Celecoxib Sandoz Uses, Dosage, Side Effects, Precautions & Warnings

CELECOXIB SANDOZ 100 mg, capsule, box of 30 >> Generic drug of the Therapeutic class: Anti-inflammatory

Active ingredient: Celecoxib

what is Celecoxib Sandoz medication used for and indication?

• CELECOXIB SANDOZ is indicated in adults for the relief of symptoms in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
• The decision to prescribe a selective cyclooxygenase-2 (COX-2) inhibitor should be based on an assessment of all the risks specific to each patient

Celecoxib Sandoz Dosage

Dosage

• Due to the possible increase in cardiovascular risks of celecoxib depending on the dose and duration of treatment, this medication should be prescribed at the minimum effective daily dose for the shortest possible time. The need for symptomatic treatment and its therapeutic efficacy for the patient should be reassessed periodically, in particular in patients with osteoarthritis (see sections Contraindications, Warnings and precautions for use, Adverse reactions and Pharmacodynamic properties).

Osteoarthritis

• The usual recommended daily dose is 200 mg divided into one or two divided doses. In some patients whose symptoms are insufficiently relieved, increasing the dose to 200 mg twice daily may increase effectiveness. In the absence of improvement in therapeutic benefit after 2 weeks, other treatment options should be considered.

Rheumatoid arthritis

• The recommended initial daily dose is 200 mg divided into 2 divided doses.
• If necessary, the dose can be further increased to 200 mg twice a day. In the absence of improvement in therapeutic benefit after 2 weeks, other treatment options should be considered.

Ankylosing spondylitis

• The recommended daily dose is 200 mg divided into one or two divided doses. For a small number of patients whose symptoms are insufficiently relieved, increasing the dose to 400 mg in one or two divided doses may increase effectiveness. In the absence of improvement in therapeutic benefit after 2 weeks, other treatment options should be considered.
• The maximum recommended daily dose for all indications is 400 mg.

Special populations

Elderly (> 65 years old)

• As for any patient, treatment will be started at 200 mg per day.
• If necessary, the dose can be further increased to 200 mg twice a day. Special attention should be paid to elderly subjects with a body weight of less than 50 kg (see sections Warnings and precautions for use and Pharmacokinetic properties).

Pediatric population

• Celecoxib is not indicated in children.

CYP2C9 poor metabolisers

• As the risk of dose-dependent adverse reactions is higher, celecoxib should be administered with caution to patients known or suspected to be poor metabolisers of CYP2C9, based on genotyping or history / previous experience with other substrates. CYP2C9. Dose reduction to half of the lowest recommended dose should be considered (see section 5.2).

Hepatic insufficiency

• In patients with known moderate hepatic impairment with serum albumin between 25 and 35 g / l, treatment should be started at half the recommended dose. The experience in this type of patient is limited to that of cirrhotic patients (see sections Contraindications, Warnings and precautions for use and Pharmacokinetic properties).

Renal failure

• As the experience with celecoxib in patients with mild to moderate renal impairment is limited, these patients should be treated with caution (see sections 4.3, 4.4 and Pharmacokinetics).

Celecoxib Sandoz Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Composition)

• · Known hypersensitivity to sulfonamides
  • – active peptic ulcer or gastrointestinal (GI) bleeding,
• · A history of asthma, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or other NSAIDs, including inhibitors COX-2,
  • – pregnancy and women of childbearing potential, in the absence of effective contraception (see section Fertility, pregnancy and lactation). In the two animal species studied, celecoxib caused malformations (see sections Fertility, pregnancy and lactation and Preclinical safety data). In humans, the risk during pregnancy is not known but cannot be excluded,
• · Breastfeeding (see sections Fertility, pregnancy and lactation and Preclinical safety data)
• · Severe hepatic impairment (serum albumin <25 g / l or Child-Pugh score of ≥ 10),
• · Patients with clearance estimated creatinine <30 ml / min,
• · Inflammatory bowel disease,
• · Congestive heart failure (NYHA II-IV)
• · Ischemic heart disease, peripheral arterial disease and / or cerebrovascular accident (including transient ischemic attack).

How To Take Celecoxib Sandoz ?

