onsenal Uses, Dosage, Side Effects, Precautions & Warnings

Generic drug of the Therapeutic class: Oncology and hematology
Active ingredients: Celecoxib

Drug withdrawn from the market on 05/05/2011

what is onsenal medication used for and indication?

Onsenal is indicated for the reduction of the number of intestinal adenomatous polyps in familial adenomatous polyposis (FAP), in combination with surgery and in addition to endoscopic monitoring.

The effect of the reduction in the number and size of polyps induced by Onsenal on the risk of intestinal cancer has not been demonstrated.

onsenal Dosage

• The recommended oral dose is one 400 mg capsule twice daily, taken with food.
• The usual management of patients with familial adenomatous polyposis should be continued during treatment with celecoxib.
• The maximum recommended daily dose is 800 mg.
• Hepatic impairment: In patients with moderate hepatic impairment (serum albumin between 25 and 35 g / l), the recommended daily dose of celecoxib should be reduced by 50% (see sections Contraindications and Pharmacokinetic properties ). Caution is necessary in the absence of experience in these patients with doses above 200 mg.
• Renal impairment: As experience with celecoxib in patients with mild or moderate renal impairment is limited, these patients should be treated with caution .
• Pediatric population: Experience with celecoxib in patients less than 18 years of age with FAP is limited to a single pilot study in a very small population in which patients received daily doses of up to 16 mg / kg of celecoxib, corresponding to the recommended daily dose of 800 mg in adults with FAP.
• CYP2C9 Poor Metabolisers: Patients who are CYP2C9 poor metabolisers or suspected of being metabolisers on the basis of genotype or history / experience with other CYP2C9 substrates, should be administered celecoxib with caution, as there is a risk of dose-dependent adverse effects is increased. A reduced dose at the start of treatment should be considered .
• Elderly: The dose in elderly patients with familial adenomatous polyposis has not been established. Special precautions may be necessary in these patients.

onsenal Contraindications

• – Hypersensitivity to the active principle or to one of the excipients (see Composition section “List of excipients”).
• – Known hypersensitivity to sulfonamides.
• – Active peptic ulcer or gastrointestinal (GI) bleeding.
• – Patients with a history of asthma, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic-type reactions triggered by the intake of acetylsalicylic acid or non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 (cyclo-oxygenase-2) inhibitors.
• – Pregnancy and women of childbearing potential, in the absence of effective contraception (see sections Interactions with other medicinal products and other forms of interactions , Pregnancy and breast-feeding and Preclinical safety data ).
• – Breast-feeding (see sections Pregnancy and breast-feeding and Preclinical safety data ).
• – Severe hepatic impairment (serum albumin <25 g / l or Child-Pugh score ≥ 10) (Class C).
• – Patients with renal impairment with estimated creatinine clearance <30 ml / min.
• – Inflammatory bowel disease.
• – Congestive heart failure (NYHA II-IV).
• – Known ischemic heart disease, peripheral arterial disease, and / or history of stroke (including transient ischemic attack).

how does onsenal work?

Pharmacotherapeutic group: Antineoplastic drugs, ATC code: L01XX33

Celecoxib is a pyrazole derivative substituted with two aryl groups, a chemical analogue of other non-arylamine sulfonamides (eg thiazides, furosemide) but differs from arylamine sulfonamides (eg sulfamethoxazole and other sulfonamide antibiotics).

Celecoxib is an oral, selective inhibitor of cyclooxygenase-2 (COX-2) No statistically significant inhibition of COX-1 (assessed by ex-vivo inhibition of thromboxane B2 [TxB2] formation) n ‘ was observed in healthy volunteers at the therapeutic dose, in familial adenomatous polyposis, of 400 mg twice daily.

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. High levels of COX-2 are found in many pre-malignant lesions (such as colorectal adenomatous polyps) and epithelial cancers. Familial adenomatous polyposis (FAP) is a genetic disease resulting from an autosomal dominant genetic alteration of a tumor suppressor gene, the APC (Adenomatous Polyposis Coli) gene. Polyps with mutation of the APC gene and untreated overexpressing COX-2, continue to form and grow in the colon or rectum with a 100% risk of progressing to colorectal cancer. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function and certain functions of the central nervous system (induction of fever, perception of pain and cognitive function). It could also play a role in the healing of ulcers. COX-2 has been demonstrated in tissues around gastric ulcers in humans but its involvement in ulcer healing has not been established. regulation of renal function and certain functions of the central nervous system (fever induction, pain perception and cognitive function). It could also play a role in the healing of ulcers. COX-2 has been demonstrated in tissues around gastric ulcers in humans but its involvement in ulcer healing has not been established. regulation of renal function and certain functions of the central nervous system (fever induction, pain perception and cognitive function). It could also play a role in the healing of ulcers. COX-2 has been demonstrated in tissues around gastric ulcers in humans but its involvement in ulcer healing has not been established.

