Compound
One ml of Denebol solution contains 25 mg of rofecoxib, tocopherol acetate, centubucridine hydrochloride, methyl carbonate, saline. One Denebol tablet contains 25 or 50 mg of rofecoxib, as well as microcrystalline cellulose, corn starch, betacyclodexphrine, povidone, magnesium stearate, purified talc, sodium propylparaben, sodium methylparaben, colloidal silicon dioxide, brilliant blue, colored tartrazine, dry starch, sodium starch glycolate. One hundred mg of Denebol gel contains 1 g of rofecoxib, 10 g of methyl salicylate, 3 g of linseed oil, 5 g of menthol, 1 g of phenoxyethanol, propylene glycol, butylated hydroxytoluene, polyethylene glycol, carbomer 934, triethanolamine, disodium edetate, isopropyl alcohol, polyoxyl, hydrogenated castor oil, purified water. One Denebola rectal suppository contains 25 mg of rofecoxib and solid fat.
Pharmacological properties
The drug Denebol is an anti-inflammatory drug. Denebol is used to treat diseases of the musculoskeletal system, dentistry, gynecology, and ENT diseases. Cyclooxygenase II, along with cyclooxygenase I, is involved in the formation of mediators of the inflammatory reaction: prostaglandins, prostacyclins and thromboxane, but COX-II is an inducible enzyme and is included in the reaction only in certain situations, most often during inflammation. Denebol blocks cyclooxygenase II, providing anti-inflammatory, analgesic, anti-edematous and antipyretic effects. At the same time, the drug has virtually no effect on the enzyme cyclooxygenase I, which works continuously in the body and performs many physiologically necessary functions. For example, such as regulation of metabolic processes in the tissues of the gastric and intestinal walls, platelets, bronchopulmonary system and others. When taken orally, Denebol is quickly absorbed from the digestive tract, and the bioavailability of the drug is over 90%. The maximum concentration in the blood plasma of Denebol's active ingredient, rofecoxib, is reached two hours after administration and is about 0.300 mcg/ml. Over 80% of rofecoxib in the body forms weak bonds with plasma proteins. It is biotransformed mainly in the liver with the formation of 6 inactive metabolites, which are excreted by the kidneys in the urine (70%). In unchanged form, rofecoxib is excreted from the body through the intestines in the feces. The pharmacokinetics of Denebol in young and elderly patients are no different.
Evolution of NSAIDs:
from non-selective to specific COX-2 inhibitors
The discovery of two isoforms of COX became the promise for the development of new forms of drugs from the class of NSAIDs that have the ability to predominantly suppress the activity of COX-2, selective COX-2 inhibitors: meloxicam, nimesulide, nabumetone, and subsequently - specific COX-2 inhibitors - coxibs. The different activities of modern NSAIDs against COX isoenzymes have made it possible to construct a classification based on the selectivity of the drugs' effects on COX-1 and COX-2. The following groups of drugs were identified [5]: - non-selective COX inhibitors (classical NSAIDs); - selective COX-2 inhibitors (meloxicam, nimesulide, nabumetone); - specific COX-2 inhibitors (coxibs: celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib); - selective COX-1 inhibitors (low doses of acetylsalicylic acid).
Subsequently, another isoenzyme was identified - COX-3, localized in the cells of the cerebral cortex, the influence of which is associated with the analgesic activity of the simple analgesic - paracetamol.
In 1999, the first representative of coxibs appeared on the pharmacological market - celecoxib, released as a specific COX-2 inhibitor; a little later, another representative of coxibs appeared - rofecoxib; in the future - valdecoxib, etoricoxib, lumiracoxib. The mechanism of action of coxibs, in contrast to traditional NSAIDs, is based on selective inhibition of PGs, which, along with the pronounced anti-inflammatory activity of coxibs, ensures a low degree of development of gastrointestinal complications with their long-term use [6].
