various pro-inflammatory mediators and is considered the primary enzyme responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is involved in the processes of ovulation, implantation, and closure of the ductus arteriosus, regulation of kidney and central nervous system function (induction of fever, pain sensation, cognitive function), and may also play a role in the process of ulcer healing. COX-2 has been detected in tissues surrounding gastric ulcers in humans, but its significance for ulcer healing has not been established.

Efficacy

In patients with osteoarthritis (OA), Etoricoxib at a dose of 60 mg once daily provided a significant reduction in pain and improvement in patient assessment of their condition. These beneficial effects were observed as early as the 2nd day of treatment and persisted for 52 weeks. Studies of etoricoxib at a dose of 30 mg once daily demonstrated superior efficacy compared to placebo over a 12-week treatment period (using similar assessment methods). In a dose-finding study, Etoricoxib at a dose of 60 mg demonstrated significantly greater improvement than the 30 mg dose for all three primary endpoints after 6 weeks of treatment. The 30 mg dose was not studied in hand OA.

In patients with rheumatoid arthritis (RA), Etoricoxib at doses of 60 mg and 90 mg once daily provided both significant reduction in pain and inflammation and improved mobility. In studies evaluating etoricoxib doses of 60 mg and 90 mg, these beneficial effects persisted over a 12-week treatment period.

In patients with acute gouty arthritis attacks, Etoricoxib at a dose of 120 mg once daily for the entire 8-day treatment period reduced moderate and severe joint pain and inflammation. Efficacy was comparable to that of indomethacin at a dose of 50 mg three times daily. Pain reduction was noted as early as 4 hours after starting treatment.

In patients with ankylosing spondylitis, Etoricoxib at a dose of 90 mg once daily provided a significant reduction in back pain, inflammation, stiffness, and improved function. The clinical efficacy of etoricoxib was observed as early as the 2nd day of treatment and persisted throughout the 52-week treatment period. In a second study comparing the etoricoxib 60 mg dose and the 90 mg dose, Etoricoxib at 60 mg once daily and 90 mg once daily demonstrated similar efficacy compared to naproxen 1000 mg once daily.

In a clinical study of pain after dental surgery, Etoricoxib at a dose of 90 mg was administered once daily for 3 days. In the subgroup of patients with moderate pain at baseline, Etoricoxib at a dose of 90 mg provided the same analgesic effect as ibuprofen 600 mg (16.11 vs. 16.39; P=0.722), and was superior to the combination of paracetamol/codeine 600 mg/60 mg (11.00; P<0.001) and placebo (6.84; P<0.001) according to the total pain relief over the first 6 hours (TOPAR6). The proportion of patients requiring rescue analgesics within the first 24 hours after taking the study drugs was 40.8% for etoricoxib 90 mg, 25.5% for ibuprofen 600 mg every 6 hours, and 46.7% for the paracetamol/codeine 600 mg/60 mg combination every 6 hours, compared to 76.2% in the placebo group. In this study, the median time to onset (perceptible pain reduction) for etoricoxib 90 mg was 28 minutes after dosing.

Safety

The MEDAL Program (Multinational Etoricoxib and Diclofenac Arthritis Long-term Program)

The MEDAL Program was a prospective safety assessment program based on cardiovascular (CV) events from pooled data from 3 randomized, double-blind, active-controlled trials: MEDAL, EDGE II, and EDGE.

The MEDAL trial was an event-driven trial (CV events) that included 17,804 patients with OA and 5,700 patients with RA who received Etoricoxib 60 mg (OA) or 90 mg (OA and RA) or diclofenac 150 mg/day for an average of 20.3 months (maximum 42.3 months, median 21.3 months). In this trial, only serious adverse events and study discontinuations due to any adverse events were recorded.

The EDGE and EDGE II trials compared the gastrointestinal tolerability of etoricoxib and diclofenac. The EDGE trial included 7,111 patients with OA who received Etoricoxib 90 mg/day (1.5 times the recommended dose for OA) or diclofenac 150 mg/day for an average of 9.1 months (maximum 16.6 months, median 11.4 months). The EDGE II trial included 4,086 patients with RA who received Etoricoxib 90 mg/day or diclofenac 150 mg/day for an average of 19.2 months (maximum 33.1 months, median 24 months).

In the pooled MEDAL Program, 34,701 patients with OA or RA were treated for an average of 17.9 months (maximum 42.3 months, median 16.3 months), with approximately 12,800 patients treated for more than 24 months. Patients enrolled in the MEDAL Program had a wide range of CV and gastrointestinal risk factors at baseline. Patients with a recent myocardial infarction, as well as those with coronary artery bypass grafting or percutaneous coronary intervention within 6 months prior to study entry, were excluded. The use of gastroprotective agents and low-dose aspirin was permitted in the studies.

Overall Safety

No significant differences were found between etoricoxib and diclofenac in the incidence of thrombotic CV events. Cardiorenal adverse events were observed more frequently with etoricoxib than with diclofenac; this effect was dose-dependent (specific results are presented below). Gastrointestinal and hepatic adverse events were significantly more frequent with diclofenac than with etoricoxib. The incidence of adverse events in the EDGE and EDGE II trials, and adverse events deemed serious or leading to treatment discontinuation in the MEDAL trial, was higher with etoricoxib than with diclofenac.

