Cybec 400

Celecoxib.

CYBEC (400 MG CAPSULE): White to off-white granules in a green-white hard capsule no. 0, with "
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" logo and "400" on the capsule shell.
Each capsule contains Celecoxib 400 mg.

Pharmacology: Pharmacodynamics: Celecoxib is a non-steroidal anti-inflammatory drug (NSAIDs) reported to be a highly selective inhibitor of cyclooxygenase-2 (COX-2).
Celecoxib inhibits prostaglandin synthesis, via inhibition of cyclooxygenase-2 (COX-2), which results in decreased formation of prostaglandin precursors. Celecoxib has antipyretic, analgesic and anti-inflammatory properties. In studies using rodent models of colon cancer indicate that Celecoxib can decrease both the incidence and multiplicity of colon tumors.
Celecoxib does not inhibit cyclooxygenase-1 (COX-1) at therapeutic concentrations. Cyclooxygenase-1 (COX-1) is involved in platelet aggregation, maintenance of the gastric mucosal barrier and maintenance of renal perfusion. COX-1 inhibition presumably is responsible for the unwanted effects on GI mucosa. Celecoxib's highly selective inhibition of cyclooxygenase-2 (COX-2) potentially may be associated with decreased risk of certain adverse effects (e.g., on GI mucosa).
Pharmacokinetics: Absorption: Celecoxib is well absorbed from the gastrointestinal tract and peak plasma concentrations of the drug generally are attained within 2-3 hours after dosing in fasting individuals. Oral bioavailability is about 99%. Bioavailability (AUC) was increased about 20% and resulting in a time to reach peak plasma concentrations of Celecoxib was about 4 hours when Celecoxib capsules were administered with high fat meal.
Distribution: The apparent volume of distribution of Celecoxib at steady state is about 400 L. Celecoxib is about 97% bound to plasma proteins, principally albumin and to a lesser extent, α₁-acid glycoprotein. Celecoxib is not preferentially bound to erythrocytes in blood.
Metabolism: Celecoxib is metabolized in the liver mainly by the cytochrome P450 isoenzyme 2C9 which shows genetic polymorphism. Three identified metabolites; a primary alcohol, corresponding carboxylic acid and its glucuronide conjugate, are inactive as inhibitors of cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2) enzymes.
In patients with poor metabolizer of the CYP2C9 isoenzyme, the metabolic clearance of Celecoxib may be decreased and plasma concentrations may be increased.
Excretion: Celecoxib is excreted in urine and feces principally as metabolites; less than 3% of the dose is excreted unchanged. Approximately 27% and 57% of the dose was excreted in the urine and feces, respectively. The principal metabolite in both urine and feces was the carboxylic acid metabolite (73% of the dose); small amounts of the glucuronide metabolites was present in urine. The plasma elimination half-life of Celecoxib is about 11 hours, and the apparent plasma clearance of the drug is about 500 mL/minute. The half-life of Celecoxib is prolonged in patients with renal or hepatic impairment and has been reported to be 13.1 hours in patients with chronic renal insufficiency and 11 to 13.1 hours in patients with mild or moderate hepatic impairment, respectively.

Symptomatic treatment of osteoarthritis (OA) and rheumatoid arthritis (RA).
Relief of sign and symptoms of ankylosing spondylitis (AS).
Management of acute pain.
Treatment of primary dysmenorrhea.
Management of low back pain.

Recommended Dose and Mode of Administration: Celecoxib capsule, at dosed up to 200 mg twice per day, can be taken with or without food.
As the cardiovascular (CV) risks of Celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used.
Symptomatic treatment of osteoarthritis (OA): The usual recommended dose of Celecoxib is 200 mg administered as a single dose. In some patients, with insufficient relief from symptoms, an increased dose of 200 mg twice daily may increase efficacy. In the absence of an increase in therapeutic benefit after 2 weeks, other therapeutic options should be considered.
Symptomatic treatment of rheumatoid arthritis (RA): The recommended dose of Celecoxib is 200 mg twice per day.
Ankylosing Spondylitis (AS): The recommended dose of Celecoxib 200 mg administered as a single dose. Some patients may benefit from a total daily dose of 400 mg.
Management of acute pain: The recommended dose of Celecoxib 400 mg initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily or 400 mg once daily as needed.
Treatment of primary dysmenorrhea: The recommended dose of Celecoxib 400 mg initially, followed by an additional 200 mg dose, if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily or 400 mg once daily as needed.
Low back pain (LBP): The recommended dose of Celecoxib is 200 mg or 400 mg daily, administered as a 200 mg single dose, or as 200 mg twice per day. Some patients may benefit from a total daily dose of 400 mg.
CYP2C9 poor metabolizers: Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered Celecoxib with caution. Consider starting treatment at half the lowest recommended dose.
Elderly: No dosage adjustment is generally necessary. However, for elderly patients weighing lower than 50 kg, it is advisable to initiate therapy at the lowest recommended dose.
Hepatic impairment: No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).
Introduce Celecoxib at half the recommended dose in arthritis or pain patients with moderate hepatic impairment (Child-Pugh class B).
Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Renal impairment: No dosage adjustment is necessary in patients with mild or moderate renal impairment.
Patients with severe renal impairment have not been studied.
Co-administration with fluconazole: Celecoxib should be introduced at half the recommended dose in patients receiving fluconazole, a CYP2C9 inhibitor. Caution is advised when co-administering Celecoxib with other CYP2C9 inhibitors.
Pediatric patients: Celecoxib has not been studied in subjects under 18 years of age.