Indications
Denebol is prescribed for diseases of the musculoskeletal system: acute and chronic periarthritis, rheumatoid arthritis, osteoarthritis, tendonitis, bursitis, as well as injuries to tendons, ligaments and muscles. The drug is effective for thrombophlebitis, pain of various origins (neuralgia, neuritis, osteochondrosis, lumbago, radicular syndrome, myalgia, toothache with pulpitis, migraine, algodismenorrhea), inflammatory processes in the ENT organs (sinusitis, otitis media, laryngitis) and dental practice (gingivitis , stomatitis, pulpitis). It can be used as symptomatic therapy for infectious and inflammatory diseases of the pharynx, trachea and bronchi, urinary system (urethritis, cystitis, cystopyelitis), in ophthalmology and gynecology.
Rofecoxib has the following properties:
- reduces the intensity of pain in osteoarthritis and diseases of the musculoskeletal system; - reduces swelling of joints; - has a chondroneutral effect; - has a high safety profile from the gastrointestinal tract; — possibility of safe use for 6–12 months; manifestation of NSAID gastropathy as a result of taking rofecoxib for 6 months. was 0.01% per 100 patients per year (comparable to that in persons not taking NSAIDs); — possibility of safe use on the part of the cardiovascular system for 6–12 months. at a dose of 25 mg; — does not change platelet function; — prolonged action — taken 1 time/day [8].
This data allows us to recommend Denebol (rofecoxib) for use in the practice of therapists, traumatologists, rheumatologists, gynecologists, dentists and other specialists for the purpose of anti-inflammatory and analgesic therapy for osteoarthritis, rheumatoid arthritis, acute pain syndrome of various origins, algodismenorrhea, toothache, and also in the postoperative period after surgical interventions.
Contraindications
Denebol is contraindicated in cases of development of allergic reactions to salicylates (aspirin) or other non-steroidal anti-inflammatory drugs in the anamnesis, with bronchial asthma, cancer and children under the age of 12 years. The solution for intramuscular injection should not be used in patients with myocardial infarction, stroke, progressive form of atherosclerosis, or malignant arterial hypertension. The drug is not recommended for use by persons with hypersensitivity to rofecoxib or auxiliary components in Denebol.
Special instructions for the use of Rofecoxib
Use with caution in the 1st and 2nd trimester of pregnancy, breastfeeding, with renal failure, asthma, or a history of the “aspirin triad”. In patients at increased risk of impaired renal perfusion, the use of rofecoxib may result in decreased renal blood flow and deterioration of renal function. The highest likelihood of such an effect is observed in patients with a history of severe renal dysfunction, decompensated heart failure, or cirrhosis of the liver. In this category of patients, careful monitoring of renal function is necessary during treatment. In patients with significant dehydration, rehydration is recommended before starting therapy. The risk of developing perforations, ulcers, or bleeding in the upper gastrointestinal tract increases in patients over 65 years of age. During the treatment period, it is necessary to monitor the prothrombin time (especially with combination therapy with anticoagulants).
Directions for use and dosage
Denebol in the form of an injection solution is administered deeply intramuscularly (into the buttock) once a day with an interval of 24 hours.
Intravenous administration of the drug is strictly prohibited! Rofecoxib is recommended for use in an initial dosage of 50 mg per day, which can be reduced to 25 mg depending on the intensity of the inflammatory process and the severity of pain. For osteoarthritis, the effective daily dosage is 12.5 mg. If necessary, it is increased to 25 mg. Intramuscular injections are often used as a short symptomatic introductory course, and after a week the patient is transferred to the tablet form of Denebol and gel. When using several forms of the drug simultaneously, the total daily dosage of rofecoxib should not exceed 50 mg. Denebol courses lasting 4-6 weeks at a dosage not exceeding 25 mg are considered safe. The decision to increase the dose in each case is made purely individually, depending on the severity of the patient’s condition. Denebol in tablet form is used for the treatment of primary dysmenorrhea and pain syndrome in a daily dose of 25 mg. Subsequent doses are taken after 24 hours and may be 12.5 or 25 mg depending on symptoms, but the maximum daily dose should not exceed 25 mg. The medication is taken until the condition is completely relieved, but the course should not exceed three days. Take Denebola tablets regardless of meals and wash them down with a small amount of water. For osteoarthritis, it is recommended to start with 12.5 mg of rofecoxib per day, the course of treatment is from 4 to 6 weeks. Denebol in the form of a gel is applied with light massaging movements to the skin up to 4 times a day. In this case, they use a small volume of gel (1-2 g), comparable in size to a pea, and try to avoid contact of rofecoxib with mucous membranes, eyes and skin defects (wounds). The duration of treatment is determined by the effect achieved. Denebol in the form of suppositories is used rectally to relieve acute pain of inflammatory origin and treat primary dysmenorrhea, one suppository 2 times a day, that is, the maximum daily dose is 50 mg. The duration of treatment is no more than 1.5 months.
