Instructions for Ranselex capsules 200 mg No. 10
Composition
active substance: celecoxib;
1 capsule contains celecoxib 100 mg or 200 mg;
auxiliary substances: lactose, monohydrate; povidone; colloidal anhydrous silicon dioxide; sodium lauryl sulfate; croscarmellose sodium; magnesium stearate;
capsule composition: gelatin, sodium lauryl sulfate, titanium dioxide (E171).
Medicinal form
Capsules.
The main physical and chemical properties:
100 mg capsules: white or almost white hard gelatin capsules with the inscription "SS" on the cap and "100" on the capsule body in black ink, which contain white or almost white granulated powder;
200 mg capsules: white or almost white hard gelatin capsules with the inscription "SS" on the cap and "200" on the capsule body in black ink, which contain a white or almost white granular powder.
Pharmacotherapeutic group
Non-steroidal anti-inflammatory and anti-rheumatic agents. Coxibs. ATX code M01A N01.
Pharmacological properties
Pharmacodynamics.
Celecoxib is an oral selective cyclooxygenase-2 (COX-2) inhibitor in the clinical dosage range (200-400 mg per day). No statistically significant inhibition of COX-1 (which was assessed as inhibition of ex vivo formation of thromboxane B2 [TxB2]) was observed in healthy volunteers in this dosage range.
Cyclooxygenase is responsible for the formation of prostaglandins. Two of its isoforms, COX-1 and COX-2, were found. COX-2 is an isoform of the enzyme that is induced by pro-inflammatory stimuli and is the main factor in the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in the process of ovulation, implantation and closure of the ductus arteriosus, regulation of kidney function and functions of the central nervous system (causing fever, sensation of pain and cognitive function). It can also play a role in the healing of ulcers. COX-2 was found in tissues around gastric ulcers in humans, but its significance for ulcer healing has not been established.
Differences in antiplatelet activity between some nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-1 and selective COX-2 inhibitors may have clinical significance for patients at risk of thromboembolic reactions. Selective COX-2 inhibitors reduce the formation of systemic (and therefore, probably, endothelial) prostacyclin without affecting platelet thromboxane.
Celecoxib is a pyrazole with a substituted diaryl chemically similar to other non-arylamine sulfonamides (for example, thiazides, furosemide), but differs from arylamine sulfonamides (for example, sulfamethoxazole and other sulfonamide antibiotics).
After the introduction of high doses of celecoxib, a dose-dependent effect on the formation of TxB2 was observed. However, in healthy patients in small studies using multiple doses of 600 mg twice a day (three times the maximum recommended dose), celecoxib did not affect platelet aggregation and bleeding time compared to placebo.
To confirm the effectiveness and safety of the drug in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, several studies were conducted.
The use of celecoxib for the treatment of inflammation and pain in knee and hip osteoarthritis has been evaluated in approximately 4,200 patients in placebo- and active-controlled studies lasting up to 12 weeks. The drug was also evaluated for the treatment of inflammation and pain in rheumatoid arthritis in approximately 2,100 patients in placebo- and active-controlled studies lasting up to 24 weeks. Daily doses of celecoxib 200-400 mg provided analgesia within 24 hours from the moment of taking the drug. Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo- and active-controlled studies lasting up to 12 weeks. Celecoxib in doses of 100 mg 2 times a day, 200 mg a day, 200 mg 2 times a day and 400 mg a day in these studies demonstrated a significant relief of pain, a decrease in the overall activity of the disease and an improvement in functioning in ankylosing spondylitis.
