Celecoxib

Celecoxib is a Cyclooxygenase-2 (COX-2) inhibitor / non-steroidal anti-inflammatory drugs (NSAIDs) belonging to Analgesic class.

Celecoxib is an NSAID used to treat osteoarthritis, rheumatoid arthritis, acute pain, menstrual symptoms, and to reduce polyps is familial adenomatous polyposis.

Celecoxib is absorbed rapidly in the gastrointestinal tract When a single oral dose of 200 mg was given to healthy research subjects, the peak plasma levels of celecoxib occurred within 3 hours. The Cmax is 705 ng/mL. When multiple doses are given, steady-state concentrations are reached on or before day 5. When taken with a high-fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. The apparent volume of distribution of celecoxib at steady state (Vss/F) is about 429, which suggests wide distribution into various tissues. The protein binding of celecoxib is 97%, and it is primarily bound to albumin. Celecoxib is mainly Metabolised in the liver by CYP2C9 to form inactive metabolites such as a primary alcohol, corresponding carboxylic acid and its glucuronide conjugate. Celecoxib is excreted mainly Via urine as 27% as metabolites, <3% as unchanged drug, faeces approximately 57% as metabolites, <3% as unchanged drug.

Celecoxib shows common side effects like Gas or bloating, sore throat, cold symptoms, constipation, dizziness, dysgeusia.

Celecoxib is available in the form of Oral capsule and solution.

Celecoxib is available in India, US, Russia, Spain, Canada, Japan, Australia, China, and Singapore.

Celecoxib is an Analgesic belonging to the class Cyclooxygenase-2 (COX-2) inhibitor / non-steroidal anti-inflammatory drug (NSAIDs).

Celecoxib inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase-2 (COX-2), which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties. Celecoxib does not inhibit cyclooxygenase-1 (COX-1) at therapeutic concentrations.

The onset of action of Celecoxib is not clinically established.

The duration of action of Celecoxib is 8-12 hours.

The peak plasma levels of celecoxib occurred within 3 hours.

Celecoxib is available in the form of Oral capsule and Oral solution.

Celecoxib capsule and solution is taken orally, usually in divided dose.

Celecoxib is used to relieve pain and inflammation in conditions like Arthritis, Dysmenorrhea. Drink adequate amount of water to minimize stomach irritation. Close monitoring of liver function is necessary while receiving Celecoxib.

Celecoxib is a Cyclooxygenase-2 (COX-2) inhibitor / non-steroidal anti-inflammatory drugs (NSAIDs) belonging to Analgesic class.

Celecoxib inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase-2 (COX-2), which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties. Celecoxib does not inhibit cyclooxygenase-1 (COX-1) at therapeutic concentrations.

Celecoxib is approved for use in the following clinical indications

• Osteoarthritis (OA) For the management of the signs and symptoms of OA
• Rheumatoid Arthritis (RA) For the management of the signs and symptoms of RA
• Juvenile Rheumatoid Arthritis (JRA) For the management of the signs and symptoms of JRA in patients 2 years and older.
• Ankylosing Spondylitis (AS) For the management of the signs and symptoms of AS.
• Acute Pain For the management of acute pain in
• Primary Dysmenorrhea For the management of primary dysmenorrhea.

Adult Dose

• Acute pain

Oral: Initial: 400 mg, followed by 200 mg approximately 12 hours later, if needed, on day 1; thereafter, 200 mg twice daily as needed or scheduled; maximum daily maintenance dose: 400 mg/day. In select patients (eg, advanced age, comorbidity), some experts may initiate at 100 mg twice daily.

• Anti-inflammatory

Oral: Initial: 200 mg once daily or 100 mg twice daily; may increase to a maximum of 200 mg twice daily for several weeks during a disease flare until the flare resolves.

• Dysmenorrhea

Oral: Initial: 400 mg, followed by an additional 200 mg approximately 12 hours later, if needed, on day 1; maintenance dose: 200 mg twice daily as needed; maximum daily maintenance dose: 400 mg/day. Begin at menses onset or 1 to 2 days prior to onset of menses for severe symptoms; usual duration: 1 to 5 days.

• Gout, treatment

Oral: Initial: 400 mg, followed by 200 mg approximately 12 hours later on day 1, then continue 200 mg twice daily thereafter; maximum daily maintenance dose: 400 mg/day. Begin within 24 to 48 hours of flare onset; discontinue 2 to 3 days after resolution of clinical signs; usual duration: 5 to 7 days.