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. COX-2 inhibitors reduce systemic (and therefore possibly endothelial) prostacyclin formation without altering platelet thromboxane.

A dose-dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in healthy subjects and in small, multiple-dose studies with 600 mg twice daily, celecoxib had no effect on platelet aggregation or bleeding time compared to placebo.

It has been experimentally proven that the mechanism (s) of action by which celecoxib leads to tumor death appears to be related to the induction of apoptosis and inhibition of angiogenesis. Inhibition of COX-2 may impact tumor viability unrelated to inflammation.

Celecoxib inhibits tumor formation in preclinical models of colon cancer, which overexpress COX-2, either chemically induced (the AOM rat model) or by genetic mutation (the MIN mouse model).

Celecoxib has been shown to reduce the number and size of colorectal adenomatous polyps. A randomized, double-blind, placebo-controlled study was conducted in 83 patients with familial adenomatous polyposis. The study population included 58 patients who had previously undergone partial or total colectomy and 25 patients presented an intact colon. Thirteen subjects had an attenuated phenotype for familial adenomatous polyposis. The mean reduction in the number of colorectal polyps after 6 months of treatment was 28% (SD ± 24%) for celecoxib at a dose of 400 mg twice daily, which is statistically superior to placebo (mean 5%, SD ± 16%). A notable reduction in the duodenal adenomatous surface was also observed compared to placebo (14,

Pilot study in adolescents with PAF: a total of 18 children aged 10 to 14 years with an FAP-positive genotype or phenotype were treated with celecoxib at doses of 4 mg / kg / day (4 patients, compared with 2 patients treated with placebo), 8 mg / kg / day (4 patients, versus 2 patients treated with the placebo), or 16 mg / kg / day (4 patients, versus 2 patients treated with the placebo). The results demonstrated a statistically significant reduction in the number of polyps in all groups treated with celecoxib compared to the corresponding groups treated with placebo. The greatest reduction was seen in patients treated with celecoxib at a dose of 16 mg / kg / day, which corresponds to the recommended dose of 800 mg per day in adults with FAP.

The long-term cardiovascular toxicity of children exposed to celecoxib has not been evaluated, and it is not known whether the long-term risk is similar to the risk seen in adults exposed to celecoxib or other selective COX-2 and non-NSAIDs. selective (see section Warnings and precautions for use; cardiovascular effects).

Cardiovascular Safety – Long Term Studies Involving Subjects With Sporadic Adenomatous Polyps : Two studies in subjects with sporadic adenomatous polyps were conducted with celecoxib, namely the APC (Celecoxib Adenoma Prevention) trial and the PreSAP trial (prevention of spontaneous adenomatous polyps). The APC trial demonstrated a dose-dependent increase in the composite endpoint (appraised) associating cardiovascular death, myocardial infarction and stroke with celecoxib compared to placebo during 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 risks compared to placebo for a composite endpoint (expertized) combining death from cardiovascular disease, myocardial infarction or stroke were 3.4 (95% CI 1.4 – 8.5) with a twice-daily intake of 400 mg of celecoxib and 2.8 (95 CI – 7.2) with a twice-daily intake of 200 mg of celecoxib. The cumulative rates for this composite endpoint over 3 years were 3.0% (20 cases / 671 subjects) and 2.5% (17 cases / 685 subjects), respectively, compared to 0.9% (6 cases / 679 subjects) for the placebo. The increases observed in the two celecoxib and placebo groups are mainly explained by an increased incidence of myocardial infarction.

In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (expertly) was 1.2 (95% CI 0.6 – 2.4) with a daily intake of 400 mg of celecoxib compared to placebo. The cumulative rates for this composite endpoint over 3 years were 2.3% (21 cases / 933 subjects) and 1.9% (12 cases / 628 subjects), respectively. The incidence of myocardial infarction (expert opinion) was 1.0% (9 subjects / 933) with a daily intake of 400 mg of celecoxib, compared with 0.6% (4 cases / 628 subjects) with placebo.