In a prospective long-term safety study of long-term results (duration from 6 to 15 months), patients with osteoarthritis and patients with rheumatoid arthritis received celecoxib at a dose of 400 mg 2 times a day (4 and 2 times higher than the doses recommended for osteoarthritis and rheumatoid arthritis), ibuprofen 800 mg 3 times a day or diclofenac 75 mg 2 times a day (therapeutic doses for both drugs). 22% of participants took accompanying low doses of acetylsalicylic acid (325 mg per day) mainly for the prevention of cardiovascular diseases. Regarding the primary endpoint of complicated ulcer (which was defined as gastrointestinal bleeding, perforation, or obstruction), celecoxib was almost indistinguishable from ibuprofen or diclofenac. Also, for the combined group taking NSAIDs, there was no statistically significant difference for complicated ulcers (relative risk 0.77, confidence interval (CI) 95% 0.41-1.46, based on the entire study duration). For the combined endpoint, complicated and symptomatic ulcers, the incidence was significantly lower in the celecoxib group than in the NSAID group (RR 0.66, 95% CI 0.45-0.97), but not between celecoxib and diclofenac. In patients who received celecoxib and accompanying low doses of acetylsalicylic acid, complicated ulcers developed 4 times more often compared to subjects who received only celecoxib. The incidence of a clinically significant decrease in hemoglobin level (> 2 g/dL), confirmed by repeated tests, was significantly lower in patients receiving celecoxib than in the group receiving NSAIDs (relative risk 0.29, CI 95% 0.17-0.48). The frequency of occurrence of this phenomenon when taking celecoxib was significantly lower, both with and without the simultaneous use of acetylsalicylic acid.
In a prospective, randomized, 24-week safety study in patients aged 60 years or with a history of gastric and duodenal ulcers (patients taking acetylsalicylic acid were excluded), the percentage of patients with a decrease in hemoglobin (2 g/dL) and/or hematocrit (10%) due to confirmed or possible gastrointestinal disorders was lower in patients receiving celecoxib at a dose of 200 mg twice a day (N = 2238) compared to patients who received diclofenac extended-release at a dose of 75 mg twice a day plus omeprazole at a dose of 20 mg once a day (N = 2246) (0.2% compared with 1.1% for etiologies associated with disturbances from the digestive tract, p = 0.004; 0.4% compared to 2.4% for possible etiology associated with disorders of the digestive tract, p = 0.0001). The frequency of clinical complications from the digestive tract, such as perforation, obstruction or bleeding, was very low, and there were no differences between the treatment groups (4-5 per group).
Cardiovascular safety: long-term studies involving patients with sporadic adenomatous polyps
When conducting studies using celecoxib, in which patients with sporadic adenomatous polyps took part. In one of the studies (study 1), a dose-dependent increase in the combined end point of cardiovascular death, myocardial infarction or stroke (confirmed) was recorded when taking celecoxib compared to placebo during 3 years of treatment. The second study (study 2) did not demonstrate a statistically significant increase in the risk of the same combined endpoint.
In study 1, relative risks compared with placebo for the combined endpoint (confirmed) of cardiovascular death, myocardial infarction, or stroke were 3.4 (CI 95% 1.4-8.5) when using 400 mg celecoxib twice daily and 2.8 (CI 95% 1.1-7.2) when using 200 mg celecoxib twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 patients) and 2.5% (17/685 patients), respectively, compared with 0.9% (6/679 patients) for placebo. The increase in values for both groups receiving celecoxib compared to placebo was mainly due to myocardial infarction.
In study 2, the relative risk compared to placebo for the same combined endpoint (validated) was 1.2 (CI 95% 0.6-2.4) when using 400 mg of celecoxib 1 time per day compared to placebo. Cumulative rates for this combined endpoint over a period of more than 3 years were 2.3% (21/933 patients) and 1.9% (12/628 patients), respectively. The frequency of myocardial infarction (confirmed) was 1.0% (9/933 patients) when using 400 mg celecoxib 1 time per day and 0.6% (4/628 patients) when using placebo.
