Stadloric: Medicine for osteoarthritis and rheumatoid arthritis

2021-06-26 04:36 AM

Stadloric treats the symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA). Relief of signs and symptoms of juvenile idiopathic arthritis (JIA). Alleviate the signs and symptoms of ankylosing spondylitis.

Producer

Stellapharm J.V.

Ingredient

Each tablet: Celecoxib 100mg or 200mg.

Describe

Stadloric 100: No. 2 hard capsule, yellow caps, and milky white bodies, inside contains white to ivory powder.

Stadloric 200: Hard capsule No. 2, cap and body opaque white, printed with the word "STADA" in black, inside containing white to ivory powder.

Pharmacodynamic

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and anti-rheumatic drugs; coxibs.

ATC code: M01AH01.

The mechanism of action of celecoxib is the initial inhibition of prostaglandin synthesis through inhibition of the enzyme cyclooxygenase-2 (COX-2). At therapeutic concentrations in humans, celecoxib does not inhibit the enzyme cyclooxygenase-1 (COX-1). COX-2 is produced in response to an inflammatory agent. This leads to the synthesis and accumulation of inflammatory prostanoids, especially prostaglandin E2, which causes inflammation, edema, and pain. Celecoxib acts as an anti-inflammatory, analgesic, and hypothermic agent in animals by inhibiting the production of inflammatory prostanoids through the inhibition of COX-2. In colon tumors in animals, celecoxib reduced the incidence and multiplication of tumors.

In vivo and ex vivo studies have shown that celecoxib has a very low affinity for the COX-1 enzyme. Therefore, at therapeutic doses, celecoxib has no effect on the prostanoids synthesized by COX-1 activation and, therefore, does not interfere with normal COX-1-related physiological processes in tissues. especially with the stomach, intestines, and platelets.

Pharmacokinetics

Absorb

The pharmacokinetics of celecoxib has been evaluated in approximately 1,500 subjects. When administered under fasting conditions, celecoxib is readily absorbed and reaches peak plasma concentrations after about 2-3 hours. The oral bioavailability of the capsule is 99% compared with the suspension (optimal oral formulation available). When administered in the fasted state, both peak plasma concentrations (Cmax) and area under the curve (AUC) are dose-proportional up to 200 mg twice daily; At higher doses, corresponding increases in Cmax and AUC were lower.

Distribution

The plasma protein binding rate (which is concentration-independent) is approximately 97% at therapeutic plasma concentrations and celecoxib does not preferentially bind to erythrocytes.

Metabolism

Celecoxib is metabolized primarily by cytochrome P450 2C9. Three metabolites with no COX-1 or COX-2 inhibitory activity were identified in human plasma as the primary alcohol, the corresponding carboxylic acid, and its glucuronide conjugate.

The activity of cytochrome P450 2C9 is decreased in individuals with genetic polymorphisms and this leads to decreased enzyme activity, for example, people who are homozygous for the CYP2C9*3 polymorphism.
 
Caution should be exercised when celecoxib is administered to patients with known or suspected poor CYP2C9 metabolizers based on history/experience with other CYP2C9 substrates. Consideration should be given to initiating treatment with half of the lowest recommended dose.

Elimination

Elimination of celecoxib is mainly by hepatic metabolism with less than 1% of the administered dose being excreted unchanged in the urine. Following multiple dosing, the half-life is 8-12 hours and the clearance rate is about 500 mL/min. With multiple doses, steady-state plasma concentrations were achieved by day 5. Intersubject variability in key pharmacokinetic parameters (AUC, Cmax, half-life) was approximately 30%. The mean steady-state volume of distribution is about 500 L/70 kg in healthy adults indicating the extensive distribution of celecoxib into tissues. Preclinical studies have identified the drug to cross the blood-brain barrier.

The influence of food

Administration of the drug with food (rich in fat) slows absorption as shown by Tmax reached after about 4 hours and bioavailability increased by 20%. In healthy volunteers, the systemic absorption (AUC) of celecoxib was comparable to that of the oral whole capsule or the apple juice-soluble form. There was no significant change in Cmax, Tmax, or T1/2 after taking the tablets whole or dissolved in apple juice.