Data from a third long-term study called ADAPT (The Alzheimer’s Disease Anti-inflammatory Prevention Trial) showed no significant increase in cardiovascular risk associated with taking 200 mg of celecoxib twice daily compared to placebo. The relative risk compared to placebo for a similar composite endpoint (CV death, MI, stroke) was 1.14 (95% CI 0.61 – 2.12) with 200 mg of celecoxib twice daily. The incidence of myocardial infarction was 1.1% (8 cases / 717 patients) with 200 mg of celecoxib twice daily, compared with 1.2% (13 cases / 1070 patients) with placebo.

Data from pooled analyzes of randomized controlled trials also suggest that cardiovascular risk may be associated with the use of celecoxib compared to placebo, indicating differences in the level of risk related to the dose of celecoxib.

A marketing authorization “under exceptional circumstances” has been granted to this drug.

This means that due to the rarity of this disease it has not been possible to obtain complete information about this medicine. The European Medicines Agency (EMEA) will reassess every year any new information that may be provided, and if necessary this SmPC will be updated.

onsenal capsule Side Effects

Adverse reactions are listed by system organ class and classified by frequency in Table 1, based on data from the following sources:

– Adverse reactions reported in patients with osteoarthritis and rheumatoid arthritis at incidence rates greater than 0.01% and greater than those reported for placebo in 12 clinical trials conducted with a reference drug and / or a placebo, lasting up to 12 weeks, with daily doses of celecoxib ranging from 100 mg to 800 mg. In additional studies using non-selective NSAIDs as comparators, approximately 7,400 arthritis patients were treated with celecoxib up to 800 mg / day, of whom approximately 2,300 were treated for at least 1 year. The adverse reactions seen with celecoxib in these additional studies were consistent with those seen in patients with osteoarthritis and rheumatoid arthritis in Table 1.

Adverse effects reported spontaneously after marketing, a period during which it is estimated that more than 70 million patients are treated with celecoxib (different doses, durations and indications). Since not all of the side effects are reported to the MA holder and included in the pharmacovigilance database, it is difficult to establish the frequency of these side effects reliably.

TABLE 1	Common ( ≥ 1/100 to <1/10)	Uncommon ( ≥ 1/1000 to <1/100)	Rare ( ≥ 1 / 10,000 to <1/1000)	Frequency not known (Post-market experience) 1
Infections and infestations	Sinusitis, upper respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders		Anemia	Leukopenia, thrombocytopenia	Pancytopenia
Immune system disorders	Allergy worsening			Severe allergic reactions, anaphylactic shock, anaphylaxis
Psychiatric disorders	Insomnia	Anxiety, depression, fatigue	Confusion	Hallucinations
Metabolism and nutrition disorders		Hyperkalaemia
Nervous system disorders	Dizziness, hypertonia	Paresthesia, drowsiness	Ataxia, disgeusia	Headache, worsening epilepsy, aseptic meningitis, ageusia, anosmia, fatal intracranial hemorrhage
Eye disorders		Blurred vision		Conjunctivitis, ocular hemorrhage, occlusion of the retinal vein or artery
Ear and labyrinth disorders		Tinnitus		Hearing loss
Cardiac disorders		Heart failure, palpitations, tachycardia	Myocardial infarction2	Arrhythmia
Vascular disorders		Hypertension, worsening of hypertension		Flushing, vasculitis
Respiratory, thoracic and mediastinal disorders	Pharyngitis, rhinitis, cough	Dyspnea		Bronchospasm
Gastrointestinal disorders	Abdominal pain, diarrhea, dyspepsia, gas	Constipation, belching, gastritis, stomatitis, vomiting, worsening gastrointestinal inflammation	Duodenal, gastric, esophageal, intestinal and colon ulcers, dysphagia, intestinal perforation, esophagitis, melena, pancreatitis	Nausea, acute pancreatitis, gastrointestinal bleeding, colitis / worsening colitis
Hepatobiliary disorders		Abnormal liver function, elevation of AST and ALT	Elevation of liver enzymes	Hepatitis, hepatic failure, jaundice
Skin and subcutaneous tissue disorders	Rash, pruritus	Urticaria	Alopecia, photosensitivity	Ecchymosis, bullous rash, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema
Musculoskeletal and connective tissue disorders		Leg cramps		Arthralgia, myositis
Kidney and urinary tract disorders		Elevated creatinine, elevated azotemia		Acute renal failure, interstitial nephritis, hyponatremia
Reproductive system and breast disorders				Menstrual disturbances
General disorders and administration site conditions	Flu-like syndrome, peripheral edema / fluid retention
1 Adverse reactions spontaneously reported to the pharmacovigilance database over a period during which it is estimated that more than 70 million patients were treated with celecoxib (different doses, durations and indications). Therefore, the frequency of side effects cannot be reliably established. The adverse reactions listed for the post-marketing population are only those that are not already listed in Table 1 for Osteoarthritis Trials or Table 2 for Polyposis Prevention. 2 In an analysis of the results of 20 placebo-controlled trials in the treatment of osteoarthritis and rheumatoid arthritis with durations ranging from more than 2 weeks to one year, the increase in myocardial infarction compared to placebo in patients treated with celecoxib 200 or 400 mg per day was 0.7 events per 1000 patients (rare incidence) and there were no additional strokes.