Data obtained from a long-term study of the prevention of Alzheimer's disease did not show a significant increase in cardiovascular risk when taking 200 mg of celecoxib 2 times a day compared to placebo. The relative risk compared to placebo for a similar combined point (cardiovascular death, myocardial infarction or stroke) was 1.14 (CI 95% 0.61-2.12) when taking 200 mg of celecoxib 2 times a day. The frequency of myocardial infarction was 1.1% (8/717 patients) when taking 200 mg of celecoxib 2 times a day and 1.2% (13/1070 patients) when using placebo.
Rancelex is well absorbed, its concentration in blood plasma reaches its maximum level after about 2-3 hours. Reception with food (with a high fat content) delays absorption for approximately 1 hour.
Celecoxib is eliminated mainly through metabolism. In the unchanged state, less than 1% of the dose is excreted in the urine. Individual variability of celecoxib exposure parameters can vary by 10 times. In the therapeutic dosage range, celecoxib exhibits dose- and time-independent pharmacokinetics. Binding to blood plasma proteins is approximately 97% at a therapeutic plasma concentration, and the drug practically does not bind to erythrocytes. The half-life is 8-12 hours. The equilibrium concentration in blood plasma is reached within 5 days of treatment. Pharmacological activity is characteristic of the original drug. The main metabolites found in the circulation did not have detectable activity against COX-1 and COX-2.
Celecoxib is metabolized mainly with the participation of cytochrome P450 2C9. Three of its metabolites found in human plasma (primary alcohol, corresponding carboxylic acid and glucuronide conjugate) are inactive in inhibiting COX-1 and COX-2.
The activity of cytochrome P450 2C9 is reduced in people with a genetic polymorphism, which leads to a decrease in the activity of this enzyme, for example, in people with a homozygous polymorphism of the CYP2C9*3 enzyme.
In a pharmacokinetic study of 200 mg of celecoxib 1 time per day in healthy volunteers genotyped as CYP2C9*1/*1, CYP2C9*1/*3 or CYP2C9*3/*3, the median Cmax and AUC0-24 of celecoxib on day 7 was almost 4 and 7 times higher in patients genotyped as CYP2C9*3/*3, compared to other genotypes. In three separate single-dose studies involving only 5 patients genotyped as CYP2C9*3/*3, the single-dose AUC0-24 value was almost 3 times greater than that in patients with normal metabolism. It was established that the homozygous *3/*3 genotype occurs with a frequency of 0.3-1% among various ethnic groups.
The use of celecoxib in patients with known or expected reduced activity of CYP2C9, based on the previous history / experience of using other CYP2C9 substrates, should be carried out with caution.
Clinically significant differences in the pharmacokinetic parameters of celecoxib between elderly African-American patients and Caucasian patients were not revealed.
Plasma concentrations of celecoxib are almost 100% higher in elderly women (> 65 years).
Compared to patients with normal liver function, in patients with mild hepatic impairment, the Cmax value of celecoxib increases by an average of 53%, and the AUC value by 26%. In patients with moderate liver dysfunction, these indicators are 41% and 146%, respectively. Metabolic capacity in patients with mild and moderate liver dysfunction correlated best with their albumin levels. In patients with mild and moderate impairment of liver function (with a serum albumin level of 25-35 g/l), treatment should be started with half the recommended dose. Patients with severe impairment of liver function (serum albumin < 25 g/l) did not participate in the study, therefore celecoxib is contraindicated in this group of patients.
The experience of using celecoxib in patients with impaired renal function is insignificant. The pharmacokinetics of celecoxib have not been studied in patients with impaired renal function, but it is unlikely that it will be significantly altered. Thus, caution should be exercised when treating patients with impaired renal function. The use of the drug in case of severe impairment of kidney function is contraindicated.
Indications for use
Symptomatic therapy of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.
Contraindications
Hypersensitivity (for example, anaphylactic reactions and serious skin reactions) to celecoxib or to any components of the drug.
Increased sensitivity to sulfonamides.
Active peptic ulcer or bleeding of the gastrointestinal tract.