Elderly

In people over 65 years of age, the Cmax and AUC of celecoxib increased by 1.5-2 times. This is mainly related to weight and not to age changes, celecoxib concentrations are higher in lower weight patients and therefore lower average weight elderly individuals have higher celecoxib concentrations. higher than young people. Therefore, older women tend to have higher plasma concentrations than older men. In general, no dose adjustment is necessary. However, for elderly patients who are below average body weight (<50 kg), the lowest recommended dose should be used.

Children

The steady-state pharmacokinetics of celecoxib administered in oral suspension was evaluated in 152 juvenile idiopathic arthritis patients aged 10 kg with juvenile idiopathic arthritis (low positive or negative) in one or several joints, maybe extensive or polyarticular, and the patient has systemic-onset juvenile idiopathic arthritis (with present systemic features of inactivity). Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for weight) of celecoxib increased at a less rate than the increase in body weight, with 10 kg and 25 kg patients predicted to have a clearance. 40% and 24% reduction, respectively, compared with a 70kg rheumatoid arthritis patient.

Using 50 mg capsules twice daily for juvenile idiopathic arthritis weighing 10-25 kg and 100 mg capsules for juvenile idiopathic arthritis weighing 25 kg or more achieved Plasma concentrations were similar to those observed in clinical trials, indicating that the effect of celecoxib was not inferior to that of naproxen 7.5 mg twice daily. Celecoxib has not been studied in patients with juvenile idiopathic arthritis younger than 2 years of age, in patients weighing less than 10 kg, or for a duration exceeding 24 weeks.

Race

A meta-analysis of pharmacokinetic studies predicted approximately 40% higher AUC rates of celecoxib in blacks than in Caucasians. The cause and clinical significance of this problem are unknown.

Liver failure

The plasma concentrations of celecoxib in patients with mild hepatic impairment (Child-Pugh class A) were not significantly different from those in controls of the same age and sex. In patients with moderate hepatic impairment (Child-Pugh class B), serum celecoxib concentrations were approximately 2 times that of the corresponding control group.

Renal failure

In elderly volunteers with age-related decreased glomerular filtration rate (GFR) (mean GFR >65mL/min/1.73m2) and patients with stable chronic renal failure (GFR 35-60mL/min/1, 73m2) The pharmacokinetics of celecoxib were comparable to that in patients with normal renal function. No significant relationship was found between serum creatinine (or creatinine clearance) and celecoxib clearance. Severe renal impairment does not change the clearance of celecoxib because the main route of elimination is through hepatic metabolism to the inactive form.

Effects on the kidneys

The relative roles of COX-1 and COX-2 in renal physiology are not fully known. Celecoxib reduced renal elimination of PGE2 and 6-keto PGF1α (a metabolite of prostacyclin) but did not affect the elimination of serum thromboxane B2 and 11-dehydro-TXB2, a metabolite of thromboxane (both products). of COX-1). Isolated studies have shown that celecoxib does not reduce GFR in elderly patients or in patients with chronic renal failure. These studies also showed a slight decrease in sodium excretion. In studies of patients with arthritis, the incidence of peripheral angioedema was observed to be comparable to that observed in patients receiving nonspecific COX inhibitors (which also inhibit COX-2). ). This is most likely to be seen in patients receiving combination therapy with diuretics. However, no increased rates of hypertension and heart failure were observed, and peripheral angioedema was usually mild and resolved spontaneously.

Indications and uses

Symptomatic treatment of osteoarthritis (OA) and rheumatoid arthritis (RA).

Alleviation of signs and symptoms of juvenile idiopathic arthritis (JIA) in patients 2 years of age and older weighing at least 10 kg.

Alleviate the signs and symptoms of ankylosing spondylitis.

Management of acute pain.

Treatment of primary dysmenorrhea.

Dosage and Administration

How to use

To be taken orally, with or without food.

For patients who have difficulty swallowing capsules, the amount of medicine in the tablets can be added to apple juice, porridge, yogurt or mashed banana to drink together. At that time, the entire amount of medicine must be put into about a small spoon of apple juice, porridge, yogurt or crushed banana at room temperature and must be taken immediately with water. The amount of medicine mixed with apple juice, porridge or yogurt is stable for about 6 hours when stored in the refrigerator (2-8oC). Do not store in the refrigerator the amount of medicine mixed with mashed banana and must be taken immediately.

Dosage

Because the cardiovascular risks of celecoxib may increase with dose and duration, the lowest dose should be used for the shortest possible duration.