Cardiovascular Safety Assessment Results

The incidence of confirmed serious thrombotic CV adverse events (including cardiac, cerebrovascular, and peripheral vascular events) was comparable between the Etoricoxib and diclofenac groups (data are presented in the table below). No statistically significant differences in the incidence of thrombotic events were found between etoricoxib and diclofenac in all analyzed subgroups, including patient categories across the baseline CV risk spectrum. Individually, the relative risk for confirmed serious thrombotic CV adverse events was similar for etoricoxib (at 60 mg or 90 mg) and diclofenac (at 150 mg).

Table “Incidence of Confirmed Thrombotic CV Events (MEDAL Program)”

¹ – number of events per 100 patient-years; CI – confidence interval; N – total number of patients included in the per-protocol population.

On-Protocol – all events occurring during study therapy or within 14 days of its discontinuation (excluded patients who received <75% of the study drug, and patients taking non-study NSAIDs >10% of the time).

Intent-to-Treat – all confirmed events occurring before the end of the study (included patients who may have undergone non-study interventions after discontinuing the study drug).

Total number of randomized patients: n=17412 for etoricoxib and n=17289 for diclofenac.

CV mortality and overall mortality were comparable between the etoricoxib and diclofenac treatment groups.

Cardiorenal Events

Approximately 50% of patients enrolled in the MEDAL trial had a history of hypertension at baseline. In this trial, the rate of discontinuation due to adverse events related to hypertension was statistically significantly higher for etoricoxib than for diclofenac. The incidence of adverse events related to congestive heart failure (study discontinuations and serious events) was similar for etoricoxib 60 mg and diclofenac 150 mg, but was higher for etoricoxib 90 mg compared to diclofenac 150 mg (statistically significantly higher for etoricoxib 90 mg compared to diclofenac 150 mg in the OA cohort of the MEDAL trial). The incidence of confirmed adverse events related to congestive heart failure (events that were serious and led to hospitalization or an emergency department visit) was slightly higher for etoricoxib compared to diclofenac 150 mg; this effect was dose-dependent. The rate of study discontinuation due to adverse events related to edema was higher for etoricoxib compared to diclofenac 150 mg; this effect was dose-dependent (statistically significant for etoricoxib 90 mg, but not for etoricoxib 60 mg).

Cardiorenal safety assessment results in the EDGE and EDGE II trials are consistent with the results in the MEDAL trial.

In the individual trials of the MEDAL Program, the absolute discontinuation rate in any treatment group for etoricoxib (60 mg or 90 mg) was up to 2.6% due to hypertension, up to 1.9% due to edema, and up to 1.1% due to congestive heart failure. Patients taking Etoricoxib 90 mg had a higher rate of study discontinuation than patients taking Etoricoxib 60 mg.

Gastrointestinal Tolerability Assessment Results in the MEDAL Program

In each of the 3 studies included in the MEDAL Program, the rate of study discontinuation for any clinical gastrointestinal adverse event (e.g., dyspepsia, abdominal pain, ulcers) was significantly lower for etoricoxib compared to diclofenac. The rate of study discontinuation due to gastrointestinal clinical adverse events per 100 patient-years over the entire study period was as follows: 3.23 for etoricoxib and 4.96 for diclofenac in the MEDAL study; 9.12 for etoricoxib and 12.28 for diclofenac in the EDGE study; and 3.71 for etoricoxib and 4.81 for diclofenac in the EDGE II study.

Results of the Gastrointestinal Safety Assessment in the MEDAL Program

Overall, upper gastrointestinal adverse events were defined as perforations, ulcers, and bleeding. Complicated upper gastrointestinal adverse events included perforation, obstruction, and complicated bleeding; uncomplicated upper gastrointestinal adverse events included uncomplicated bleeding and uncomplicated ulcers. The overall rate of upper gastrointestinal adverse events was significantly lower for etoricoxib compared to diclofenac. No significant differences were found between etoricoxib and diclofenac in the rate of complicated events. For the subgroup of hemorrhagic upper gastrointestinal adverse events (complicated and uncomplicated combined), no significant differences were found between etoricoxib and diclofenac. The gastrointestinal advantage of etoricoxib over diclofenac in patients concurrently taking low-dose aspirin (approximately 33% of patients) was not statistically significant. The rate of confirmed complicated and uncomplicated clinical upper gastrointestinal adverse events per 100 patient-years (perforations, ulcers, and bleeding) was 0.67 (95% CI 0.57, 0.77) for etoricoxib and 0.97 (95% CI 0.85, 1.10) for diclofenac, resulting in a relative risk of 0.69 (95% CI 0.57, 0.83).

The rate of confirmed upper gastrointestinal adverse events in elderly patients was studied; the maximum reduction in rate was observed in patients aged ≥75 years – 1.35 (95% CI 0.94, 1.87) compared to 2.78 (95% CI 2.14, 3.56) events per 100 patient-years for etoricoxib and diclofenac, respectively. The rate of confirmed lower gastrointestinal adverse events (perforation of the small or large intestine, obstruction, or bleeding) did not differ significantly between the groups receiving Etoricoxib and diclofenac.

Results of the Hepatic Safety Assessment in the MEDAL Program

Etoricoxib was characterized by a statistically significantly lower rate of study discontinuation due to hepatic adverse events compared to diclofenac. In the combined MEDAL Program, 0.3% of patients receiving Etoricoxib and 2.7% of patients receiving diclofenac discontinued the study due to hepatic adverse events. The rate of adverse events per 100 patient-years was 0.22 for etoricoxib and 1.84 for diclofenac (p<0.001 for etoricoxib compared to diclofenac). Most hepatic adverse events in the MEDAL Program were non-serious.