Asthma, acute rhinitis, nasal polyps, angioedema, urticaria, or other allergic reactions after taking acetylsalicylic acid or nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) inhibitors, in the anamnesis.
Use during pregnancy and breastfeeding.
Application to women of reproductive age who do not use an effective method of contraception.
Severe liver dysfunction (serum albumin < 25 g/l or Child-Pugh score ≥ 10).
Violation of kidney function of a severe degree (established creatinine clearance < 30 ml/min).
Inflammatory intestinal diseases.
Congestive heart failure (class II-IV according to the criteria of the New York Heart Association NYHA).
Diagnosed ischemic heart disease, peripheral artery disease and/or cerebrovascular disease.
Use after a surgical operation on aortocoronary shunting (see the section "Peculiarities of application");
Interaction with other medicinal products and other types of interaction
In patients receiving warfarin or other anticoagulants, anticoagulant activity should be monitored especially closely during the first days of celecoxib use and when changing its dose, since these patients have an increased risk of bleeding. Therefore, in patients taking oral anticoagulants, the prothrombin time and international normalized ratio (INR) should be frequently checked, in particular during the first days of celecoxib use or when changing its dose.
Bleeding (sometimes fatal) due to an increase in prothrombin time has been reported, mainly in elderly patients, as well as in patients who simultaneously use celecoxib and warfarin.
NSAIDs can reduce the effect of antihypertensive agents, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, diuretics, and β-blockers. The risk of acute renal failure, usually reversible, increases in some patients with impaired renal function (for example, in patients with dehydration or in elderly patients) when ACE inhibitors or angiotensin II receptor antagonists are prescribed in combination with NSAIDs, including celecoxib. Therefore, such combined therapy should be prescribed with caution, especially to elderly patients. Patients should have adequate hydration. After the start of concomitant therapy, and then periodically, kidney function should be monitored.
According to the data of a clinical study lasting 28 days with the participation of patients with arterial hypertension of the I and II stages, which is controlled with the help of lisinopril, taking celecoxib in a dose of 200 mg 2 times a day did not lead to a clinically significant increase in the average daily indicator of diastolic or systolic pressure when compared with placebo, which was determined during daily ambulatory blood pressure monitoring. Among patients receiving celecoxib 200 mg twice daily, 48% were considered refractory to lisinopril at the last clinic visit (defined as cuff diastolic pressure > 90 mm Hg or > 10% increase in cuff diastolic pressure from baseline). In the placebo group, there were 27% of such patients, and this difference was statistically significant.
It is believed that concomitant use of NSAIDs and cyclosporine or tacrolimus enhances the nephrotoxic effect of the latter. With the combined use of celecoxib and any of these drugs, kidney function should be monitored.
Rancelex can be used with low doses of acetylsalicylic acid, but it does not replace it in the prevention of cardiovascular diseases. As with the use of other NSAIDs, in the information presented according to the results of clinical studies, an increased risk of formation of ulcers of the digestive tract or other gastrointestinal complications was noted with the simultaneous use of low doses of acetylsalicylic acid compared to monotherapy with celecoxib.
Pharmacokinetic interactions
The effect of celecoxib on other drugs
Celecoxib is a CYP2D6 inhibitor. With simultaneous use of celecoxib, plasma concentrations of drugs that are substrates of this enzyme may increase. A 2.6-fold increase in the plasma concentration of dextromethorphan and 1.5-fold increase of metoprolol was reported with simultaneous use of 200 mg of celecoxib twice a day. Examples of drugs that are metabolized by CYP2D6 are antidepressants (tricyclics and serotonin reuptake inhibitors), antipsychotics, antiarrhythmic drugs, etc. At the beginning of treatment with celecoxib, when increasing the dose or stopping treatment, it may be necessary to decrease the dose of CYP2D6 substrates, which are titrated individually.
In vitro studies revealed the potential of celecoxib to suppress metabolism catalyzed by CYP2C19. The clinical significance of these in vitro data is unknown. Examples of drugs metabolized by CYP2C19 include diazepam, citalopram, and imipramine.