Adults

Symptomatic Treatment in Osteoarthritis (OA): The recommended dose of celecoxib is 200 mg as a single dose or 100 mg twice daily.

Symptomatic treatment in rheumatoid arthritis (RA): The recommended dose of celecoxib is 100 mg or 200 mg twice daily.
 
Ankylosing spondylitis (AS): The recommended dose of celecoxib is 200 mg as a single dose or 100 mg twice daily. Some patients may be better off taking a total daily dose of 400 mg.

Acute pain management: The recommended starting dose of celecoxib is 400 mg, with an additional 200 mg dose on the first day if necessary. For the following days, the recommended dose is 200 mg twice daily as needed.

Treatment of primary dysmenorrhea: The recommended starting dose of celecoxib is 400 mg, with an additional 200 mg dose on the first day if necessary. For the following days, the recommended dose is 200 mg twice daily as needed.

Elderly

Generally, no dose adjustment is required. However, in elderly patients weighing less than 50 kg, treatment should be initiated with the lowest recommended dose.

Children

Juvenile idiopathic arthritis (JIA)

Pediatric patients (2 years and older), weighing ≥10 kg to ≤ 25 kg: 50 mg capsule, twice daily.

Pediatric patients (2 years and older), weighing >25 kg: 100 mg capsules, twice daily.

Celecoxib has been studied in juvenile idiopathic arthritis patients aged 2 to 17 years. The safety and efficacy of celecoxib in children have not been studied for more than 6 months or in patients weighing less than 10 kg or in patients with systemic manifestations.

Liver failure

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A). Use half the recommended dose of celecoxib in patients with arthritis or pain in moderate hepatic impairment (Child-Pugh class B).

There are no studies in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment: No dose adjustment is required in patients with moderate to mild renal impairment. There are no clinical studies in patients with severe renal impairment.

CYP2C9 poor metabolizers: Patients with known or suspected CYP2C9 poor metabolizers based on history/experience with other CYP2C9 substrates should use celecoxib with caution. Initiate treatment with ½ of the lowest recommended dose.

Concomitant use with fluconazole: Celecoxib should be used at half the recommended dose in patients being treated with fluconazole, a CYP2C9 inhibitor. Caution should be exercised when celecoxib is coadministered with CYP2C9 inhibitors.

Warning

The risk of cardiovascular thrombosis

Systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs), other than aspirin, may increase the risk of cardiovascular thrombotic events, including myocardial infarction and stroke, which can lead to death. death. This risk may appear as early as the first few weeks of taking the drug and may increase with duration of use. The risk of cardiovascular thrombosis was observed mainly at high doses.

Clinicians should periodically evaluate the occurrence of cardiovascular events, even if the patient has no prior cardiovascular symptoms. Patients should be alerted to the symptoms of a serious cardiovascular event and should seek medical attention as soon as these symptoms appear.

To minimize the risk of adverse events, Stadloric should be used at the lowest effective daily dose for the shortest possible time. Two large, controlled clinical trials showed an increased incidence of myocardial infarction and stroke with the use of another COX-2-selective NSAID for pain during the first 10-14 days after coronary artery bypass graft (CABG) surgery.

Celecoxib is not a substitute for acetylsalicylic acid for the prevention of cardiovascular thromboembolic diseases due to its lack of effect on platelet function. Because celecoxib does not inhibit platelet aggregation, antiplatelet therapy (eg, acetylsalicylic acid) should not be discontinued while celecoxib is being used.

Hypertension

As with all NSAIDs, celecoxib may initiate a hypertensive crisis or worsen an already existing hypertension, both of which may increase the risk of cardiovascular events. Caution should be exercised when NSAIDs, including celecoxib, are used in hypertensive patients. Blood pressure should be closely monitored at the start of treatment with celecoxib as well as throughout treatment.

Fluid retention and edema

As with drugs that inhibit prostaglandin synthesis, edema and fluid retention have been observed in some patients receiving celecoxib. Therefore, patients with pre-existing congestive heart failure or hypertension should be closely monitored. Celecoxib should be used with caution in patients with compromised cardiac function, edema, or other conditions that may be aggravated by fluid retention and edema, including patients on diuretics or at risk. reduced blood volume.