Additional adverse reactions listed by system organ class and classified by frequency in Table 2 have been reported with higher incidence rates than placebo in subjects treated with celecoxib 400 to 800 mg per day. in long-term polyposis prevention trials lasting up to 3 years (APC and PreSAP trials; see section Pharmacodynamic properties, Pharmacodynamic properties: Cardiovascular safety – Long-term studies involving subjects with adenomatous polyps sporadic).

TABLE 2	Very common ( ≥ 1/10)	Common ( ≥ 1/100 to <1/10)	Uncommon ( ≥ 1/1000 to <1/100)
Infections and infestations		Otitis, mycotic infection (mycotic infections were mostly non-systemic)	Helicobacter infection, shingles, erysipelas, superinfection of a wound, gum infection, labyrinthitis, bacterial infection
Neoplasms benign, malignant and unspecified (incl cysts and polyps)			Lipoma
Psychiatric disorders			Sleeping troubles
Nervous system disorders			Cerebral infarction
Eye disorders			Vitreous floaters, conjunctival hemorrhage
Ear and labyrinth disorders			Hearing loss
Cardiac disorders		Angina pectoris; myocardial infarction	Unstable angina, aortic valve failure, coronary atherosclerosis, sinus bradycardia, ventricular hypertrophy
Vascular disorders	Hypertension*		Deep vein thrombosis ; hematoma
Respiratory, thoracic and mediastinal disorders		Dyspnea	Dysphonia
Gastrointestinal disorders	Diarrhea*	Nausea, gastroesophageal reflux disease, diverticulum, vomiting *, dysphagia, irritable bowel syndrome	Hemorrhoidal bleeding, frequent bowel movements, mouth ulcers, stomatitis
Skin and subcutaneous tissue disorders			Allergic dermatitis
Musculoskeletal and connective tissue disorders		Muscle spasms	Ganglia
Kidney and urinary tract disorders		Nephrolithiasis, increased blood creatinine level	Nocturia
Reproductive system and breast disorders		Benign prostatic hyperplasia, prostatitis, increased prostate specific antigen	Vaginal bleeding, mastodynia, dysmenorrhea, ovarian cyst, symptoms of menopause
General disorders and administration site conditions		Edema
Investigations		Weight gain	Increase in blood levels of: potassium, sodium, hemoglobin Decrease in blood levels of: hematocrit, testosterone
Injury, poisoning and procedural complications			Foot fracture, lower limb fracture, epicondylitis, tendon rupture, fracture
* Hypertension, vomiting and diarrhea are listed in Table 2 because these symptoms were reported more often in these studies, which took place over a period of 3 years, compared to Table 1, which shows the adverse reactions that occurred as part of studies lasting 12 weeks.

The final (expert) data of the APC trial carried out in patients treated with celecoxib at a dose of 800 mg / day for a maximum duration of three years shows that the increase in myocardial infarction compared to placebo was 11 events per 1000 patients (common); and 5 events per 1000 stroke patients (uncommon; undifferentiated types of stroke).