In the interaction study, celecoxib did not have a clinically significant effect on the pharmacokinetics of oral contraceptives (norethisterone 1 mg/ethinyl estradiol 35 μg).
Celecoxib has no clinically significant effect on the pharmacokinetics of tolbutamide (CYP2C9 substrate) or glibenclamide.
In patients with rheumatoid arthritis, celecoxib had no statistically significant effect on the pharmacokinetics (plasma and renal clearance) of methotrexate (in a dose for the treatment of rheumatic diseases). However, with the combined use of these two agents, proper monitoring of toxicity associated with the use of methotrexate should be carried out.
In healthy volunteers, the simultaneous use of celecoxib 200 mg 2 times a day and lithium 450 mg 2 times a day led to an increase in the value of the maximum concentration in blood plasma (Cmax) of lithium on average by 16%, and the value of the area under the "concentration-time" curve (AUC) - by 18%. Therefore, at the beginning of celecoxib use or when it is discontinued, the condition of patients receiving lithium drugs should be closely monitored.
In patients with poor CYP2C9 metabolism and increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors may lead to further increase in celecoxib exposure. Patients with poor CYP2C9 metabolism should not be prescribed such combinations.
Since the metabolism of celecoxib occurs mainly with the help of CYP2C9, patients receiving fluconazole should be given half the recommended dose. Simultaneous use of a single dose of celecoxib 200 mg and fluconazole 200 mg 1 time per day, a potent inhibitor of CYP2C9, led to an increase in the Cmax value of celecoxib by an average of 60%, and the AUC value by 130%. Concomitant use of CYP2C9 inducers, such as rifampicin, carbamazepine, and barbiturates may reduce plasma concentrations of celecoxib.
The influence of ketoconazole or antacids on the pharmacokinetics of celecoxib was not observed.
Children
Interaction with other medicinal products was studied only in adults.
Features of application
Cardiovascular thrombotic phenomena. Clinical studies of several selective and non-selective COX-2 inhibitors of the NSAID group lasting up to 3 years have demonstrated an increased risk of serious adverse thrombotic events, including myocardial infarction and stroke, which can be fatal. From the available data, it is not clear whether the risk of developing thrombotic cardiovascular complications is similar when using all NSAIDs. The relative increase in the frequency of serious thrombotic cardiovascular complications compared to the frequency at the initial level, which is associated with the use of NSAIDs, occurs both in patients with cardiovascular diseases and risk factors for their occurrence, and in patients without such diseases and factors. However, patients with cardiovascular disease or risk factors for cardiovascular disease had an even higher absolute frequency of serious thrombotic cardiovascular complications. In some observational studies, it was established that this increased risk of serious thrombotic cardiovascular complications appeared already in the first weeks of treatment. An increase in the risk of thrombotic cardiovascular complications was most consistently observed when using the drug in higher doses.
In the APC (celecoxib-based adenoma prevention) clinical trial, there was an approximately threefold increase in the risk of the combined endpoint (death from cardiovascular disease, myocardial infarction, or stroke) in the celecoxib 400 mg twice daily and 200 mg twice daily groups compared with placebo. This increased risk in both celecoxib groups compared to the placebo group was mainly due to an increase in the incidence of myocardial infarction.
According to the conclusion of the controlled clinical study "Prospective randomized evaluation of the complex safety of celecoxib compared with ibuprofen or naproxen (PRECISION)" regarding the relative risk of cardiovascular thrombotic events associated with the COX-2 inhibitor celecoxib compared to that with the use of non-selective NSAIDs naproxen and ibuprofen, celecoxib was no less effective than naproxen and ibuprofen.