Administration mode

• Oral route.
• CELECOXIB SANDOZ can be taken with or without food. Patients who have difficulty swallowing the capsules can add the contents of the celecoxib capsule to applesauce, rice pudding, yogurt or mashed bananas. For this, the entire contents of the capsule must be emptied thoroughly into a level teaspoon of applesauce, rice pudding, yogurt or mashed banana cold or at room temperature and must be ingested. immediately with 240 ml of water. Once sprinkled on applesauce, rice pudding or yogurt, the content of the capsule remains stable for 6 hours placed in the refrigerator (between 2 and 8 ° C). If the contents of the capsule are sprinkled over mashed bananas, they should not be refrigerated and should be immediately ingested.

how does Celecoxib Sandoz work?

Pharmacotherapeutic group: non-steroidal anti-inflammatory drug, antirheumatic drug, NSAIDs, Coxibs, ATC code: M01AH01 .

Action mechanism

• Celecoxib is a selective oral cyclooxygenase-2 (COX-2) inhibitor at doses used clinically (200 mg to 400 mg per day). No statistically significant inhibition of COX-1 assessed by ex-vivo inhibition of thromboxane B2 (TxB2) formation was observed at these doses in healthy volunteers.

Pharmacodynamic effects

• Cyclo-oxygenase is responsible for the synthesis of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. Cyclo-oxygenase-2 (COX-2) is the isoform of the enzyme induced by pro-inflammatory stimuli and is believed to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation and pain. fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and certain functions of the CNS (induction of fever, pain perception and cognitive function). It could also play a role in the healing of ulcers. COX-2 has been demonstrated in the tissues around gastric ulcers in humans, but its implication in the healing of ulcers is not
• The difference in antiplatelet activity between some COX-1 inhibitor NSAIDs and selective COX-2 inhibitors may be of clinical significance in patients at risk for thromboembolic reactions. Selective COX-2 inhibitors reduce systemic (and therefore possibly endothelial) prostacyclin formation without altering platelet thromboxane.
• Celecoxib is a pyrazole derivative substituted with two aryl groups, a chemical analogue of other non-arylamine sulfonamides (eg thiazides, furosemide) but it differs from arylamine sulfonamides (eg sulfamethoxazole and other sulfonamide antibiotics).
• A dose-dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in healthy subjects and in small, multi-dose studies with 600 mg twice daily (equivalent to three times the highest recommended dose), celecoxib had no effect on platelet aggregation. nor on bleeding time compared to placebo.