Additional Safety Data Related to Thrombotic Cardiovascular Events

In clinical studies, excluding the MEDAL Program studies, approximately 3100 patients received Etoricoxib at a dose of ≥60 mg/day for 12 weeks or longer. No notable differences were found in the rate of confirmed serious thrombotic cardiovascular events in patients receiving Etoricoxib at a dose of ≥60 mg, placebo, or NSAIDs not containing naproxen. However, compared to patients receiving naproxen at a dose of 500 mg twice daily, the rate of these events was higher in patients receiving Etoricoxib. The difference in antiplatelet activity between some NSAIDs that inhibit COX-1 and selective COX-2 inhibitors may have clinical significance in patients at risk for thromboembolic events. Selective COX-2 inhibitors suppress the formation of systemic (and possibly endothelial) prostacyclin without affecting platelet thromboxane. The clinical significance of these observations has not been established.

Additional Gastrointestinal Safety Data

In two double-blind endoscopic studies lasting 12 weeks, the cumulative incidence of gastroduodenal ulcers was significantly lower in patients receiving Etoricoxib at a dose of 120 mg once daily than in patients receiving naproxen at a dose of 500 mg twice daily or ibuprofen at a dose of 800 mg three times daily. The incidence of ulcers with etoricoxib was higher compared to placebo.

Renal Function Study in the Elderly

A randomized, double-blind, placebo-controlled, parallel-group study assessed the effects of 15-day therapy with etoricoxib (90 mg), celecoxib (200 mg twice daily), naproxen (500 mg twice daily), and placebo on renal sodium excretion, blood pressure, and other renal function parameters in patients aged 60 to 85 years receiving a diet containing 200 mEq/day of sodium. Etoricoxib, celecoxib, and naproxen had similar effects on renal sodium excretion after 2 weeks of treatment. All active comparators led to an increase in systolic blood pressure relative to placebo; however, etoricoxib therapy resulted in a statistically significant increase in systolic blood pressure on day 14 compared to celecoxib and naproxen (mean change in systolic blood pressure from baseline: Etoricoxib – 7.7 mmHg, celecoxib – 2.4 mmHg, naproxen – 3.6 mmHg).

Pharmacokinetics

Absorption

Etoricoxib is rapidly absorbed after oral administration. The absolute oral bioavailability is approximately 100%. When the drug is administered to fasting adults at a dose of 120 mg once daily until steady state is reached, C_max is 3.6 μg/ml. The time to reach C_max in plasma is 1 hour after drug administration. The geometric mean AUC_0-24 is 37.8 μg×h/ml. The pharmacokinetics of etoricoxib are linear within the therapeutic dose range.

When etoricoxib is administered at a dose of 120 mg with food (high-fat meal), no clinically significant effect on the extent of absorption was observed. The rate of absorption changed, leading to a 36% decrease in C_max and a 2-hour increase in T_max. These results are not considered clinically significant. In clinical studies, Etoricoxib was administered without regard to meals.

Distribution

Etoricoxib is approximately 92% bound to human plasma proteins at concentrations of 0.05-5 μg/ml. The volume of distribution at steady state (V_dss) is about 120 L.

Etoricoxib crosses the placental barrier and the blood-brain barrier.

Metabolism

Etoricoxib is extensively metabolized. Less than 1% of etoricoxib is excreted unchanged in the urine. The main metabolic pathway is the formation of 6′-hydroxymethyletoricoxib, catalyzed by cytochrome P450 enzymes. CYP3A4 appears to be involved in the metabolism of etoricoxib in vivo. In vitro studies indicate that the CYP2D6, CYP2C9, CYP1A2, and CYP2C19 isoenzymes may also catalyze the main metabolic pathway, but their quantitative impact in vivo has not been studied.

Five metabolites of etoricoxib have been identified in humans. The main metabolite is 6′-carboxyacetyletoricoxib, formed by further oxidation of 6′-hydroxymethyletoricoxib. These major metabolites do not exhibit significant activity or are weak inhibitors of COX-2. None of these metabolites inhibit COX-1.

Excretion

After a single intravenous administration of radiolabeled etoricoxib at a dose of 25 mg to healthy volunteers, 70% of the radioactivity was detected in urine and 20% in feces, predominantly as metabolites. Less than 2% was detected unchanged.

Elimination of etoricoxib occurs mainly via metabolism followed by renal excretion.

Steady-state concentrations of etoricoxib with daily administration of 120 mg are achieved within 7 days with an accumulation factor of about 2, corresponding to a T_1/2 of about 22 hours. Plasma clearance after intravenous administration of 25 mg is approximately 50 ml/min.

Pharmacokinetics in Special Patient Populations

Elderly Patients

Pharmacokinetics in elderly patients (≥65 years) are comparable to those in young subjects.

Hepatic Impairment

In patients with mild hepatic impairment (Child-Pugh score 5-6), administration of etoricoxib at a dose of 60 mg once daily was associated with an approximately 16% increase in mean AUC compared to healthy subjects receiving the same dose.

In patients with moderate hepatic impairment (Child-Pugh score 7-9) receiving Etoricoxib at a dose of 60 mg every other day, the mean AUC was the same as in healthy subjects receiving Etoricoxib daily at the same dose. Etoricoxib at a dose of 30 mg once daily has not been studied in this population.

Clinical and pharmacokinetic data are lacking in patients with severe hepatic impairment (Child-Pugh score ≥10).