Overdose and Treatment: Clinical experience of overdose is limited. Single doses up to 1,200 mg and multiple doses up to 1,200 mg twice daily have been administered to healthy subjects without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided. Dialysis is unlikely to be an efficient method of drug removal because of high protein binding of the drug.

Celecoxib is contraindicated in: Patients with a history of hypersensitivity to Celecoxib or any other ingredient of the product; Patients with a history of hypersensitivity to sulfonamide; Patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid (aspirin) or other NSAIDs; Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery; Children under 18 years old.

Based on Notification of the Ministry of Public Health: 1. Celecoxib is contraindicated in patients who are hypersensitive to this drug, in pregnant and lactating women.
2. Celecoxib is contraindicated in patients who have coronary artery surgery in the immediately postoperative period.
3. Celecoxib is contraindicated in patients with cardiovascular or cerebrovascular diseases.
4. If there is erythema multiforme or flu-like symptom after use, stop using this drug and consult the physician immediately.
5. Celecoxib is contraindicated in patients who have ever been hypersensitive to this drug and patients with history of sulfonamide hypersensitivity.
6. If the following symptoms occur during using this drug, e.g. fever, erythema multiforme, vesicle, skin lesions and other lesions appear in the mucous membranes (such as in the mouth cavity, throat, nasal cavity, sexual organs) and conjunctivitis, stop using this drug and consult the physician immediately as this may be Stevens-Johnson syndrome.
7. Celecoxib is contraindicated in patients who have had myocardial infarction or congestive heart failure (NYHA II-IV).
8. Celecoxib is contraindicated in patients who have had coronary heart disease (stenosed or occluded) or paresis, paralysis due to cerebrovascular accident.
9. Use Celecoxib with caution in patients with risk factors for developing coronary heart disease, e.g., hypertension, hyperlipidemia, diabetes, smoking, elderly, etc.
10. Use with caution in patients with hepatic and renal disorders.