Clinical efficacy and safety

• Several clinical trials confirming the efficacy and safety of celecoxib in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis have been performed. Celecoxib has been evaluated for 12 weeks in the treatment of inflammation and pain of osteoarthritis of the knee and hip in approximately 4,200 patients in placebo-controlled trials and benchmarks. It has also been evaluated for 24 weeks in the treatment of inflammation and pain in rheumatoid arthritis in approximately 2,100 patients in placebo-controlled trials and reference products. Celecoxib, 200 mg to 400 mg daily, provided pain relief within 24 hours of administration.
• Celecoxib has been evaluated for 12 weeks in the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo-controlled trials and benchmarks. In these trials celecoxib, at doses of 100 mg twice daily, 200 mg once daily, 200 mg twice daily and 400 mg once daily, demonstrated significant improvement in pain, index overall disease activity and function in ankylosing spondylitis.
• Five randomized, double-blind controlled trials, including endoscopy of the upper gastrointestinal tract, were conducted at doses of 50 to 400 mg, twice daily, of celecoxib in approximately 4,500 patients without initial ulceration. In 12 week endoscopic studies versus naproxen (1000 mg per day) and ibuprofen (2400 mg per day), celecoxib (100 to 800 mg per day) was associated with a significantly lower risk of peptic ulcers.
• The data obtained in comparison with diclofenac (150 mg per day) were inconsistent. In two of the 12-week studies, the percentage of patients with peptic ulceration detected by endoscopy was not significantly different on placebo, celecoxib 200 mg twice daily and celecoxib 400 mg twice daily.
• In a prospective long-term safety study (duration 6 to 15 months, CLASS study), 5,800 patients with osteoarthritis and 2,200 patients with rheumatoid arthritis received celecoxib 400 mg twice daily (i.e. four times and two times a day, respectively). times the recommended dosage for osteoarthritis and rheumatoid arthritis), ibuprofen 800 mg three times a day or diclofenac 75 mg twice a day (each in therapeutic doses). Twenty-two percent of the patients included were simultaneously taking low doses of acetylsalicylic acid (≤ 325 mg per day), mainly for cardiovascular prevention. With regard to the primary endpoint designated as complicated ulcers (defined as bleeding,
• There was also no statistically significant difference in the combined NSAID group for complicated ulcers (relative risk 0.77; 95% CI 0.41 – 1.46; values ​​based on the entire duration of the study). For the mixed endpoint of complicated and symptomatic ulcers, the incidence was significantly lower in the celecoxib group compared to the NSAID group (relative risk 0.66; 95% CI 0.45 – 0.97), but not between celecoxib and diclofenac. Patients taking celecoxib and low doses of acetylsalicylic acid at the same time had 4-fold higher rates of complicated ulcers compared to those taking celecoxib alone. The incidence of clinically significant drops in hemoglobin (> 2 g / dl), confirmed by repeated dosages, was significantly lower in patients receiving celecoxib compared to the NSAID group (relative risk 0.29; 95% CI 0.17 – 0.48). The significantly lower incidence of this event with celecoxib was maintained with or without taking acetylsalicylic acid.
• p = 0.0001). The rates of gastrointestinal complications with clinical manifestation such as perforation, obstruction or hemorrhage were very low and not different between treatment groups (4-5 per group).
• Cardiovascular safety – Long-term studies in patients with sporadic adenomatous polyps.
• Two studies evaluating celecoxib in subjects with sporadic adenomatous polyps have been conducted: the APC (Adenoma Prevention with Celecoxib) trial and the PreSAP (Prevention of Spontaneous Adenomatous Polyps) trial.
• In the APC trial, a dose-dependent increase in the composite endpoint combining cardiovascular death, myocardial infarction (MI) and Cerebral Vascular Accident (CVA) was observed with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not show a statistically significant increase in risk for the same composite endpoint.
• In the APC trial, the relative risk of cardiovascular death, MI and stroke (composite endpoint) was 3.4 (95% CI 1.4-8.5) with 400 mg of celecoxib twice daily and 2.8 (95% CI 1.1-7.2) with 200 mg celecoxib twice daily compared to placebo. The cumulative values ​​for this composite endpoint over a 3-year period were 3.0% (20/671 subjects) and 2.5% (17/685 subjects), respectively compared to 0.9% (6/679 subjects) for the placebo. The increases observed compared to placebo for the two celecoxib dose groups were mainly due to an increased incidence of myocardial infarction.
• In the PreSAP trial, the relative risk for this same composite endpoint was 1.2 (95% CI 0.6-2.4) with celecoxib 400 mg twice daily compared to placebo. The cumulative values ​​for this composite endpoint over a 3-year period were 2.3% (21/933 subjects) and 1.9% (12/628 subjects) for celecoxib and placebo, respectively. The incidence of myocardial infarction number was 1.0% (9/933 subjects) with a daily administration of 400 mg of celecoxib and 0.6% (4/628 subjects) with placebo.
• Data from a third long-term study, ADAPT (The Alzheimer’s Disease Anti-inflammatory Prevention Trial) did not show a significant increase in cardiovascular risk with celecoxib 200 mg twice daily compared to placebo. The relative risk for a similar composite endpoint (cardiovascular death, myocardial infarction, stroke) was 1.14 (95% CI 0.61 – 2.15) with 200 mg celecoxib twice daily compared to placebo . The incidence of myocardial infarction was 1.1% (8/717 patients) with 200 mg celecoxib twice daily and 1.2% (13/1070 patients) with placebo.

A prospective randomized evaluation integrating celecoxib versus ibuprofen or naproxen (PRECISION – Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen)

• The PRECISION study is a double-blind study of cardiovascular safety in patients with osteoarthritis or rheumatoid arthritis at high risk of cardiovascular disease, comparing celecoxib (200 – 400 mg per day) with naproxen (750 – 1000 mg per day) and ibuprofen (1800 – 2400 mg per day). The primary endpoint, the Antiplatelet Trialists Collaboration (APTC), was a composite endpoint assessed independently of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, or non-fatal stroke. The study was planned to have 80% power to assess non-inferiority. Of the’ Open-label esomeprazole (20 – 40 mg) has been prescribed to all patients for gastric protection. Patients on low dose aspirin were allowed to continue treatment; at baseline, nearly half of the subjects were taking aspirin. Secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal outcomes. The mean administered dose was 209 ± 37 mg / day for celecoxib, 2045 ± 246 for ibuprofen and 852 ± 103 for naproxen.
• For the primary endpoint, celecoxib compared to naproxen or ibuprofen met all four pre-established non-inferiority criteria, see Table 2.
• Other independently assessed secondary and tertiary outcomes included cardiovascular, gastrointestinal, and renal outcomes. In addition, a four-month study investigating the effects of the three drugs on blood pressure, as measured by outpatient monitoring (ABPM), was conducted.