Renal Impairment

Pharmacokinetic parameters after a single dose of etoricoxib 120 mg in patients with moderate and severe renal impairment and patients with end-stage chronic renal failure on hemodialysis did not differ significantly from those in healthy subjects. Hemodialysis had a minor effect on elimination (dialysis clearance about 50 ml/min) (see sections “Contraindications” and “Special Instructions”).

Children

The pharmacokinetics of etoricoxib in pediatric patients under 12 years of age have not been studied.

In a pharmacokinetic study (n=16) conducted in adolescents aged 12 to 17 years, the pharmacokinetics in adolescents weighing 40 to 60 kg receiving etoricoxib 60 mg once daily and in adolescents weighing more than 60 kg receiving etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults receiving etoricoxib 90 mg once daily.

The safety and efficacy of etoricoxib in pediatric patients have not been established (see section “Dosage Regimen”).

Gender

The pharmacokinetics of etoricoxib are similar in men and women.

Indications

• Treatment of chronic low back pain;
• Symptomatic therapy of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and inflammation associated with acute gouty arthritis;
• Short-term therapy of moderate acute pain after dental surgery.

The decision to prescribe a selective COX-2 inhibitor should be justified taking into account the overall risks for each individual patient (see sections “Contraindications” and “Special Instructions”).

ICD codes

Dosage Regimen

Orally, regardless of meals, with a small amount of water.

Dolocox^® should be used at the lowest effective dose for the shortest possible duration.

For osteoarthritis the recommended dose is 30 mg once daily or 60 mg once daily.

For rheumatoid arthritis and ankylosing spondylitis the recommended dose is 60 mg once daily. In some patients with insufficient symptom relief, an increased dose of 90 mg once daily may improve efficacy. After the patient’s clinical condition stabilizes, it is advisable to reduce the dose by titration to 60 mg once daily. If no enhancement of therapeutic effect is observed, other treatment options should be considered.

For chronic low back pain the recommended dose is 60 mg once daily. The duration of treatment should not exceed 12 weeks.

For conditions accompanied by acute pain, Dolocox^® should be used only during the acute symptomatic period.

For acute gouty arthritis the recommended dose is 120 mg once daily. The duration of use of the drug at a dose of 120 mg is no more than 8 days.

Acute pain after dental surgery: the recommended dose is 90 mg once daily. For the treatment of acute pain after dental surgery, Dolocox^® should be used only during the acute symptomatic period for no more than 3 days.

Doses exceeding those recommended for each indication either do not provide additional efficacy or have not been studied. Thus

• The daily dose for osteoarthritis should not exceed 60 mg;
• The daily dose for rheumatoid arthritis should not exceed 90 mg;
• The daily dose for ankylosing spondylitis should not exceed 90 mg;
• The daily dose for chronic low back pain should not exceed 60 mg; maximum duration of treatment is limited to 12 weeks;
• The daily dose for acute gouty arthritis should not exceed 120 mg; maximum duration of treatment is limited to 8 days;
• The daily dose for pain relief after dental surgery should not exceed 90 mg; for a period not exceeding 3 days.

Since the risk of cardiovascular complications with the use of selective COX-2 inhibitors may increase depending on the dose and duration of therapy, the shortest possible course and the lowest effective daily dose should be used. Periodic assessment of the patient’s need for symptom relief and their response to therapy should be conducted (see section “Special Instructions”).

Special Patient Groups

Elderly Patients
Dose adjustment in elderly patients is not required. As with the use of other drugs in elderly patients, caution should be exercised when using Dolocox^® (see section “Special Instructions”).

Patients with Hepatic Impairment

Regardless of the indication for use, patients with mild hepatic impairment (Child-Pugh score 5-6) should not exceed a dose of 60 mg once daily, patients with moderate hepatic impairment (Child-Pugh score 7-9) should not exceed a dose of 30 mg once daily. Caution is recommended when using Dolocox^® in patients with moderate hepatic impairment, as clinical experience with etoricoxib in this patient group is limited. Due to the lack of clinical experience with etoricoxib in patients with severe hepatic impairment (Child-Pugh score >10), the drug is contraindicated for this patient group (see sections “Pharmacokinetics”, “Contraindications” and “Special Instructions”).

Patients with Renal Impairment

Dose adjustment in patients with CrCl >30 ml/min is not required (see section “Pharmacokinetics”). The use of etoricoxib in patients with CrCl <30 ml/min is contraindicated (see sections “Contraindications” and “Special Instructions”).

Children

Etoricoxib is contraindicated for children and adolescents under 16 years of age (see section “Contraindications”).

Adverse Reactions

Summary of Safety Profile

The safety of etoricoxib was evaluated in clinical studies involving 9295 participants, including 6757 patients with OA, RA, chronic low back pain, and ankylosing spondylitis (approximately 600 patients with OA or RA received treatment for one year or longer). In clinical studies, the adverse event profile was similar in patients with OA or RA who took Etoricoxib for 1 year or longer.

In a clinical study of acute gouty arthritis, patients received Etoricoxib at a dose of 120 mg/day for 8 days. The adverse event profile in this study was generally the same as in the combined OA, RA, and chronic low back pain studies.

In the Cardiovascular Safety Assessment Program, which included data from 3 active-controlled studies, 17412 patients with OA or RA received Etoricoxib at a dose of 60 mg or 90 mg for an average of 18 months (see section “Pharmacological Action”).