onsenal Interactions

Pharmacodynamic interactions

• The majority of interaction studies have been performed with celecoxib doses of 200 mg twice daily (such as those used in osteoarthritis and rheumatoid arthritis). A more pronounced effect with doses of 400 mg twice a day cannot therefore be excluded.
• Anticoagulant activity should be monitored in patients taking warfarin or other anticoagulants, especially in the first few days after initiating or changing the dose of celecoxib, as these patients have an increased risk of bleeding complications. For this reason, taking oral anticoagulants should be accompanied by close monitoring of patients’ prothrombin time INR.
• Anticoagulant activity should be monitored in patients taking warfarin or related products, especially in the first few days after initiating or changing the dose of celecoxib. Bleeding, some with fatal outcome, associated with prolonged prothrombin time has been reported in patients with osteoarthritis (mainly in the elderly), concomitantly receiving celecoxib and warfarin ( see section Warnings and precautions for use).
• NSAIDs can reduce the effects of diuretic and antihypertensive drugs. As with NSAIDs, the risk of acute renal failure, which is usually reversible, may be increased in certain patients with impaired renal function (for example: dehydrated patients or elderly patients) when taking ACE inhibitors or antagonists of the receptor receptor. angiotensin II with these NSAIDs, including celecoxib. Therefore, this combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and renal function should be monitored after initiation of concomitant therapy and then periodically.
• In a 28-day clinical study in patients with grade 1 and 2 hypertension controlled by lisinopril, administration of 200 mg celecoxib twice daily did not show a clinically significant increase. , compared to treatment with placebo, of the mean daily systolic or diastolic blood pressure, determined by ambulatory blood pressure monitoring over 24 hours. Among the patients treated with celecoxib 200 mg twice daily, 48% were considered to be non-responders to lisinopril at the final clinical visit (either a diastolic blood pressure at the cuff> 90 mmHg or increased> 10% compared to the value basal), compared to 27% of patients treated with placebo; this difference was statistically significant.
• An increased nephrotoxicity of ciclosporin and tacrolimus has been suggested when NSAIDs are administered concomitantly with cyclosporin D derivatives or tacrolimus. Renal function should be monitored if celecoxib is combined with any of these drugs.
• Celecoxib can be used in combination with a low dose of acetylsalicylic acid, but cannot substitute for acetylsalicylic acid for cardiovascular prevention. As with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications has been demonstrated with the concomitant administration of low doses of acetylsalicylic acid, compared to the use of celecoxib alone. (see section Pharmacodynamic properties).

Pharmacokinetic interactions

Effects of celecoxib on other drugs

• Celecoxib is a weak inhibitor of cytochrome CYP2D6. During treatment with celecoxib, the mean plasma concentrations of dextromethorphan, a CYP2D6 substrate, increased by 136%. 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.
• In vitro studies have shown that celecoxib has the potential to inhibit the metabolism catalyzed by CYP2C19. The clinical significance of this in vitro observation is not known. Drugs metabolized by CYP2C19 are, for example, diazepam, citalopram and imipramine.
• In an interaction study, celecoxib had no clinically relevant effect on the pharmacokinetics of oral contraceptives (1 mg norethistherone / 35 µg ethinyl estradiol).
• Celecoxib does not affect the pharmacokinetics of tolbutamide (cytochrome CYP2C9 substrate) or glibenclamide in a clinically relevant manner.
• In patients with rheumatoid arthritis, celecoxib did not have a statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (at the doses used in rheumatology). However, adequate monitoring of methotrexate-related toxicity should be considered when combining these two drugs.
• In healthy subjects, the concomitant administration of 200 mg twice daily of celecoxib with 450 mg twice daily of lithium resulted in an average increase of 16% in C max and 18% in ASC of lithium. Therefore, patients treated with lithium should be closely monitored when initiating or stopping celecoxib.

Effects of Other Drugs on Celecoxib

• In subjects who are poor metabolisers of CYP2C9 and who have increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors could result in subsequent increases in celecoxib exposure. These combinations should be avoided in proven poor metabolisers of CYP2C9 (see  Pharmacokinetic properties).
• Since celecoxib is primarily metabolized by 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 an average 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.

Warnings and Precautions

Treatment of familial adenomatous polyposis with celecoxib has been studied for up to 6 months and has not been shown to reduce the risk of gastrointestinal cancer or other cancer or reduce the need for resort to surgery. Therefore, the usual management of patients with familial adenomatous polyposis should not be altered by concomitant administration of celecoxib. In particular, the frequency of routine endoscopic monitoring should not be reduced and surgery for familial adenomatous polyposis should not be delayed.

Gastrointestinal disturbances

• Upper gastrointestinal complications, [perforations, ulcers or hemorrhages (PUH)], some of which have been observed with fatal outcome in patients treated with celecoxib Caution is advised when treating patients most at risk of developing a complication gastrointestinal with NSAIDs: the elderly, patients taking concomitant treatment with other NSAIDs or acetylsalicylic acid or patients with a history of gastrointestinal illness such as ulceration and GI bleeding.
• There is a potentiation of the 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 / acetylsalicylic acid and the combination of NSAIDs / acetylsalicylic acid has not been demonstrated in long-term clinical trials (see section Properties). pharmacodynamics).
• The combination of celecoxib and an NSAID other than aspirin should be avoided.
• Patients with familial adenomatous polyposis with an ileorectal anastomosis or an ileo-anal anastomosis may develop anastomotic ulcerations. In the event of an anastomotic ulcer, patients should not receive concomitant treatment including anticoagulants or acetylsalicylic acid.