• Migraine, acute treatment

Oral: 120 mg as a single dose. Maximum: 120 mg per 24 hours.

• Osteoarthritis

Oral: 200 mg once daily or 100 mg twice daily.

Pediatric Dose:

• Juvenile idiopathic arthritis

Children ≥2 years and Adolescents: Consider alternate therapy in JIA patients who are poor metabolizers; experience in adult patients suggests dosing adjustment.

Celecoxib is available in various strengths as 50 mg; 100 mg; 200 mg; 400 mg; 120mg/4.8ml.

Celecoxib is available in the form of Oral capsule and Oral solution.

• Dosage Adjustment in Kidney Patient

CrCl ≥60 mL/minute: No dosage adjustment necessary (<1% of the drug excreted in the urine).

CrCl >30 to <60 mL/minute: No dosage adjustment necessary (<1% of the drug excreted in the urine). However, use the lowest effective dose for the shortest duration possible. Use of analgesics other than nonsteroidal anti-inflammatory drugs (NSAIDs) or topical NSAIDs may be preferred. Avoid use in patients at high risk for acute kidney injury (ie, volume depleted, hypotensive, elderly, or taking concurrent nephrotoxic medications).

CrCl ≤30 mL/minute: Avoid use due to increased risk of acute kidney injury; Use of analgesics other than NSAIDs or topical NSAIDs are preferred. However, in select patients where alternatives are not effective, after careful assessment of risks versus benefits, use of celecoxib may be considered; use the lowest effective dose for the shortest duration possible with close monitoring of kidney function.

• Dosage Adjustment in Hepatic impairment Patient

Mild impairment (Child-Pugh class A): No dosage adjustment necessary; AUC increased ~40% in mild hepatic impairment compared with healthy subjects.

Moderate impairment (Child-Pugh class B): Reduce dose by 50%.

Severe impairment (Child-Pugh class C): Use is not recommended.

Abnormal liver function tests (persistent or worsening): Discontinue use.

Celecoxib is contraindicated in patients with

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to celecoxib, any components of the drug product.
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs, have been reported in such patients.
• In the setting of coronary artery bypass graft (CABG) surgery.
• In patients who have demonstrated allergic-type reactions to sulfonamides.

• Medication-overuse headache

Acute migraine agents used more frequently than recommended (eg, >14 days per month) may lead to worsening of headaches (medication-overuse headache). Symptoms include migraine-like daily headaches or a marked increase in frequency of migraine attacks. Withdrawal treatment may be necessary in the setting of overuse.

• Sulfonamide ("sulfa") allergy

The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO₂NH₂). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low. Mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are not well understood, and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (SJS/TEN), some clinicians choose to avoid exposure to these classes.

• Asthma

The manufacturer's labeling states to not administer to patients with aspirin-sensitive asthma due to severe and potentially fatal bronchospasm that has been reported in such patients having received aspirin and the potential for cross reactivity with other NSAIDs. The manufacturer also states to use with caution in patients with other forms of asthma. However, in patients with known aspirin-exacerbated respiratory disease (AERD), the use of celecoxib initiated at a low dose with gradual titration in patients with stable, mild to moderate persistent asthma has been used without incident.

• Bariatric surgery

Gastric ulceration: Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations/perforations may occur. Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain.

• Cytochrome P450 isoenzyme 2C9 deficiency

Use with caution in patients with known or suspected deficiency of cytochrome P450 isoenzyme 2C9 (CYP 2C9*3/*3); poor metabolizers may have higher plasma levels due to reduced metabolism; consider reduced initial doses (initiate therapy with 25% to 50% of the lowest starting dose [eg, 50% to 75% dose reduction]). Alternate therapies should be considered in patients with juvenile idiopathic arthritis (JIA) who are poor metabolizers of CYP2C9.

• Hepatic impairment

Use with caution in patients with moderate hepatic impairment; dosage adjustment recommended. Not recommended for patients with severe hepatic impairment.

• Renal impairment

Use with caution in patients with renal impairment.

Avoid consumption of alcohol it may increases the risk of gastrointestinal irritation.

Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of Celecoxib in breast milk. The calculated average daily infant dose was 10-40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when Celecoxib is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Celecoxib and any potential adverse effects on the breast-fed infant from the Celecoxib or from the underlying maternal condition.