Effects on the digestive tract

Perforation, ulceration, or bleeding of the upper and lower gastrointestinal tract have occurred in patients receiving celecoxib. Patients at risk for these gastrointestinal complications when taking NSAIDs are mostly elderly, patients with cardiovascular disease, patients taking aspirin, glucocorticoids, or other NSAIDs, medical alcohol users, or patients with a history of or ongoing gastrointestinal diseases such as ulcers, bleeding conditions, or inflammation of the gastrointestinal tract. Most incidental reports of celecoxib-related gastrointestinal deaths occurred in the elderly or in frail patients.

Effects on the kidneys

NSAIDs including celecoxib can be nephrotoxic. Clinical trials have shown that celecoxib has renal effects similar to those of other NSAIDs. Patients most at risk of nephrotoxicity are those with impaired renal function, heart failure, impaired liver function, and the elderly, and these patients should be carefully monitored during treatment with celecoxib.

Caution should be exercised when initiating treatment in dehydrated patients. The patient should be rehydrated first before starting treatment with celecoxib.

Progressive kidney disease

Renal function should be closely monitored in patients with the advanced renal disease treated with celecoxib.

Anaphylactic reaction

As with NSAIDs in general, anaphylactoid reactions have occurred in patients receiving celecoxib.

Serious skin reactions

Serious skin reactions, some of which can be fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely with the use of celecoxib. . Patients are often at high risk for these events early in treatment, most of which occur mainly within the first month of treatment, and should be discontinued as soon as skin rash appears. , mucosal damage or any signs of hypersensitivity.

Effects on the liver

There are no studies in patients with severe hepatic impairment (Child-Pugh class C). Do not use celecoxib in patients with severe hepatic impairment, celecoxib should be used with caution in patients with moderate hepatic impairment (Child-Pugh class B) and should be started at half the recommended dose.

Very few serious liver reactions, including fulminant hepatitis (in some cases fatal), hepatic necrosis, and liver failure (some fatal or requiring liver transplantation) have been reported. reported when using celecoxib. Patients with symptoms and/or signs of hepatic impairment or those with abnormal liver function tests should be closely monitored for signs of worsening of liver reactions during treatment with celecoxib. .

Use with oral anticoagulants

Concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding and requires caution. Oral anticoagulants include the warfarin/coumarin class and newer oral anticoagulants (such as apixaban, dabigatran, and rivaroxaban). Cases of serious bleeding have been reported in patients receiving concomitant warfarin or similar agents, some of which have been fatal. Since increased prothrombin time (INR) has been reported, anticoagulant effect/prothrombin time should be monitored in patients receiving warfarin/coumarin anticoagulants after initiation of therapy with celecoxib or adjust the dose of these drugs.

Systemic-onset juvenile idiopathic arthritis

NSAIDs, including celecoxib, should be used with caution in patients with systemic-onset juvenile idiopathic arthritis, due to the risk of disseminated intravascular coagulation. Patients with systemic-onset juvenile idiopathic arthritis receiving celecoxib should be monitored for the development of abnormal coagulation tests.

Overview

With its anti-inflammatory effect, celecoxib can obscure diagnostic markers, such as fever, in the diagnosis of infections.

Concomitant use of celecoxib with non-aspirin NSAIDs should be avoided.

Inhibition of CYP2D6

Celecoxib is a moderate inhibitor of CYP2D6. For drugs metabolized by CYP2D6, the dose of these drugs should be reduced when co-administered with celecoxib or increased when celecoxib is discontinued.

Excipients

Stadloric contains the excipient lactose. This medicine should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

Effects of the drug on the ability to drive and use machinery

The effects of celecoxib on the ability to drive and use machines have not been studied, but based on the pharmacodynamic properties and general description of the safety of the drug, it is expected to have no effect.

Overdose

Clinical experience with overdose is limited. Single doses up to 1200 mg or multiple doses (2 times daily) for a total dose of 1200 mg in healthy subjects showed no clinically significant adverse effects. In case of a suspected overdose, appropriate medical assistance should be instituted. Dialysis is not an effective means of drug removal because the drug is strongly protein-bound.

Contraindications

Celecoxib is contraindicated for:

Patients with a history of hypersensitivity to celecoxib or any of the excipients.

Patients with a history of hypersensitivity to sulfonamides.