In clinical studies of acute postoperative pain associated with dental surgery, in which 614 patients received Etoricoxib at a dose of 90 mg or 120 mg, the adverse event profile was generally similar to the profile in the combined OA, RA, and chronic low back pain studies.

List of Adverse Reactions (AR)

The following ARs were reported more frequently with the drug than with placebo in clinical studies including patients with OA, RA, chronic low back pain, or ankylosing spondylitis who took Etoricoxib at a dose of 30 mg, 60 mg, or 90 mg with dose escalation to the recommended dose for up to 12 weeks, in the MEDAL Program studies lasting up to 3.5 years, in short-term acute pain studies for up to 7 days, and during post-marketing use. According to frequency reported in the clinical study database: very common (>1/10), common (from >1/100 to <1/10), uncommon (from >1/1000 to <1/100), rare (from >1/10000 to <1/1000), very rare (<1/10000).

Infectious and parasitic diseases common – alveolar osteitis; uncommon – gastroenteritis, upper respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders uncommon – anemia (mainly as a result of gastrointestinal bleeding), leukopenia, thrombocytopenia.

Immune system disorders: uncommon – hypersensitivity reactions^1,3; rare – angioedema, anaphylactic/anaphylactoid reactions, including shock¹.

Metabolism and nutrition disorders common – edema/fluid retention; uncommon – decreased or increased appetite, weight gain.

Psychiatric disorders uncommon – anxiety, depression, concentration impaired, hallucinations¹; rare – confusion¹, restlessness¹.

Nervous system disorders common – dizziness, headache; uncommon – dysgeusia, insomnia, paresthesia/hypoesthesia, somnolence.

Eye disorders: uncommon – blurred vision, conjunctivitis.

Ear and labyrinth disorders uncommon – tinnitus, vertigo.

Cardiac disorders: common – palpitations, arrhythmia¹; uncommon – atrial fibrillation, tachycardia¹, chronic heart failure, nonspecific ECG changes, angina pectoris¹, myocardial infarction⁴.

Vascular disorders: common – hypertension; uncommon – flushing, cerebrovascular accident⁴, transient ischemic attack, hypertensive crisis¹, vasculitis¹.

Respiratory, thoracic and mediastinal disorders: common – bronchospasm¹; uncommon – cough, dyspnea, epistaxis.

Gastrointestinal disorders very common – abdominal pain; common – constipation, flatulence, gastritis, heartburn/gastroesophageal reflux, diarrhea, dyspepsia/epigastric discomfort, nausea, vomiting, esophagitis, mouth ulceration; uncommon – abdominal distension, altered bowel habit, dry mouth, gastroduodenal ulcer, gastric ulcer, including gastrointestinal perforations and bleeding, irritable bowel syndrome, pancreatitis¹.

Hepatobiliary disorders common – increased ALT, increased AST; rare – hepatitis¹; rare² – hepatic failure¹, jaundice¹.

Skin and subcutaneous tissue disorders: common – ecchymosis; uncommon – face edema, pruritus, rash, erythema¹, urticaria¹; rare² – Stevens-Johnson syndrome¹, toxic epidermal necrolysis¹, fixed drug eruption¹.

Musculoskeletal and connective tissue disorders: uncommon – muscle cramps, musculoskeletal pain/stiffness.

Renal and urinary disorders: uncommon – proteinuria, increased blood creatinine, decompensated renal failure/renal failure¹.

General disorders and administration site conditions common – asthenia/fatigue, influenza-like illness; uncommon – chest pain.

Investigations: uncommon – increased blood urea nitrogen, increased creatine phosphokinase, hyperkalemia, increased uric acid; rare – decreased blood sodium.

¹This adverse reaction was identified during post-marketing surveillance. Its reporting frequency is estimated based on the highest frequency observed in clinical trials, pooled by dose and indication.

²The frequency category “Rare” was determined in accordance with the guideline (version 2, September 2009) for the Summary of Product Characteristics (SmPC) based on the calculated upper bound of the 95% confidence interval for 0 events, considering the number of patients receiving Etoricoxib in the pooled Phase III data analysis by dose and indication (n=15470).

³Hypersensitivity includes the terms “allergy”, “drug allergy”, “drug hypersensitivity”, “hypersensitivity”, “hypersensitivity unspecified”, “hypersensitivity reaction”, and “nonspecific allergy”.

⁴Based on data from long-term placebo-controlled and active-controlled clinical trials, the use of selective COX-2 inhibitors increases the risk of serious arterial thrombotic events, including myocardial infarction and stroke. Based on available data, it is unlikely that the absolute risk of these events exceeds 1% per year (uncommon).

The following serious adverse events have been reported in association with NSAID use and cannot be excluded for etoricoxib: nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

If any of the above side effects worsen, or if any other side effects occur, the patient should inform their doctor.

Contraindications

• Hypersensitivity to any component of the drug;
• Active peptic ulcer disease, active gastrointestinal bleeding;
• Complete or incomplete syndrome of bronchial asthma, acute rhinitis, recurrent nasal and sinus polyposis, and intolerance to acetylsalicylic acid or other NSAIDs (including history);
• Severe hepatic impairment (serum albumin <25 g/l or ≥10 points on the Child-Pugh scale);
• Severe renal failure (CrCl <30 ml/min);
• Progressive kidney disease;
• Inflammatory bowel disease;
• Chronic heart failure (NYHA functional class II-IV);
• Uncontrolled arterial hypertension, where blood pressure readings consistently exceed 140/90 mm Hg;
• Confirmed coronary artery disease, peripheral arterial disease and/or cerebrovascular disease;
• Confirmed hyperkalemia;
• Pregnancy;
• Breastfeeding period;
• Children under 16 years of age;
• Rare hereditary galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption (the drug contains lactose monohydrate).