Cardiovascular effects: Celecoxib may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI) and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with dose and duration of use. Patients with cardiovascular disease or cardiovascular risk factors may be at greater risk. To minimize the potential risk for an adverse cardiovascular event in patients treated with Celecoxib, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and symptoms of serious cardiovascular toxicity and the steps to take if they occur.
Celecoxib is not a substitute for aspirin for prophylaxis of cardiovascular thromboembolic disease because the lack of effect on platelet function. Because Celecoxib does not inhibit platelet aggregation, antiplatelet therapies (e.g., aspirin) should not be discontinued.
Renal effects: Celecoxib may cause renal toxicity like those of the non-selective NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, and the elderly. Such patients should be carefully monitored while receiving treatment with Celecoxib.
Cautions should be used when initiating treatment in patients with dehydration. It is advisable to rehydrate patients first and then start therapy with Celecoxib.
Avoid use Celecoxib in patients with advanced renal disease.
Hepatic effects: The use of Celecoxib in patients with severe hepatic impairment (Child-Pugh class C) is not recommended. Celecoxib should be used with caution when treating patients with moderate hepatic impairment (Child-Pugh class B), and initiated at half the recommended dose.
Rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis (some fatal), liver necrosis, and hepatic failure (some fatal or requiring liver transplant), have been reported in patients receiving Celecoxib.
A patient with symptoms and/or sign of liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored carefully for evidence of the development of a more severe hepatic reaction while on therapy with Celecoxib.
Gastrointestinal effects: NSAIDs cause an increased risk of serious gastrointestinal inflammation, ulceration, bleeding, and perforation (may be fatal). Upper and lower GI perforations, ulcers or bleeds have occurred in patients treated with Celecoxib. Patients most at risk of developing these types of GI complications with NSAIDs are the elderly, patients with cardiovascular disease, patients using concomitant glucocorticoids, antiplatelet drugs (such as aspirin), or other NSAIDs, patients using alcohol or patients with a prior history of, or active, GI disease such as ulceration, GI bleeding or inflammatory conditions. Most spontaneous reports of fatal GI events have been elderly or debilitated patients.
Hypertension: As with all NSAIDs, Celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension. Celecoxib should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with Celecoxib and throughout the course of therapy.
Fluid retention and edema: As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in some patients taking 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, pre-existing edema, or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolemia.
Anaphylactoid reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients exposed to Celecoxib.
Serious skin reactions: Serious skin reactions, some of them fatal, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrosis, have been occurred very rarely in association with the use of Celecoxib. Patients appear to be the highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within first month of treatment. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
Use with other NSAIDs: The concomitant use of Celecoxib and a non-aspirin NSAIDs should be avoided.
Use with oral anticoagulants: The concomitant use of NSAIDs with oral anticoagulants, including warfarin/coumarin-type and novel oral anticoagulants (e.g., apixaban, dabigatran and rivaroxaban), increases risk of bleeding and should be given with cautions. Serious bleeding events, some of them fatal, have been reported. Because increases in prothrombin time (INR) have been reported, anticoagulation/INR should be monitored after initiating treatment with Celecoxib or changing the dose.
General: By reducing inflammation, Celecoxib may diminish the utility of diagnostic signs, such as fever, in detecting infections.
CYP2D6 inhibition: Celecoxib has shown to be a moderately potent CYP2D6 inhibitor. For drugs that are metabolized by CYP2D6, a dose reduction during initiation of Celecoxib treatment or a dose increase upon termination of Celecoxib treatment may be necessary.
Effects on ability to drive and use machines: Celecoxib may have minor influence on the ability to drive and use machines. Patients who experience dizziness, vertigo or somnolence while taking Celecoxib should refrain from driving or operating machinery.

Pregnancy: There are no adequate and controlled studied to date using Celecoxib in pregnant women or during labor and delivery, the drug should be used during pregnancy only when the potential benefits justify the possible risk. Celecoxib should not be used during the third trimester of pregnancy, since inhibitors of prostaglandin synthesis may have adverse effects on the fetal cardiovascular system (e.g., premature closure of the ductus arteriosus).
The use of NSAIDs may be associated with an increased risk of miscarriage.
If used during second or third trimester of pregnancy, NSAIDs may cause fetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe case. Such effects may occur shortly after treatment initiation and are usually reversible. Pregnant women on Celecoxib should be closely monitored for amniotic fluid volume.
Lactation: Celecoxib is very low transfer into breast milk. Because of the potential for adverse reactions in nursing infants from Celecoxib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the expected benefit of the drug to the mother.