Patients with a history of asthma, urticaria, or allergic-type reactions following administration of acetylsalicylic acid (ASA [aspirin]) or other nonsteroidal anti-inflammatory drugs (NSAIDs), including specific cyclooxygenase-inhibitors- 2 (COX-2) other.

Treatment of pain in coronary artery bypass graft (CABG) surgery.

Use in pregnant and lactating women

Fertility

Based on their mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent ovulation, leading to reversible infertility in some women. Women who have difficulty conceiving or are undergoing treatment for infertility should consider discontinuing NSAIDs, including celecoxib.

Pregnant

There are no studies on pregnant women. Some animal studies have shown reproductive toxicity. There are no comparable data in humans. Since celecoxib, as with other prostaglandin synthesis inhibitors, can cause uterine muscle impotence and premature closure of the aortic duct, celecoxib should be avoided during the third trimester of pregnancy.

Celecoxib should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.

Inhibition of prostaglandin synthesis may adversely affect pregnant women. Data from epidemiological studies suggest an increased risk of spontaneous abortion after administration of prostaglandin synthesis inhibitors in early pregnancy. In animals, the use of drugs that inhibit prostaglandin synthesis increases the risk of miscarriage before and after implantation.

Breastfeeding Women

Studies in rats have shown that celecoxib is excreted in milk at concentrations comparable to those in plasma. In nursing women receiving celecoxib, very little celecoxib is passed into breast milk. Because of the potential adverse effects of celecoxib in the nursing infant, depending on the desired benefit to the mother, discontinuation or discontinuation of breastfeeding should be considered.

Interactive

Overview

Celecoxib is mainly metabolized via cytochrome P450 (CYP) 2C9 in the liver. Caution should be exercised when celecoxib is administered to patients with known or suspected poor CYP2C9 metabolizers based on history with other CYP2C9 substrates as these patients may have abnormally elevated plasma concentrations of celecoxib due to decreased plasma concentrations of celecoxib. metabolic clearance. Treatment should be initiated at half the lowest recommended dose.

Co-administration of celecoxib with CYP2C9 inhibitors increases plasma concentrations of celecoxib. Therefore, it is necessary to reduce the dose of celecoxib when co-administered with a CYP2C9 inhibitor.

Co-administration of celecoxib with inducers of CYP2C9 such as rifampicin, carbamazepine, and barbiturates reduces plasma concentrations of celecoxib. Therefore, it is necessary to increase the dose of celecoxib when co-administered with CYP2C9 inducers.

Clinical pharmacokinetic studies and in vitro studies have shown that although celecoxib is not a substrate, it is an inhibitor of CYP2D6. Therefore, there may be in vivo drug interactions with drugs metabolized by CYP2D6.

Warfarin or similar drugs

See section ''Use with oral anticoagulants'', section Warnings.

Lithium

In healthy subjects, plasma lithium concentrations increased by approximately 17% with concomitant administration of lithium and celecoxib. Patients on lithium therapy should be closely monitored when initiating or discontinuing concomitant use of celecoxib.

Aspirin

Celecoxib does not affect the antiplatelet effect of low-dose aspirin. Because of its lack of effect on platelets, celecoxib is not a substitute for aspirin in the prevention of cardiovascular disease.

Antihypertensives include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II antagonists (known as angiotensin receptor blockers, ARBs), diuretics, and beta-blockers.

Inhibition of prostaglandins may reduce the antihypertensive effect of angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin II antagonists, diuretics, and beta-blockers. These interactions should be considered when celecoxib and angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II antagonists, diuretics, and beta-blockers are co-administered.

In elderly patients, those with hypovolemia (including those taking diuretics) or impaired renal function, the concomitant use of NSAIDs, including selective COX-2 inhibitors, with Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II antagonists or diuretics can lead to impaired renal function including acute renal failure. These effects are usually reversible. Therefore, caution should be exercised when celecoxib is co-administered with these drugs. Patients should be adequately rehydrated and renal function monitored at the start of the combination regimen as well as periodically thereafter.

Results from the lisinopril study

In a 28-day clinical study in lisinopril-controlled stage I and II hypertensive patients, the use of celecoxib 200 mg twice daily did not increase systolic and diastolic blood pressure when compared with a placebo control group during 24-hour blood pressure control. In the group of patients co-administered with celecoxib 200 mg twice daily, 48% of patients did not respond to lisinopril at the last visit (i.e., diastolic blood pressure greater than 90 mm Hg or diastolic blood pressure increased by more than 10 % from baseline), for the placebo group this was 27%. This difference is statistically significant.