Table 2. Main analysis of the APTC composite endpoint evaluated

Analysis of the intent-to-treat (ITT – Intent to treat until 30 th month)
	Celecoxib 100 – 200 mg twice daily	Ibuprofen 600 – 800 mg three times a day		Naproxen 375 – 500 mg twice daily
NOT	8,072	8,040		7 969
Subjects presenting events	188 (2.3%)	218 (2.7%)		201 (2.5%)
Pairwise comparison	Celecoxib versus naproxen	Celecoxib versus ibuprofen		Ibuprofen versus naproxen
RR (95% CI)	0.93 (0.76, 1.13)	0.86 (0.70, 1.04)		1.08 (0.89, 1.31)
Analysis of the population in modified intent to treat (MITT under treatment until 43 th month)
	Celecoxib 100 – 200 mg twice daily	Ibuprofen 600 – 800 mg three times a day		Naproxen 375 – 500 mg twice daily
NOT	8,030	7 990		7 933
Subjects presenting events	134 (1.7%)	155 (1.9%)		144 (1.8%)
Pairwise comparison	Celecoxib versus naproxen	Celecoxib versus ibuprofen		Ibuprofen versus naproxen
RR (95% CI)	0.90 (0.72, 1.14)	0.81 (0.64, 1.02)		1.12 (0.889; 1.40)

Overall, the results were numerically similar in the celecoxib and comparator groups for the secondary and tertiary endpoints, and overall, no unexpected safety results were observed.

Celecoxib Sandoz Side Effects

Adverse events listed by system organ class and classified by frequency in Table 1 correspond to data presented in the following sources:

• adverse events reported at incidence rates greater than 0.01% and greater than those reported for placebo in 12 placebo-controlled clinical trials and standard treatment, conducted for up to 12 weeks in patients with d osteoarthritis and rheumatoid arthritis treated with daily doses of celecoxib of 100 mg to 800 mg. In additional studies using comparators such as non-selective NSAIDs, approximately 7,400 patients with OA were treated with celecoxib at daily doses up to 800 mg, of which approximately 2,300 patients were treated for 1 year or more. more. The adverse events seen with celecoxib in these additional studies were consistent with those seen in patients with
• Adverse events reported at higher rates than placebo for subjects treated with celecoxib 400 mg daily for the long term testing, for a maximum of 3 years, in preventing polyps (Adenoma Prevention with Celecoxib trial (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP); see section Pharmacodynamic properties, Cardiovascular safety – Long-term studies in patients with sporadic adenomatous polyps),

spontaneously reported post-marketing adverse events over a period in which it is estimated that over 70 million patients have been treated with celecoxib (various doses, durations and indications). Although these were identified as effects from post-marketing reports, trial data were consulted to estimate frequency. Frequencies are based on a cumulative meta-analysis pooling trials pooling exposure from 38,102 patients.

Table 1. Adverse reactions observed in clinical trials with celecoxib and during postmarketing surveillance (MedDRA terms) 1,2