To minimize the potential risk of adverse reactions from the cardiovascular system in patients using NSAIDs, the minimum effective dose should be used for the shortest possible period of treatment. Doctors and patients should carefully monitor the development of such reactions during the entire course of treatment, even in the absence of previous symptoms from the cardiovascular system. Patients should be informed about the symptoms of serious adverse reactions from the cardiovascular system and about the measures to be taken in case of their occurrence.
There is no direct evidence that the simultaneous use of aspirin reduces the increased risk of serious thrombotic cardiovascular complications associated with the use of NSAIDs. The simultaneous use of aspirin and NSAIDs, such as Rancelex, increases the risk of serious reactions from the gastrointestinal tract (see the section "Particulars of use", subsection "Gastrointestinal bleeding, ulceration and perforation").
In the CLASS study, the cumulative Kaplan-Meier scores after 9 months for peripheral edema in patients receiving celecoxib at a dose of 400 mg twice a day, ibuprofen at a dose of 800 mg three times a day, and diclofenac at a dose of 75 mg twice a day were 4.5%, 6.9%, and 4.7%, respectively. According to the CLASS study, the incidence of arterial hypertension in patients receiving celecoxib, ibuprofen, and diclofenac was 2.4%, 4.2%, and 2.5%, respectively.
Patients after myocardial infarction. In the course of observational studies, according to the Danish National Register, it was demonstrated that patients who used NSAIDs in the period after myocardial infarction had an increased risk of recurrent heart attack, fatal outcome caused by cardiovascular disease, and fatal outcome from any cause, starting from the first week of treatment. In the same cohort, among patients who used NSAIDs, the rate of death in the first hour after myocardial infarction was 20 cases per 100 person-years compared to 12 cases per 100 person-years among patients who did not use NSAIDs. Although the absolute number of fatal outcomes decreases after the first year after a myocardial infarction, the analysis of the results of at least four subsequent years of follow-up has demonstrated that the increased relative risk of fatal outcomes in patients using NSAIDs remains.
Celecoxib should be avoided in patients with a recent myocardial infarction, unless the benefit of treatment is expected to outweigh the risk of recurrent thrombotic cardiovascular complications. If celecoxib is used in patients with a recent myocardial infarction, the patient should be monitored for signs of cardiac ischemia.
Gastrointestinal bleeding, ulcers and perforations. NSAIDs, including Rancelex, cause serious side effects from the gastrointestinal tract, including inflammation, bleeding, ulcer formation, perforation of the esophagus, stomach, small and large intestines, which can be fatal. These serious side effects can occur at any time in patients who have used celecoxib with or without previous symptoms. Only in 1 out of 5 patients, the development of serious adverse reactions in the upper part of the gastrointestinal tract during treatment with NSAIDs is accompanied by clinical manifestations. In approximately 1% of patients who used celecoxib for 3-6 months, and in approximately 2-4% of patients who used celecoxib for one year, upper gastrointestinal ulcers, severe bleeding, or perforation due to NSAID use were observed. However, even short-term NSAID therapy is associated with risk.
Risk factors for gastrointestinal bleeding, ulcers and perforation. Patients with a history of peptic ulcer and/or gastrointestinal bleeding who took NSAIDs had a more than 10-fold increased risk of gastrointestinal bleeding compared to patients without such risk factors. Other factors that increase the risk of gastrointestinal bleeding in patients using NSAIDs include long duration of NSAID treatment, concomitant oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors, tobacco smoking, alcohol consumption, advanced age, and poor general health. Most post-marketing reports of fatal gastrointestinal side effects have been reported in elderly or debilitated patients. In addition, patients with progressive liver disease and/or coagulopathy have an increased risk of gastrointestinal bleeding.
In the CLASS study, the frequency of complicated and symptomatic ulcers in all patients after 9 months was 0.78%, and in the subgroup of patients receiving low doses of acetylsalicylic acid - 2.19%. In patients over 65 years of age, the frequency of cases was 1.40% after 9 months and 3.06% with simultaneous use of acetylsalicylic acid.