With caution

• Patients at increased risk of gastrointestinal complications due to NSAID use; elderly, concurrently taking other NSAIDs, including acetylsalicylic acid, or patients with a history of gastrointestinal diseases such as peptic ulcer and gastrointestinal bleeding;
• Patients with a history of risk factors for cardiovascular complications, such as dyslipidemia/hyperlipidemia, diabetes mellitus, arterial hypertension, smoking;
• Patients with a history of heart failure, left ventricular dysfunction or arterial hypertension, and patients with pre-existing edema and fluid retention;
• Patients with mild hepatic impairment (5-6 points on the Child-Pugh scale) should not exceed the dose of 60 mg once daily. Patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale) must not exceed the dose of 30 mg once daily;
• Patients with dehydration;
• Patients with renal impairment, concurrently using ACE inhibitors, diuretics, angiotensin II antagonists, especially the elderly;
• Patients with CrCl <60 ml/min;
• Patients with pre-existing significant renal impairment, compromised renal function, decompensated heart failure or liver cirrhosis, at risk during long-term NSAID use.

Caution should be exercised with concomitant therapy with the following drugs

• Anticoagulants (e.g., warfarin);
• Antiplatelet agents (e.g., acetylsalicylic acid, clopidogrel);
• Drugs metabolized by sulfotransferases.

Use in Pregnancy and Lactation

Pregnancy

There are no clinical data on the use of etoricoxib during pregnancy.

In experimental animal studies, toxic effects on the reproductive system were observed. The potential risk in pregnant women is unknown. The use of etoricoxib, like other drugs that inhibit prostaglandin synthesis, may lead to suppression of uterine contractions and in the last trimester of pregnancy – to premature closure of the fetal ductus arteriosus.

Etoricoxib is contraindicated during pregnancy (see section “Contraindications”). If pregnancy occurs during treatment, Etoricoxib should be discontinued.

Breastfeeding period

It is not known whether Etoricoxib is excreted in human milk. In lactating rats, Etoricoxib is excreted in milk.

If it is necessary to use the drug during lactation, the issue of discontinuing breastfeeding should be decided (see section “Contraindications”).

Fertility

The use of etoricoxib, like other COX-2 inhibiting drugs, is not recommended for women who are planning a pregnancy.

Use in Hepatic Impairment

The drug is contraindicated in patients with severe hepatic impairment (>10 points on the Child-Pugh scale). Caution is recommended when using Dolocox^®in patients with moderate hepatic impairment, as clinical experience with etoricoxib in this patient group is limited.

Use in Renal Impairment

The use of etoricoxib in patients with CrCl <30 ml/min is contraindicated. Dose adjustment in patients with CrCl >30 ml/min is not required.

Pediatric Use

The drug is contraindicated for children and adolescents under 16 years of age.

Geriatric Use

Dose adjustment in elderly patients is not required. As with the use of other drugs in elderly patients, caution should be exercised when using Dolocox^®

Special Precautions

Effect on the gastrointestinal tract

Cases of complications from the upper gastrointestinal tract (perforations, ulcers or bleeding), sometimes fatal, have been observed in patients receiving Etoricoxib. Caution is advised when treating patients at high risk of gastrointestinal complications with NSAIDs, particularly the elderly, patients concurrently taking other NSAIDs, including acetylsalicylic acid, as well as patients with a history of gastrointestinal diseases such as ulcer or gastrointestinal bleeding.

There is an additional increased risk of gastrointestinal adverse reactions (gastrointestinal ulcers or other gastrointestinal complications) with the concomitant use of etoricoxib and acetylsalicylic acid (even in low doses). In long-term clinical trials, no significant differences in gastrointestinal safety were observed with the use of selective COX-2 inhibitors in combination with acetylsalicylic acid compared to the use of NSAIDs in combination with acetylsalicylic acid (see section “Pharmacological properties”).

Effect on the cardiovascular system.

Results from clinical trials suggest that the use of drugs of the selective COX-2 inhibitor class may be associated with a risk of thrombotic events (especially myocardial infarction and stroke) relative to placebo and some NSAIDs. Since the risk of cardiovascular disease with etoricoxib may increase with increasing dose and duration of use, the shortest possible duration of use and the lowest effective daily dose should be selected. The patient’s need for symptomatic treatment and response to therapy should be periodically assessed, especially for patients with osteoarthritis (see sections “Pharmacological properties”, “Contraindications”, “Dosage and administration” and “Adverse reactions”).

Patients with significant risk factors for cardiovascular complications (such as hypertension, hyperlipidemia, diabetes mellitus, smoking) should be prescribed Etoricoxib only after careful assessment of benefit and risk (see section “Pharmacological properties”).

Selective COX-2 inhibitors are not a substitute for acetylsalicylic acid in the prevention of cardiovascular disease, as they do not have a sufficient effect on platelets. Therefore, antiplatelet therapy should not be discontinued (see sections “Pharmacological properties” and “Drug interactions”).

Effect on renal function.

Renal prostaglandins may play a compensatory role in maintaining renal perfusion. Therefore, under conditions that adversely affect renal perfusion, the use of Dolocox^® may cause a decrease in prostaglandin formation and a decrease in renal blood flow, and thus impair renal function. The greatest risk of this reaction exists for patients with significant renal impairment, decompensated heart failure, or a history of cirrhosis. In such patients, renal function should be monitored.