	Frequency of adverse reactions
System organ class	Very common (≥1 / 10)	Frequent (≥1 / 100 to <1/10)	Rare (≥1 / 1,000 to <1/100)	Rare (≥1 / 10,000 to <1 / 1,000)	Very rare (<1 / 10,000)	Frequency not known
Infections and infestations		Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection
Blood and lymphatic system disorders			Anemia	Leukopenia, thrombocytopenia	Pancytopenia4
Immune system disorders		Hypersensitivity			Anaphylactic shock4, anaphylactic reaction4
Metabolism and nutrition disorders			Hyperkalaemia
Psychiatric disorders		Insomnia	Anxiety, depression, fatigue	Confusional state, hallucinations4
Nervous system disorders		Dizziness, hypertonia, headache4	Cerebral infarction1, paraesthesia, somnolence	Ataxia, dysgeusia	Intracranial haemorrhage (including fatal intracranial haemorrhage) 4, aseptic meningitis4, epilepsy (including worsening epilepsy) 4, ageusia4, anosmia4
Eye disorders			Blurred vision, conjunctivitis4	Eye bleeding4	Retinal artery occlusion4, retinal vein occlusion4
Ear and labyrinth disorders			Tinnitus, hearing loss1
Cardiac disorders		Myocardial infarction1	Heart failure, palpitations, tachycardia	Arrhythmia4
Vascular disorders	Hypertension1 (including worsening hypertension)			Pulmonary embolism4, flushing4	Vasculitis4
Respiratory, thoracic and mediastinal disorders		Rhinitis, cough, dyspnea1	Bronchospasm4	Inflammatory lung disease4
Gastrointestinal disorders		Nausea4, abdominal pain, diarrhea, dyspepsia, gas, vomiting1, dysphagia1	Constipation, gastritis, stomatitis, gastrointestinal inflammation (including worsening gastrointestinal inflammation), belching	Gastrointestinal bleeding4, duodenal ulcer, gastric ulcer, esophageal ulcer, intestinal ulcer and large intestinal ulcer, intestinal perforation, esophagitis, melena, pancreatitis, colitis4
Hepatobiliary disorders			Abnormal liver function, increased liver enzyme levels (including increased ALT and AST)	Hepatitis4	Hepatic failure4 (sometimes fatal or requiring liver transplantation), fulminant hepatitis4, (sometimes fatal), hepatic necrosis4, cholestasis4, cholestatic hepatitis4, jaundice4
Skin and subcutaneous tissue disorders		Rash, pruritus (includes generalized pruritus)	Urticaria, bruising4	Angioedema4, alopecia, photosensitivity	Exfoliative dermatitis4, erythema multiforme4, Stevens-Johnson syndrome4, Lyell syndrome4, drug hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS) 4, acute generalized exanthemous pustulosis (AGEP) 4, bullous dermatitis4
Musculoskeletal and connective tissue disorders		Arthralgia4	Muscle contractures (lower limb cramps)		Myositis4
Kidney and urinary tract disorders			Blood creatinine increased, blood urea increased	Acute renal failure4, hyponatremia4	Tubulointerstitial nephritis4, nephrotic syndrome4, minimal lesion glomerulonephritis4
Reproductive system and breast disorders				Menstrual disorders4		Female infertility (decrease in fertility in women) 3
General disorders and administration site conditions		Flu-like syndrome, peripheral edema / fluid retention	Face edema, chest pain4
Injury, poisoning and procedural complications		Injury (accidental injury)
1 Adverse reactions occurring in polyp prevention studies in subjects treated with 400 mg celecoxib per day in two clinical trials of up to 3 years duration (APC and PreSAP trials). The adverse reactions listed above for polyp prevention trials are only those already identified during pharmacovigilance notifications or which occurred more frequently than in osteoarthritis trials. ² In addition, the following previously unknown adverse reactions occurred in polyps prevention studies involving subjects treated with 400 mg celecoxib per day in two clinical trials lasting up to 3 years (APC and PreSAP trials): Common: angina pectoris, irritable bowel syndrome, nephrolithiasis, increased blood creatinine, benign prostatic hyperplasia, weight gain. Uncommon: helicobacter infection, shingles, erysipelas, bronchopneumonia, labyrinthitis, gingival infection, lipoma, vitreous floaters, conjunctival haemorrhage, deep vein thrombosis, dysphonia, haemorrhoidal haemorrhage, frequent stools, mouth ulcers, allergic dermatitis, lymph nodes nocturia, vaginal haemorrhages, breast tenderness, lower limb fracture, increased sodium in the blood. 3 Women who wish to have a child are excluded from all studies. Therefore, consulting the study database to determine the frequency of this event was not valid. 4 Frequencies based on a cumulative meta-analysis pooling the trials grouping the exposure of 38,102 patients.

Evaluation of the final results of the APC and PreSAP trials (pooled data from the two trials; for the results of the individual trials, see section 5.1), for patients treated with 400 mg celecoxib per day for up to 3 years showed a increase in the number of myocardial infarctions of 7.6 events per 1000 patients (uncommon) compared to placebo; no increase in the number of strokes (undifferentiated types) was observed compared to placebo.

