Celecoxib (Page 7 of 11)

8.7 Renal Impairment

Celecoxib is not recommended in patients with severe renal insufficiency [see WARNINGS AND PRECAUTIONS (5.6) and CLINICAL PHARMACOLOGY (12.3)].

8.8 Poor Metabolizers of CYP2C9 Substrates

In patients who are known or suspected to be poor CYP2C9 metabolizers (i.e., CYP2C9*3/*3) based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) administer celecoxib capsules starting with half the lowest recommended dose. Alternative management should be considered in JRA patients identified to be CYP2C9 poor metabolizers. [see DOSAGE AND ADMINISTRATION (2.6) and CLINICAL PHARMACOLOGY (12.5)].

10 OVERDOSAGE

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occured, but were rare [see WARNINGS AND PRECAUTIONS (5.1, 5.2, 5.4, 5.6)].

No overdoses of celecoxib were reported during clinical trials. Doses up to 2400 mg/day for up to 10 days in 12 patients did not result in serious toxicity. No information is available regarding the removal of celecoxib by hemodialysis, but based on its high degree of plasma protein binding (>97%) dialysis is unlikely to be useful in overdose.

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

11 DESCRIPTION

Celecoxib capsules is a nonsteroidal anti-inflammatory drug, available as capsules containing 50 mg, 100 mg, 200 mg and 400 mg celecoxib for oral administration. The chemical name is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole. The molecular weight is 381.38. Its molecular formula is C17 H14 F3 N3 O2 S, and it has the following chemical structure:

image-01

Celecoxib is a white to off-white powder with a pKa of 11.1 (sulfonamide moiety). Celecoxib is hydrophobic (log P is 3.5) and is practically insoluble in aqueous media at physiological pH range.

The inactive ingredients in celecoxib include: black iron oxide, croscarmellose sodium, FD&C blue #1, FD&C red #40, gelatin, lactose monohydrate, magnesium stearate, potassium hydroxide, povidone, propylene glycol, shellac, sodium lauryl sulphate, titanium dioxide, red iron oxide and yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Celecoxib has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of COX-2.

Celecoxib is a potent inhibitor of prostaglandin synthesis in vitro. Celecoxib concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Since celecoxib is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.2 Pharmacodynamics

Platelets

In clinical trials using normal volunteers, celecoxib capsules at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses) had no effect on reduction of platelet aggregation or increase in bleeding time. Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib.

Fluid Retention

Inhibition of PGE2 synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2 appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.

12.3 Pharmacokinetics

Celecoxib exhibits dose-proportional increase in exposure after oral administration up to 200 mg twice daily and less than proportional increase at higher doses. It has extensive distribution and high protein binding. It is primarily metabolized by CYP2C9 with a half-life of approximately 11 hours.

Absorption

Peak plasma levels of celecoxib occur approximately 3 hours after an oral dose. Under fasting conditions, both peak plasma levels (Cmax ) and area under the curve (AUC) are roughly dose-proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in Cmax and AUC [see Food Effects]. Absolute bioavailability studies have not been conducted. With multiple dosing, steady-state conditions are reached on or before Day 5. The pharmacokinetic parameters of celecoxib in a group of healthy subjects are shown in Table 4.

Table 4 Summary of Single Dose (200 mg) Disposition Kinetics of Celecoxib in Healthy Subjects1

1 Subjects under fasting conditions (n=36, 19 to 52 yrs.)

Mean (% CV ) PK Parameter Values
Cm a x , ng / mL Tm a x , hr Effective t1 / 2 , hr Vs s / F , L CL / F , L / hr
705 (38) 2.8 (37) 11.2 (31) 429 (34) 27.7 (28)

Food Effects

When celecoxib capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media.

Coadministration of celecoxib with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. Celecoxib, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption.

In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax , Tmax or t1/2 after administration of capsule contents on applesauce [see DOSAGE AND ADMINISTRATION (2)].

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