Strategy for minimizing risks from the gastrointestinal tract in patients taking NSAIDs:
apply the lowest effective dose of the drug for the shortest possible period;
avoid using more than one NSAID at the same time;
Avoid use in high-risk patients, unless the benefit is expected to outweigh the increased risk of bleeding. In such patients, as well as in patients with active gastrointestinal bleeding, the possibility of using alternative drugs instead of NSAIDs should be considered;
constantly monitor the patient for signs and symptoms of gastrointestinal ulcer formation and/or bleeding during NSAID therapy;
if a serious adverse reaction from the gastrointestinal tract is suspected, the examination and treatment should be started immediately, the use of celecorsib should be stopped until a serious adverse reaction from the gastrointestinal tract is excluded;
Hepatotoxicity. An increase in the levels of alanine aminotransferase or aspartate aminotransferase (3 times or more than the upper limit of normal) was reported in approximately 1% of patients who used NSAIDs in clinical studies. In addition, rare, sometimes fatal cases of severe liver dysfunction, including fulminant hepatitis, liver necrosis, and liver failure, have been reported.
An increase in the level of alanine aminotransferase or aspartate aminotransferase (less than 3 times the upper limit of normal) can be observed in up to 15% of patients using NSAIDs, including celecoxib.
During controlled clinical studies of celecoxib, the number of cases of minor elevations (exceeding the upper limit of normal by 1.2 to 3 times the upper limit of normal) of the levels of enzymes related to liver function was 6% in patients who received celecoxib and 5% in patients who received placebo, while approximately 0.2% of patients who received celecoxib and 0.3% of patients who received placebo had a significant increase in the level of alanine aminotransferase and aspartate aminotransferase.
Patients should be informed about the symptoms of hepatotoxicity (for example, nausea, increased fatigue, lethargy, diarrhea, itching, jaundice, pain in the right hypochondrium and flu-like symptoms). In the case of the appearance of clinical signs and symptoms indicating liver disease, or the appearance of systemic manifestations of the disease (for example, eosinophilia, rash, etc.), the use of celecoxib should be stopped immediately and a clinical examination of the patient should be carried out.
Arterial hypertension. The use of NSAIDs, including celecoxib, can lead to the development of arterial hypertension or the strengthening of already existing arterial hypertension, and in each case, an increase in the frequency of adverse reactions from the cardiovascular system is possible. In patients taking ACE inhibitors, diuretics of the thiazide group or loop diuretics, a violation of the response to these drugs may be observed when using NSAIDs (see the section "Interaction with other drugs and other types of interactions").
It is necessary to monitor blood pressure at the beginning of treatment with NSAIDs and during the course of therapy.
Heart failure and edema. Objective - The Trialists' Collaboration analysis of the results of randomized controlled trials of coxib and traditional NSAIDs demonstrated an approximately two-fold increase in heart failure hospitalizations in patients receiving COX-2-selective and non-selective drugs and in patients receiving non-selective NSAIDs compared to patients receiving placebo. According to the Danish National Register, in patients with heart failure, the use of NSAIDs increased the risk of myocardial infarction, hospitalization due to heart failure, and death.
In addition, in some patients who used NSAIDs, fluid retention and edema were observed. The use of Ranselex may weaken the cardiovascular effects of several drugs used to treat these diseases (for example, diuretics, ACE inhibitors or angiotensin receptor blockers) (see the section "Interaction with other drugs and other types of interactions").
In the CLASS study, the cumulative incidence of peripheral edema, calculated by the Kaplan-Meier method, after 9 months of celecoxib at a dose of 400 mg twice a day (which was 4 and 2 times higher than the dose recommended for the treatment of osteoarthritis and rheumatoid arthritis, respectively), ibuprofen at a dose of 800 mg three times a day and diclofenac at a dose of 75 mg twice a day was 4.5%, 6.9 mg and 4.7%, respectively.
It follows from