Celecoxib Sandoz Interactions

Pharmacodynamic interactions

Anti coagulants

• Anticoagulant activity should be monitored in patients taking warfarin or similar products, especially in the first few days after initiating or modifying the dosage of celecoxib as these patients have an increased risk of bleeding complications. For this reason, the use of oral anticoagulants should be accompanied by close monitoring of the prothrombin INR level of patients, mainly during the first days after initiation of treatment with celecoxib or when the dosage of the drug is changed. celecoxib (see section Warnings and precautions for use). Bleeding, some with fatal outcome, associated with an increase in the prothrombin level and INR have been observed in patients, especially in the elderly,

Anti-hypertensives

• NSAIDs may reduce the effects of antihypertensive drugs, including ACE inhibitors, angiotensin II receptor blockers, diuretics, and beta blockers. As with NSAIDs, the risk of acute renal failure, which is generally reversible, may be increased in certain patients with impaired renal function (for example: dehydrated patients or elderly patients) when the combination of ACE inhibitors, antagonists of the receptors of angiotensin II, and / or diuretics with NSAIDs, including celecoxib (see section 4.4). Therefore, this combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and renal function should be monitored after
• In a 28-day clinical study in patients with stage I and stage II hypertension controlled by lisinopril, administration of 200 mg celecoxib twice daily did not result in a clinical increase. significant systolic or diastolic blood pressure compared to placebo. Assessment was performed by ambulatory blood pressure monitoring for 24 hours. Among the patients treated with 200 mg celecoxib twice daily, 48% of them were considered non-responders to lisinopril at the final clinical visit compared to 27% of patients treated with placebo (were defined as non-responders, subjects whose diastolic blood pressure measured with a blood pressure monitor> 90 mmHg or whose

Ciclosporin and tacrolimus

• Co-administration of NSAIDs with ciclosporin or tacrolimus may increase the nephrotoxicity of ciclosporin or tacrolimus, respectively. Renal function should be monitored if celecoxib is combined with any of these drugs.

Acetylsalicylic acid

• Celecoxib can be used in combination with a low dose of acetylsalicylic acid but cannot be used as a substitute for acetylsalicylic acid for cardiovascular prevention. In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications was demonstrated with the concomitant administration of low doses of acetylsalicylic acid, in comparison for the use of celecoxib alone .

Pharmacokinetic interactions

Effects of celecoxib on other drugs

CYP2D6 inhibition

• Celecoxib is an inhibitor of cytochrome CYP2D6. The plasma concentrations of drugs which are substrates of this enzyme may be increased when combined with celecoxib. Drugs metabolized by CYP2D6 are, for example, antidepressants (tricyclics and selective serotonin reuptake inhibitors), neuroleptics, antiarrhythmics, etc. The dosage of CYP2D6 substrates, the dose of which is appropriate for each patient, may be reduced if necessary at the start of treatment with celecoxib or increased when stopping treatment with celecoxib.
• Concomitant administration of 200 mg celecoxib twice daily resulted in 2.6-fold and 1.5-fold increased plasma concentrations of dextromethorphan and metoprolol (substrates of CYP2D6), respectively. These increases are due to the inhibition of the metabolism of CYP2D6 substrates by celecoxib.

CYP2C19 inhibition

• In vitro studies have shown that celecoxib has the potential to inhibit the metabolism catalyzed by the cytochrome CYP2C19. The clinical significance of this in vitro observation is not known. Drugs metabolized by CYP2C19 are, for example, diazepam, citalopram and imipramine.

Methotrexate

• In patients with rheumatoid arthritis, celecoxib has no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (at the doses used in rheumatology). However, adequate monitoring of methotrexate toxicity should be considered when combining these two drugs.

Lithium

• In healthy subjects, the concomitant administration of 200 mg twice daily of celecoxib and 450 mg twice daily of lithium resulted in a mean increase of 16% in Cmax and 18% in AUC of lithium. Therefore, patients treated with lithium should be closely monitored when initiating or stopping celecoxib.

Oral contraceptives

• In an interaction study, celecoxib did not have clinically significant effects on the pharmacokinetics of oral contraceptives (1 mg norethisterone / 35 µg ethinyl estradiol).