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) in pregnant women can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered this drug during the period of organogenesis.

• Common

Acute myocardial infarction, angina pectoris, chest pain, coronary artery disease, edema, exacerbation of hypertension, palpitations, peripheral edema, tachycardia Alopecia, cellulitis, contact dermatitis, dermatitis, diaphoresis, ecchymoses, erythematous rash, maculopapular rash, pruritus, skin changes, skin photosensitivity, urticaria, xeroderma, Albuminuria, hot flash, hypercholesterolemia, hyperglycemia, hypokalemia, increased nonprotein nitrogen, weight gain, Abdominal pain, anorexia, constipation, diarrhea, diverticulitis of the gastrointestinal tract, dysgeusia, dyspepsia, dysphagia, eructation, esophagitis, flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, hemorrhoids, hiatal hernia, increased appetite, melena, stomatitis, tenesmus, vomiting, xerostomia, Cystitis, dysuria, hematuria, urinary frequency, Anemia, thrombocythemia, increased liver enzymes (<3 x ULN: ≤6%), increased serum alkaline phosphatase, Facial edema, hypersensitivity reaction, Anxiety, depression, drowsiness, fatigue, hypertonia, hypoesthesia, migraine, nervousness, pain, paresthesia, peripheral pain, vertigo, Arthralgia, increased creatine phosphokinase in blood specimen, lower limb cramp, myalgia, synovitis, tendinopathy, Deafness, tinnitus, Increased blood urea nitrogen, increased serum creatinine, nephrolithiasis, Aggravated bronchospasm, bronchitis, bronchospasm, cough, dyspnea, epistaxis, flu-like symptoms, laryngitis, pharyngitis, pneumonia, rhinitis, sinusitis, upper respiratory tract infection, Cyst, fever, Heart failure, pulmonary embolism, syncope, thrombophlebitis, ventricular fibrillation, Gangrene of skin and/or subcutaneous tissue, Cholelithiasis, esophageal perforation, gastrointestinal hemorrhage, hemorrhagic colitis, intestinal obstruction, intestinal perforation, pancreatitis, Thrombocytopenia, Sepsis, Ataxia, cerebrovascular accident, suicidal tendencies, Acute kidney injury, Coronary thrombosis, Erythema multiforme, exfoliative dermatitis, Gastrointestinal inflammation, gastrointestinal perforation, gastrointestinal ulcer, Alveolar osteitis (post-oral surgery patients).

• Rare

Acute coronary syndrome, deep vein thrombosis, hypertension, vasculitis, Acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis of the skin, Hypoglycemia, hyponatremia, Ageusia, Agranulocytosis, aplastic anemia, leukopenia, pancytopenia, Cholestasis, hepatic failure, hepatic necrosis, hepatitis, jaundice, Anaphylaxis, angioedema, drug reaction with eosinophilia and systemic symptoms, fixed drug eruption, nonimmune anaphylaxis, Anosmia, aseptic meningitis, intracranial hemorrhage, Interstitial nephritis, renal papillary necrosis.

• 5-Aminosalicylic Acid Derivatives

Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives.

• Alcohol (Ethyl)

May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination.

• Aliskiren

Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren.

• Alpelisib

May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers).

• Aminoglycosides

Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants.

• Aminolevulinic Acid (Systemic)

Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic).

• Aminolevulinic Acid (Topical)

Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical).

• Angiotensin II Receptor Blockers

May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function.

• Angiotensin-Converting Enzyme Inhibitors

May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors.

• Aspirin

May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Management: Concurrent use of aspirin at doses beyond cardioprotective levels is not recommended. While concurrent use of low-dose aspirin with a COX-2 inhibitor is permissable, patients should be monitored closely for signs/symptoms of GI ulceration/bleeding.

• Bile Acid Sequestrants

May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents.

• Corticosteroids (Systemic)

May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective).

• CYP2C9 Inducers (Moderate)

May decrease the serum concentration of Celecoxib.

• CYP2C9 Inhibitors (Moderate)

May increase the serum concentration of Celecoxib.

• Drospirenone-Containing Products

May enhance the hyperkalemic effect of Nonsteroidal Anti-Inflammatory Agents.

• Ketorolac (Nasal)

May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents.

• Lithium

Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased.

The common side effects of Celecoxib include the following

• Common side effects

Gas or bloating, sore throat, cold symptoms, constipation, dizziness, dysgeusia.