Blood and lymphatic disorders / Cardiovascular disorders

• Compared with placebo, an increase in the number of serious cardiovascular events, mainly myocardial infarctions, was observed in a long-term clinical trial in patients with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg twice times daily and 400 mg twice daily.
• Since the cardiovascular risks of celecoxib were increased with a twice-daily intake of 400 mg celecoxib during the APC clinical trial (section Pharmacodynamic properties), the response to celecoxib in the patient with PAF should be reviewed periodically in order to avoid any unnecessary exposure in patients with FAP for whom celecoxib is not effective.
• 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 platelet effects, selective COX-2 inhibitors cannot substitute for acetylsalicylic acid in the prevention of thromboembolic cardiovascular disease. Therefore, antiplatelet therapy should not be stopped (see section Pharmacodynamic properties).
• 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 high blood pressure, and in patients with pre-existing edema regardless of the origin, as inhibition of prostaglandins can lead to deterioration of renal function and fluid retention. Precautions are also necessary in patients treated with diuretics or at risk of hypovolaemia.
• Like all NSAIDs, celecoxib may cause the onset of hypertension or worsening of pre-existing hypertension, which may contribute to an increase in the incidence of cardiovascular events. Therefore, blood pressure should be closely monitored when starting celecoxib therapy and throughout therapy.
• In the case of elderly subjects with mild to moderate cardiac dysfunction requiring therapy, special attention and monitoring is warranted. The existence of impaired renal or hepatic function and particularly cardiac dysfunction is more likely in the elderly, therefore appropriate medical supervision should be ensured.

Renal and hepatic disorders

• NSAIDs, including celecoxib, can cause kidney toxicity. Clinical trials with celecoxib have shown renal effects similar to those seen with comparator NSAIDs. Patients at higher risk of renal toxicity are those with impaired renal function, heart failure, hepatic dysfunction and the elderly. These patients should be carefully monitored during treatment with celecoxib.
• Experience with celecoxib in patients with mild or moderate renal or hepatic impairment is limited; therefore, these patients should be treated with caution (see Pharmacokinetic properties).
• Appropriate measures should be taken and discontinuation of celecoxib treatment should be considered if there is any functional deterioration of any of the above mentioned organs during treatment.

Skin reactions

• Serious skin reactions, some with fatal outcome, such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell syndrome), have been very rarely reported in association with the use of celecoxib.
• unwanted). 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 skin reactions. hypersensitivity (see section Contraindications). Celecoxib treatment should be stopped at the first sign of skin rash, mucosal damage or any other sign of hypersensitivity.

Other

• Patients known to be poor metabolisers of CYP2C9 should be treated with caution.
• Celecoxib may mask fever and other signs of inflammation.
• Serious bleeding has been reported in patients treated with warfarin. Care should be taken when concomitantly administering celecoxib with warfarin and other oral anticoagulants.
• Onsenal 400 mg hard capsules contain lactose (99.6 mg). Patients with rare hereditary problems of galactose intolerance, LAPP lactase deficiency, or glucose or galactose malabsorption should not take this medicine.

PREGNANCY & BREAST-FEEDING & FERTILITY

• There are no clinical data from pregnancies exposed to celecoxib. Studies in animals (rats and rabbits) have demonstrated toxicity on the reproductive functions (see sections Contraindications and Preclinical safety data). The potential risk to humans is unknown. Like other drugs that inhibit prostaglandin synthesis, celecoxib can cause uterine inertia and premature closure of the ductus arteriosus in the last trimester.
• Celecoxib is contraindicated during pregnancy and in women of childbearing potential in the absence of effective contraception (see section Contraindications). If pregnancy is discovered during treatment, celecoxib should be stopped.
• Celecoxib is excreted in the milk of lactating rats at concentrations similar to those found in plasma. Administration of celecoxib to a limited number of nursing women has shown a very low rate of celecoxib passage into breast milk. Patients treated with celecoxib should not breast-feed.

What happens if I overdose from onsenal ?

There is no clinical experience with overdose in clinical trials. 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 events. 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 should I do if I miss a dose?

What happens if you stop taking onsenal ?

• Not applicable
• Not applicable
• Not applicable
• Not applicable

What is  Forms and Composition ?

Appearance and shape

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.