Glibenclamide / tolbutamide

• Celecoxib does not affect the pharmacokinetics of tolbutamide (cytochrome CYP2C9 substrate) or glibenclamide in a clinically meaningful way.

Effect of other drugs on celecoxib

CYP2C9 poor metabolisers

• In subjects who are poor metabolizers of CYP2C9 with increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors, such as fluconazole, may further increase exposure to celecoxib. Such combinations should be avoided in known poor metabolisers of CYP2C9 .

CYP2C9 inhibitors and inducers

• Since celecoxib is primarily metabolized by cytochrome CYP2C9, it should be used at half the recommended dose in patients treated with fluconazole. Concomitant use of a single 200 mg dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in Cmax of 60% and AUC of 130 % of celecoxib. Concomitant use with CYP2C9 inducers such as rifampicin, carbamazepine, or barbiturates may result in reduced plasma concentrations of celecoxib.

Ketoconazole and antacids

• No changes in the pharmacokinetics of celecoxib have been observed with ketoconazole or antacids.

Pediatric population

• Interaction studies have only been performed in adults.

Warnings and Precautions

Gastrointestinal (GI) effects

• Upper and lower gastrointestinal complications [perforations, ulcers or hemorrhages (PUH)], some with fatal outcome, have been observed in patients treated with celecoxib.
• Caution should be exercised in patients most at risk of developing a gastrointestinal complication with NSAIDs: the elderly, patients also treated with other NSAIDs, or with acetylsalicylic acid, with glucocorticoids, patients consuming alcohol, or patients with a history of gastrointestinal illness such as ulcer and bleeding.
• There is an increased risk of gastrointestinal side effects (gastrointestinal ulceration or other gastrointestinal complications) when celecoxib is used in combination with acetylsalicylic acid (even at low doses).
• A significant difference in gastrointestinal tolerance between the combination of selective COX-2 inhibitors and acetylsalicylic acid compared to the combination of NSAIDs and acetylsalicylic acid has not been demonstrated in long-term clinical trials (see section Pharmacodynamic properties).

Concomitant use of NSAIDs

• Concomitant use of celecoxib and an NSAID other than aspirin should be avoided.

Cardiovascular effects

• In comparison to placebo, an increase in the number of serious cardiovascular events, mainly myocardial infarctions, was observed in a long-term study in patients with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg twice per day and 400 mg twice daily.
• Due to the possible increase in cardiovascular risks of celecoxib depending on the dose and duration of treatment, this medication should be prescribed at the minimum effective daily dose for the shortest possible time. The need for symptomatic treatment and its therapeutic efficacy for the patient should be reassessed periodically, in particular in patients with osteoarthritis (Contraindications, Adverse reactions and Pharmacodynamic properties).
• Patients with significant risk factors for cardiovascular events (eg hypertension, hyperlipidaemia, diabetes, smoking) should be treated with celecoxib only after careful evaluation.
• Due to their lack of antiplatelet effects, selective COX-2 inhibitors cannot be substituted for acetylsalicylic acid in the prevention of cardiovascular thromboembolic diseases. Therefore, antiplatelet therapy should not be stopped.

Fluid retention and edema

• As with other drugs known to inhibit prostaglandin synthesis, fluid retention and edema have been observed in patients treated with celecoxib. Therefore celecoxib should be administered with caution in patients with a history of heart failure, left ventricular dysfunction or arterial hypertension and in patients with pre-existing edema regardless of its origin because inhibition of Prostaglandins can cause deterioration of kidney function and fluid retention. Precautions will also be necessary in patients treated with diuretics or at risk of hypovolaemia.

Hypertension

• Like all NSAIDs, celecoxib can cause hypertension or worsen pre-existing hypertension, thus increasing the incidence of cardiovascular events. Close monitoring of blood pressure at the start of treatment with celecoxib and then during treatment should therefore be carried out.

Renal and hepatic effects

• The existence of impaired renal or hepatic function, and particularly cardiac dysfunction, is more likely in the elderly. Therefore, appropriate medical surveillance should be ensured.
• NSAIDs, including celecoxib, may be responsible for renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those seen with comparator NSAIDs. The patients most at risk of developing renal toxicity are patients with renal failure, heart failure, hepatic disorders, and the elderly. These patients should be closely monitored while receiving celecoxib therapy.
• A few cases of serious hepatic reactions have been reported with celecoxib, including fulminant hepatitis (some fatal), hepatic necrosis and hepatic failure (some fatal or requiring liver transplantation). In cases for which time to onset was reported, most serious hepatic reactions occurred within one month of starting treatment .
• During treatment, appropriate measures will be taken and discontinuation of celecoxib treatment should be considered if there is any functional deterioration of the above mentioned organs.