Cyclosporin

Because NSAIDs have an effect on renal prostaglandins, they may increase the risk of cyclosporin-induced nephrotoxicity.

Fluconazole and ketoconazole

Concomitant administration of fluconazole at a dose of 200 mg once daily resulted in a doubling of plasma celecoxib concentrations because fluconazole inhibits the celecoxib-metabolizing enzyme CYP P450 2C9. The use of celecoxib at half the recommended dose should be initiated in patients receiving drugs that inhibit CYP2C9 such as fluconazole. Ketoconazole, a CYP3A4 inhibitor, has no clinically significant inhibition of celecoxib metabolism.

Dextromethorphan and metoprolol

Co-administration of celecoxib 200 mg twice daily resulted in a 2.6- and 1.5-fold increase in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. This is because celecoxib inhibits the metabolism of CYP2D6 substrates. Therefore, it is necessary to reduce the dose of drugs that are CYP2D6 substrates when starting concomitant celecoxib and increase the dose of these drugs when celecoxib is discontinued.

Diuretic

Clinical studies have shown that in some patients, NSAIDs may reduce the urinary sodium excretion effects of furosemide and thiazides by inhibiting renal prostaglandin synthesis.

Methotrexate

There were no clinically important and pharmacokinetic interactions between celecoxib and methotrexate in clinical studies between the two drugs.

Oral contraceptives

In an interaction study, celecoxib had no clinically apparent effect on the pharmacokinetics of combined oral contraceptives (1 mg norethindrone/0.035 mg Ethinyl estradiol).

Other drugs

No clinically important interactions have been reported between celecoxib and antacids (aluminum and magnesium), omeprazole, glibenclamide (glyburide), phenytoin or tolbutamide.

Incompatibility

Since there are no incompatibility studies, this drug should not be mixed with other drugs.

Side effects

Risk of cardiovascular thrombosis (see also Precautions).

The frequency of undesirable effects is defined as follows: Very common (≥1/10), common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000) and frequency unknown (cannot be estimated from the available data).

A. Adverse drug reactions from 12 placebo- and/or active-controlled clinical trials and frequency of adverse events from 89 RCTs involving pain and inflammation with daily doses of 25-800 mg in adult subjects

Infections and parasitic infections

Common: Bronchitis, sinusitis, upper respiratory tract infection, urinary tract infection.

Uncommon: Pharyngitis, rhinitis.

Blood and Lymph

Uncommon: Anemia.

Rare: Thrombocytopenia.

Immune

Uncommon: Hypersensitivity.

Mental

Common: Insomnia.

Uncommon: Anxiety.

Rare: Confusion state.

Nerve

Common: Dizziness.

Uncommon: Increased muscle tone, somnolence.

Eye

Uncommon: Blurred vision.

Ear and inner ear

Uncommon: Tinnitus.

Heart

Uncommon: Tachycardia.

Rare: Congestive heart failure, arrhythmia, tachycardia.

Circuit

Common: Hypertension (including progressive hypertension).

Rare: Blushing.

Respiratory, thoracic, and mediastinal

Common: Cough.

Digest

Common: Vomiting, abdominal pain, diarrhea, dyspepsia, abdominal bloating.

Uncommon: Stomach ulcers, dental problems.

Rare: Duodenal ulcer, an esophageal ulcer.

Very rare: Intestinal perforation, pancreatitis.

Liver and bile

Uncommon: Increased liver enzymes (including increases in Alanine aminotransferase and Aspartate aminotransferase).

Skin and subcutaneous tissue

Common: Pruritus (including generalized pruritus), rash.

Uncommon: Urticaria, ecchymosis.

Rare: Angioedema, alopecia.

Very rare: Bullous dermatitis.

Whole-body and local drug use

Common: Peripheral edema.

Uncommon: Facial edema, flu-like illness.

Injuries, toxicity, and conditions caused by the procedure

Uncommon: Lesions.

B. Adverse events in polyp prevention studies of up to 3 years with daily doses of 400-800 mg

Infections and parasitic infections

Common: Ear infections, fungal infections (mainly local fungal infections).

Uncommon: Helicobacter infection, Herpes zoster, erysipelas, wound infection, gingivitis, otitis media, a bacterial infection.