Infections and infestations: Common: Bronchitis, sinusitis, upper respiratory tract infection, urinary tract infection.
Uncommon: Pharyngitis, rhinitis.
Blood and lymphatic system disorders: Uncommon: Anaemia.
Rare: Thrombocytopenia, leukopenia.
Very rare: Pancytopenia.
Immune system disorders: Common: Hypersensitivity.
Very rare: Anaphylactic reaction.
Metabolism and nutrition disorders: Uncommon: Hyperkalaemia.
Psychiatric disorders: Common: Insomnia.
Uncommon: Anxiety, depression, fatigue.
Rare: Confusional state, hallucination.
Nervous system disorders: Common: Dizziness, hypertonia, headache.
Uncommon: Somnolence, cerebral infarction, paraesthesia.
Rare: Ataxia, dysgeusia.
Very rare: Cerebral haemorrhage, meningitis aseptic, ageusia, anosmia, epilepsy.
Eye disorders: Uncommon: Vision blurred, conjunctivitis.
Rare: Eye haemorrhage.
Very rare: Retinal artery occlusion, retinal vein occlusion.
Ear and labyrinth disorders: Uncommon: Tinnitus, hypoacusis.
Cardiac disorders: Common: Myocardial infarction.
Uncommon: Palpitations, congestive cardiac failure, tachycardia.
Rare: Arrhythmia.
Vascular disorder: Very common: Hypertension (including aggravated hypertension).
Rare: Flushing.
Very rare: Vasculitis.
Respiratory, thoracic and mediastinal disorders: Common: Cough, dyspnoea.
Uncommon: Bronchospasm.
Rare: Pulmonary embolism, pneumonitis.
Gastrointestinal disorders: Common: Vomiting, abdominal pain, diarrhoea, dyspepsia, flatulence, nausea, dysphagia.
Uncommon: Gastric ulcer, tooth disorder, constipation, gastritis, stomatitis, eructation, gastrointestinal inflammation.
Rare: Duodenal ulcer, oesophageal ulcer, gastrointestinal haemorrhage, intestinal ulcer, large intestinal ulcer, intestinal perforation, pancreatitis, oesophagitis, melaena, colitis.
Hepatobiliary disorders: Uncommon: Hepatic enzyme increased (includes alanine aminotransferase increased and aspartate aminotransferase increased), abnormal hepatic function.
Rare: Hepatitis.
Very rare: Hepatic failure, hepatitis fulminant, hepatic necrosis, cholestasis, hepatitis cholestatic, jaundice.
Skin and subcutaneous tissue disorders: Common: Pruritus (includes pruritus generalized), rash.
Uncommon: Urticaria, ecchymosis.
Rare: Angioedema, alopecia, photosensitivity reaction.
Very rare: Dermatitis bullous, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), dermatitis exfoliative.
Musculoskeletal and connective tissue disorders: Common: Arthralgia.
Uncommon: Muscle spasms (leg cramps).
Very rare: Myositis.
Renal and urinary disorders: Uncommon: Blood creatinine increased, blood urea increased.
Rare: Renal failure acute, hyponatraemia.
Very rare: Tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion.
Reproductive system and breast disorders: Rare: Menstrual disorder.
Not known: Infertility female (female fertility decreased).
General disorders and administration site conditions: Common: Influenza like illness, oedema peripheral.
Uncommon: Face oedema, chest pain.
Injury, poisoning and procedural conditions: Common: Injury.

Celecoxib metabolism is predominantly mediated via cytochrome P450 CYP2C9 in the liver. Concomitant administration of Celecoxib with inhibitors of CYP2C9 can lead to increase in plasma concentrations of Celecoxib. And concomitant administration of Celecoxib with inducers of CYP2C9, such as rifampicin, carbamazepine and barbiturates, can lead to decrease in plasma concentrations of Celecoxib, a dose increase of Celecoxib may be necessary. Therefore, Celecoxib and drugs that inhibit or induce the CYP2C9 should be administered concomitantly with caution. In addition, Celecoxib also inhibits CYP2D6, and the potential therefore exists for an effect on drugs metabolized by this enzyme.
Fluconazole and Ketoconazole: Concomitant administration of Celecoxib with fluconazole can result in increased in plasma concentrations of Celecoxib. This increase may occur because of inhibition of Celecoxib metabolism. Ketoconazole, a CYP3A4 inhibitor, showed on inhibition in the metabolism of Celecoxib.
Lithium: Celecoxib can decrease renal clearance of lithium, which may lead to increased serum or plasma lithium concentrations.
Diuretics, e.g. furosemide, thiazides: NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.
Warfarin: Concomitant administration of Celecoxib with warfarin may prolong prothrombin time. Caution should be used when coadministering Celecoxib with warfarin. Patients receiving such concomitant therapy should be monitored appropriately.
Anti-hypertensive including angiotensin-converting enzyme (ACE) inhibitors, Angiotensin II receptor antagonists, diuretics and beta-blockers: Concomitant administration of Celecoxib, may reduce the blood pressure response to ACE inhibitors, angiotensin II receptor antagonists, diuretics or beta-blockers because of inhibition of prostaglandins. Therefore, blood pressure should be monitored carefully.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE-inhibitors, angiotensin II antagonists or diuretics, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.
Cyclosporine: Concomitant administration of cyclosporine and Celecoxib may result in an increased risk of cyclosporine nephrotoxicity.
Dextromethorphan and metoprolol: Concomitant administration of Celecoxib resulted in increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates). These increases are due to Celecoxib inhibition to the CYP2D6 metabolism.
Aspirin: Celecoxib dose not interfere with the anti-platelet effect of low-dose aspirin. Because of its lack of platelet effects, Celecoxib is not a replacement for aspirin in the prophylactic treatment of cardiovascular disease.
Other drugs: No clinically important interactions have been observed with Celecoxib and antacids (aluminium and magnesium), omeprazole, glibenclamide (glyburide), phenytoin or tolbutamide.

Store below 30°C.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

M01AH01 - celecoxib ; Belongs to the class of non-steroidal antiinflammatory and antirheumatic products, coxibs.

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