Fluid retention, edema and hypertension.

As with the use of other drugs that inhibit prostaglandin synthesis, fluid retention, edema, and hypertension have been observed in patients using Etoricoxib. The use of all NSAIDs, including Etoricoxib, may be associated with the onset or recurrence of chronic heart failure. Information on the dose-dependent effect of etoricoxib is provided in the “Pharmacological properties” section. Caution should be exercised when prescribing Dolocox^® to patients with a history of heart failure, left ventricular dysfunction, or hypertension, as well as to patients with pre-existing edema from any other cause. If clinical signs of deterioration appear in such patients, appropriate measures should be taken, including discontinuation of etoricoxib.

The use of etoricoxib, especially at high doses, may be associated with more frequent and severe hypertension than with the use of some other NSAIDs and selective COX-2 inhibitors. During treatment with etoricoxib, special attention should be paid to blood pressure control (see section “Contraindications”), which should be monitored within 2 weeks after starting treatment and periodically thereafter. If blood pressure increases significantly, alternative treatment should be considered.

Effect on hepatic function.

In clinical trials lasting up to 1 year, approximately 1% of patients treated with etoricoxib at doses of 30 mg, 60 mg, and 90 mg daily experienced elevated ALT and/or AST (approximately 3 times or more the upper limit of normal).

All patients with symptoms and/or signs of liver dysfunction, as well as patients with abnormal liver function tests, should be monitored. If signs of liver insufficiency appear or persistent abnormalities in liver function tests (3 times above the upper limit of normal) are detected, Dolocox^® should be discontinued.

General instructions.

If a patient experiences worsening function of any of the organ systems mentioned above during treatment, appropriate measures should be taken and discontinuation of etoricoxib should be considered. When using etoricoxib in elderly patients and in patients with impaired renal, hepatic, or cardiac function, appropriate medical supervision is necessary.

Treatment with etoricoxib should be initiated with caution in patients with dehydration. Rehydration is recommended before starting etoricoxib.

During post-marketing surveillance, very rare cases of serious skin reactions have been reported with the use of NSAIDs and some selective COX-2 inhibitors. Some of these (including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) were fatal (see section “Adverse reactions”). The risk of such reactions is highest at the beginning of therapy, in most cases within the first month of treatment. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported in patients receiving Etoricoxib (see section “Adverse reactions”). The use of some selective COX-2 inhibitors has 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.

The use of etoricoxib may mask fever or other signs of inflammation.

Caution should be exercised when co-administering etoricoxib with warfarin or other oral anticoagulants (see section “Drug interactions”).

The use of etoricoxib, like other drugs that inhibit COX and prostaglandin synthesis, is not recommended for women who are planning a pregnancy (see section “Pharmacological properties” and section “Pregnancy and lactation”).

Dolocox^® contains lactose. Patients with rare hereditary conditions such as lactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effect on ability to drive and operate machinery

Patients who experience spatial disorientation, dizziness, or drowsiness during the use of etoricoxib should refrain from driving and operating complex machinery.

Overdose

In clinical trials, single doses of etoricoxib up to 500 mg or multiple doses up to 150 mg/day for 21 days did not cause significant toxic effects. Reports of acute etoricoxib overdose have been received, but in most cases no adverse reactions were reported.

Symptoms the most common adverse reactions were consistent with the safety profile of etoricoxib (e.g., gastrointestinal disorders, cardiorespiratory events).

Treatment in case of overdose, it is advisable to employ usual supportive measures, such as removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring and, if necessary, supportive therapy.

Etoricoxib is not removed by hemodialysis; the removal of etoricoxib by peritoneal dialysis has not been studied.

Drug Interactions

Pharmacodynamic interactions

Oral anticoagulants (warfarin). In patients stabilized on long-term warfarin therapy, administration of etoricoxib 120 mg once daily was associated with an approximately 13% increase in prothrombin time INR. Consequently, in patients receiving oral anticoagulants, prothrombin time INR should be carefully monitored at the start of treatment or when changing the dose of Dolocox^®, especially in the first few days.

Diuretics, ACE inhibitors and angiotensin II antagonists. NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), the concomitant use of an ACE inhibitor or angiotensin II antagonist and COX-inhibiting drugs may lead to further deterioration of renal function, including possible development of acute renal failure, which is usually reversible. The possibility of such interactions should be considered in patients taking Etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, such a combination should be prescribed with caution, especially in elderly patients. At the start of combination therapy and periodically thereafter, adequate fluid replenishment should be ensured and monitoring of renal function should be considered.

Acetylsalicylic acid. In a study involving healthy volunteers, Etoricoxib at a dose of 120 mg/day at steady state did not affect the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Dolocox^® can be used concomitantly with low-dose acetylsalicylic acid intended for the prevention of CV diseases. However, the concomitant administration of low-dose acetylsalicylic acid and Dolocox^® may lead to an increased incidence of gastrointestinal ulceration or other complications compared with using Dolocox^® alone. Concomitant use of etoricoxib with acetylsalicylic acid at doses exceeding those recommended for CV disease prophylaxis, as well as with other NSAIDs, is not recommended (see sections “Pharmacological action”, “Special instructions”).

Cyclosporine and tacrolimus. The interaction of etoricoxib with these drugs has not been studied; however, concomitant use of NSAIDs with cyclosporine or tacrolimus may increase the nephrotoxic effect of these drugs. When etoricoxib is used concomitantly with any of these drugs, renal function should be monitored.