Benign, malignant, and unclassified tumors

Uncommon: Lipoma.

Mental

Uncommon: Sleep disturbance.

Nerve

Uncommon: Cerebral infarction.

Eye

Uncommon: Conjunctival hemorrhage, black spots flying before eyes.

Ear and inner ear

Uncommon: Hearing loss.

Heart

Common: Myocardial infarction, angina.

Uncommon: Unstable angina, valvular insufficiency, coronary atherosclerosis, sinus bradycardia, ventricular hypertrophy.

Blood vessel

Very common: Hypertension.

Uncommon: Deep vein thrombosis, hematoma.

Respiratory, thoracic, and mediastinal

Common: Shortness of breath.

Uncommon: Difficulty in pronunciation.

Digest

Very common: Diarrhea.

Common: Vomiting, dysphagia, irritable bowel syndrome, gastroesophageal reflux disease, nausea, diverticulosis.

Uncommon: Hemorrhoids, frequent bowel movements, mouth ulcers, gastritis.

Liver and bile

Rare: Increased liver enzymes (including elevations of Alanine aminotransferase and Aspartate aminotransferase).

Skin and subcutaneous tissue

Uncommon: Atopic dermatitis.

Skeletal muscle and connective tissue

Common: Muscle spasm.

Uncommon: Synovial cyst.

Kidneys and Urinary

Common: Kidney stone disease.

Uncommon: Nocturia.

Mammary glands and reproductive system

Common: Vaginal bleeding, prostatitis, benign prostatic hyperplasia.

Uncommon: Ovarian cyst, amenorrhea symptoms, breast tenderness, dysmenorrhea.

Whole-body and local drug use

Uncommon: Edema.

Tests

Common: Increased blood creatinine, increased prostate-specific antigen, weight gain.

Uncommon: Hyperkalemia, hypernatremia, decreased testosterone, decreased erythrocyte percentage, increased hemoglobin.

Injury, toxicity, and complications from the procedure

Uncommon: Leg fracture, lower limb fracture, bone fracture, mucositis, tendon rupture.

Pediatric patient

In general, the adverse events observed in the pediatric pivotal study were similar to those observed in the adult arthritis study (see section A). In addition, the following adverse events not listed in section A were observed by the investigators and may be related to celecoxib: headache (11.3%, very common), urine bleeding (0.6%, uncommon), and asthma attacks [1 patient had controlled asthma at baseline] (0.6%, uncommon). Compared with naproxen, celecoxib at doses of 3 and 6 mg/kg twice daily had no adverse effects on growth and maturity during the 12-week double-blind study period.

Adverse effects reported post-marketing

Adverse effects reported during marketing are provided below. Although these adverse events were identified through post-marketing experience, their frequency was evaluated with reference to clinical trials. As above, the frequency of these adverse events is based on a survey of clinical trials involving 38,102 patients receiving celecoxib.

Immune

Very rare: Anaphylactoid reactions.

Mental

Rare: Hallucinations.

Nerve

Very rare: Brain hemorrhage, aseptic meningitis, loss of taste, loss of smell.

Eye

Uncommon: Conjunctivitis.

Blood vessel

Very rare: Vasculitis.

Respiratory, thoracic, and mediastinal

Rare: Pulmonary embolism, pneumonia.

Digest

Rare: Gastrointestinal bleeding.

Liver and bile

Rare: Hepatitis.

Very rare: Liver failure, hepatitis flare, hepatic necrosis, cholestasis, cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue

Rare: Photosensitive reaction.

Very rare: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS or hypersensitivity syndrome), rash acute generalized pustulosis (AGEP), exfoliative dermatitis.

Kidneys and Urinary

Rare: Acute renal failure, hyponatremia.

Very rare: Interstitial nephritis, nephrotic syndrome, minimally damaged glomerulonephritis.

Mammary glands and reproductive system

Rare: Menstrual disorders.

Frequency unknown: Fertility disorders in women.

Women planning to become pregnant were excluded from these trials, therefore it is inappropriate to consult clinical data on the frequency of these adverse events.

Preservation

In sealed packaging, in a dry place, away from moisture. The temperature should not exceed 30oC.

Presentation and packaging

Capsules: box of 3 blisters x 10 tablets, box of 6 blisters x 10 tablets, box of 10 blisters x 10 tablets.