• Rare side effects

Unexplained weight gain, shortness of breath or difficulty breathing, swelling of the abdomen, feet, ankles, or lower legs, diarrhea, nausea, excessive tiredness, unusual bleeding or bruising, itching, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, flu-like symptoms, blisters, fever, rash, hives, swelling of the face, throat, tongue, lips, eyes, or hands, hoarseness, difficulty swallowing or breathing, pale skin, fast heartbeat, cloudy, discolored, or bloody urine, back pain, difficult or painful urination, frequent urination, especially at night.

• Pregnancy

Pregnancy Category C. Pregnancy category D from 30 weeks of gestation onward.

Use of NSAIDs, including Celecoxib, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Celecoxib, in pregnant women starting at 30 weeks of gestation. There are no adequate and well-controlled studies of Celecoxib in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryo-fetal deaths and an increase in diaphragmatic hernias were observed in rats administered celecoxib daily during the period of organogenesis at oral doses approximately 6 times the maximum recommended human dose of 200 mg twice daily. In addition, structural abnormalities (e.g., septal defects, ribs fused, sternebrae fused and sternebrae misshapen) were observed in rabbits given daily oral doses of celecoxib during the period of organogenesis at approximately 2 times the MRHD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as celecoxib, resulted in increased pre- and post-implantation loss. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss.

• Nursing Mothers

Limited data from 3 published reports that included a total of 12 breastfeeding women showed low levels of Celecoxib in breast milk. The calculated average daily infant dose was 10-40 mcg/kg/day, less than 1% of the weight-based therapeutic dose for a two-year old-child. A report of two breastfed infants 17 and 22 months of age did not show any adverse events. Caution should be exercised when Celecoxib is administered to a nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Celecoxib and any potential adverse effects on the breast-fed infant from the Celecoxib or from the underlying maternal condition.

• Pediatric Use

Celecoxib is approved for relief of the signs and symptoms of Juvenile Rheumatoid Arthritis in patients 2 years and older. Safety and efficacy have not been studied beyond six months in children. The long-term cardiovascular toxicity in children exposed to Celecoxib has not been evaluated and it is unknown if long-term risks may be like that seen in adults exposed to Celecoxib or other COX-2 selective and nonselective NSAIDs.

• Geriatric Use

Of the total number of patients who received Celecoxib in pre-approval clinical trials, more than 3,300 were 65-74 years of age, while approximately 1,300 additional patients were 75 years and over. No substantial differences in effectiveness were observed between these subjects and younger subjects. In clinical studies comparing renal function as measured by the GFR, BUN and creatinine, and platelet function as measured by bleeding time and platelet aggregation, the results were not different between elderly and young volunteers. However, as with other NSAIDs, including those that selectively inhibit COX-2, there have been more spontaneous post-marketing reports of fatal GI events and acute renal failure in the elderly than in younger patients.

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 occurred, but were rare. 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.

• Pharmacodynamic

Celecoxib, an NSAID, is a selective cyclooxygenase-2 (COX-2) inhibitor primarily responsible for inhibition of prostaglandin synthesis. It exhibits anti-inflammatory, analgesic, and antipyretic activities.

• Pharmacokinetics

Absorption

Celecoxib is absorbed rapidly in the gastrointestinal tract When a single oral dose of 200 mg was given to healthy research subjects, the peak plasma levels of celecoxib occurred within 3 hours. The Cmax is 705 ng/mL. When multiple doses are given, steady-state concentrations are reached on or before day 5. When taken with a high-fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%.

Distribution

The apparent volume of distribution of celecoxib at steady state (Vss/F) is about 429, which suggests wide distribution into various tissues. The protein binding of celecoxib is 97%, and it is primarily bound to albumin.

Metabolism and Excretion

Celecoxib is mainly Metabolized in the liver by CYP2C9 to form inactive metabolites such as a primary alcohol, corresponding carboxylic acid and its glucuronide conjugate.

Celecoxib is excreted mainly Via urine as 27% as metabolites, <3% as unchanged drug, faeces approximately 57% as metabolites, <3% as unchanged drug.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020998s050lbl.pdf
• https://go.drugbank.com/drugs/DB00482
• https://www.uptodate.com/contents/celecoxib-drug-information?search=celecoxib&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://www.drugs.com/pregnancy/celecoxib.html
• https://medlineplus.gov/druginfo/meds/a699022.html