Pharmacokinetic Interaction

Effect of Etoricoxib on the Pharmacokinetics of Other Drugs

Lithium. NSAIDs reduce the renal excretion of lithium and consequently increase plasma lithium concentrations. Frequent monitoring of serum lithium concentration and dose adjustment of lithium is recommended during the period of concomitant use with NSAIDs and upon NSAID discontinuation.

Methotrexate. Two studies examined the effects of etoricoxib at doses of 60, 90, and 120 mg once daily for 7 days in patients receiving methotrexate once weekly at doses ranging from 7.5 to 20 mg for RA. Etoricoxib at doses of 60 and 90 mg had no effect on methotrexate plasma concentrations and renal clearance. In one study, Etoricoxib 120 mg had no effect on methotrexate plasma concentration (as measured by AUC change) or renal clearance. In another study, Etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and decreased methotrexate renal clearance by 13%. When Dolocox^® and methotrexate are administered concomitantly, adequate monitoring for the possible appearance of methotrexate toxic effects should be carried out.

Oral contraceptives. Etoricoxib administered at 60 mg for 21 days with oral contraceptives containing 35 mcg ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone increased the steady-state AUC_0-24 for EE by 37%. Etoricoxib administered at 120 mg with the aforementioned oral contraceptives simultaneously or 12 hours apart increased the steady-state AUC_0-24 for EE by 50-60%. This increase in EE concentration should be considered when selecting an appropriate oral contraceptive for concomitant use with Dolocox^®. Increased EE exposure may lead to an increased incidence of adverse events associated with oral contraceptives (e.g., venous thromboembolism in women at risk).

Hormone replacement therapy (HRT). Administration of etoricoxib 120 mg concomitantly with hormone replacement therapy drugs containing 0.625 mg conjugated estrogens for 28 days increased the mean steady-state AUC_0-24 of unconjugated estrone (41%), equilin (76%), and 17-β-estradiol (22%). The effect of etoricoxib doses recommended for long-term use (30, 60, and 90 mg) has not been studied. Etoricoxib 120 mg altered the AUC_0-24 exposure of these estrogenic components to less than double that observed with monotherapy with the conjugated estrogen-containing drug when its dose was increased from 0.625 mg to 1.25 mg. The clinical significance of such increases is unknown. The use of a combination of etoricoxib and a drug containing higher doses of conjugated estrogens has not been studied. The increase in estrogen concentrations should be considered when selecting a hormonal drug for postmenopausal use concomitantly with etoricoxib, as increased estrogen exposure may increase the risk of adverse events associated with HRT.

Prednisone/prednisolone. In drug interaction studies, Etoricoxib had no clinically significant effect on the pharmacokinetics of prednisone/prednisolone.

Digoxin. When etoricoxib 120 mg once daily was administered for 10 days to healthy volunteers, no change in the steady-state plasma AUC_0-24 or effect on the renal excretion of digoxin was observed. An increase in the C_max of digoxin (by approximately 33%) was noted. Such an increase is generally not significant for most patients. However, patients at high risk of digoxin toxicity should be monitored when etoricoxib and digoxin are used concomitantly.

Effect of Etoricoxib on drugs metabolized by sulfotransferases. Etoricoxib is an inhibitor of human sulfotransferase (particularly SULT1E1) and may increase serum concentrations of EE. Since there is currently insufficient data on the effects on various sulfotransferases, and their clinical significance for the use of many drugs is still under investigation, Etoricoxib should be co-administered with caution with other drugs that are metabolized primarily by human sulfotransferases (e.g., oral salbutamol and minoxidil).

Effect of Etoricoxib on drugs metabolized by cytochrome P450 isoenzymes. Based on in vitro results, Etoricoxib is not expected to inhibit cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4. In a study involving healthy volunteers, daily administration of etoricoxib 120 mg had no effect on hepatic CYP3A4 activity, according to the erythromycin breath test results.

Effect of other drugs on the pharmacokinetics of etoricoxib

The primary metabolic pathway of etoricoxib is dependent on cytochrome P450 enzymes. The CYP3A4 isoenzyme appears to be involved in the in vivo metabolism of etoricoxib. In vitro studies suggest that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 isoenzymes may also catalyze the primary metabolic pathway, but their quantitative characteristics in vivo have not been studied.

Ketoconazole. Ketoconazole is a potent inhibitor of the CYP3A4 isoenzyme. When ketoconazole was administered to healthy volunteers at a dose of 400 mg once daily for 11 days, it had no clinically significant effect on the pharmacokinetics of a single 60 mg dose of etoricoxib (AUC increased by 43%).

Voriconazole and miconazole. Concomitant administration of strong CYP3A4 isoenzyme inhibitors (oral voriconazole or oral miconazole gel) and etoricoxib caused a slight increase in etoricoxib exposure, which based on published data was not considered clinically significant.

Rifampicin. Concomitant administration of etoricoxib and rifampicin, a potent cytochrome P450 inducer, resulted in a 65% decrease in etoricoxib plasma concentration. This interaction may be accompanied by a recurrence of symptoms when etoricoxib is used concomitantly with rifampicin. Although these data may indicate a need for dose increase, the use of etoricoxib at doses exceeding those recommended for each indication has not been studied and is therefore not recommended (see section “Dosage and administration”).

Antacids. Antacids have no clinically significant effect on the pharmacokinetics of Dolocox^®.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.