CYP2D6 inhibition

• Celecoxib inhibits CYP2D6. Even though it is not a strong inhibitor of this enzyme, a dosage reduction may be necessary for medicines whose dose is adjusted for each patient and which are metabolized by CYP2D6 . and other forms of interactions).

CYP2C9 poor metabolisers

• Patients known to be poor metabolisers of CYP2C9 should be treated with caution.

Skin reactions and systemic hypersensitivity reactions

• Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and Lyell syndrome, have been very rarely reported in association with the use of celecoxib (see section 4.8). The risk of these effects occurring seems to be greatest at the start of treatment, the onset of these effects occurring in the majority of cases during the first month of treatment. Serious hypersensitivity reactions (anaphylaxis and angioedema) have been reported in patients receiving celecoxib .
• Patients with a history of allergy to sulfonamides or to any other medication may be at increased risk of serious skin reactions or hypersensitivity . Celecoxib should be stopped at the first sign of skin rash, mucosal damage, or any other sign of hypersensitivity.

General effects

• Celecoxib may mask fever and other signs of inflammation.

Use with oral anticoagulants

• In patients treated with warfarin, severe bleeding has been reported. An increased prothrombin time (INR) has been reported with concomitant treatments. It should therefore be closely monitored in patients receiving warfarin / oral coumarin-type anticoagulants, particularly when initiating therapy with celecoxib or when the dose of celecoxib is changed (see section 4.5). and other forms of interactions). The concomitant use of anticoagulants and NSAIDs may increase the risk of bleeding. Caution should be exercised when co-administering celecoxib with warfarin or other oral anticoagulants, including with newer anticoagulants (for example: apixaban,

Excipients

• CELECOXIB SANDOZ contains lactose. Patients with galactose intolerance, lactase deficiency, or glucose or galactose malabsorption syndrome (rare hereditary diseases) should not take this medicine.

PREGNANCY & BREAST-FEEDING & FERTILITY

Pregnancy

• Studies in animals (rats and rabbits) have shown toxicity on the reproductive functions including malformations (see sections Contra-indications and Preclinical safety data). Inhibition of prostaglandin synthesis could have a deleterious effect on pregnancy. Data from epidemiological studies point to an increased risk of spontaneous miscarriages after the use of prostaglandin synthesis inhibitors in early pregnancy. In humans, the risk during pregnancy is unknown but cannot be excluded. Like other drugs that inhibit prostaglandin synthesis, celecoxib can cause uterine inertia and premature closure of the ductus arteriosus in the last trimester of pregnancy. Celecoxib is contraindicated during pregnancy and in women who may become pregnant (see sections Contraindications and Warnings and precautions for use). If pregnancy is discovered during treatment, celecoxib should be stopped.

Feeding with milk

• Celecoxib is excreted in the milk of rats at concentrations similar to those found in plasma. Administration of celecoxib to a small number of breastfeeding women has shown very little passage of celecoxib into breast milk. Patients treated with celecoxib should not breast-feed.

Fertility

• Due to their mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent the rupture of ovarian follicles, which has been associated with reversible infertility in some women.

What happens if I overdose from Celecoxib Sandoz ?

There is no clinical experience with overdose. Single doses up to 1200 mg and repeated doses up to 1200 mg, twice daily, have been administered for 9 days to healthy subjects without causing clinically significant adverse effects. 

In the event of a possible overdose, appropriate medical management is necessary, for example evacuation of gastric contents, clinical monitoring and, if necessary, symptomatic treatment. 

Dialysis is unlikely to be an effective means of eliminating the drug due to its strong protein binding.

What is  Forms and Composition ?

NOT’s

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Additional information:

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Special warnings:

• For pregnant and breastfeeding women, the elderly, boys and drivers, and use before surgery.

Side effects:

• It treats possible side effects and drug interactions that require attention and its effect on continuous use.
• The information contained in this medicine is based on medical literature, but it is not a substitute for consulting a doctor.