Esomeprazole Canon 20 mg, 28 enteric film-coated tablets
Registration Certificate Holder
KANOPHARMA PRODUCTION (Russia)
Dosage form
Medicine - Esomeprazole Canon
Description
Enteric tablets, film-coated
from light green to green with a bluish tint, round, biconvex; on cross section from almost white to light yellow.
1 tab.
esomeprazole magnesium dihydrate 21.8 mg, which corresponds to the content of esomeprazole 20 mg
Excipients
: low-substituted hyprolose (hydroxypropylcellulose) - 14 mg, pregelatinized corn starch - 37.2 mg, colloidal silicon dioxide - 2 mg, mannitol - 23 mg, sodium stearyl fumarate - 2 mg, microcrystalline cellulose - 140 mg.
Film shell composition:
opadry transparent - 8 mg (hypromellose (hydroxypropyl methylcellulose) - 6.4 mg, macrogol (polyethylene glycol) - 1.6 mg); Acrylic-Iz green - 22 mg (copolymer of methacrylic acid and ethacrylate (1:1) - 14.52 mg, colloidal silicon dioxide - 0.22 mg, sodium bicarbonate - 0.22 mg, sodium lauryl sulfate - 0.11 mg, iron oxide yellow - 0.154 mg, indigo carmine dye - 0.176 mg, brilliant blue dye - 0.066 mg, talc - 3.63 mg, titanium dioxide - 2.904 mg); triethyl citrate - 2 mg.
7 pcs. — contour cellular packaging (1) — cardboard packs. 7 pcs. — contour cellular packaging (2) — cardboard packs. 7 pcs. — contour cellular packaging (4) — cardboard packs. 10 pieces. — contour cellular packaging (1) — cardboard packs. 10 pieces. — contour cellular packaging (2) — cardboard packs. 10 pieces. — contour cellular packaging (4) — cardboard packs. 14 pcs. — contour cellular packaging (1) — cardboard packs. 14 pcs. — contour cellular packaging (2) — cardboard packs. 14 pcs. — contour cellular packaging (4) — cardboard packs.
Indications
Gastroesophageal reflux disease (GERD)
Treatment of erosive reflux esophagitis:
- long-term maintenance treatment after healing of erosive reflux esophagitis, prevention of relapses;
- symptomatic treatment of GERD.
Peptic ulcer of the stomach and duodenum as part of combination therapy:
- treatment of duodenal ulcer associated with Helicobacter pylori;
- prevention of relapses of peptic ulcers associated with Helicobacter pylori.
Long-term acid suppression therapy in patients who have suffered bleeding from a peptic ulcer (after IV use of drugs that reduce the secretion of gastric glands to prevent relapse)
Patients taking NSAIDs for a long time:
- treatment of stomach ulcers caused by taking NSAIDs;
- prevention of gastric and duodenal ulcers caused by taking NSAIDs in patients at risk.
Zollinger-Ellison syndrome or other conditions characterized by pathological hypersecretion of the gastric glands, incl. idiomatic hypersecretion
Contraindications for use
- hypersensitivity to esomeprazole, substituted benzimidazoles or other components of the drug;
- children under 12 years of age (due to the lack of data on the effectiveness and safety of the drug in this group of patients);
- children's age from 12 to 18 years for all indications except GERD;
- simultaneous use with atazanavir and nelfinavir.
With caution:
Severe renal failure (experience is limited).
pharmachologic effect
Pharmacodynamics
Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion by specifically inhibiting the proton pump in gastric parietal cells. The S- and R-isomers of omeprazole have similar pharmacodynamic activities.
Mechanism of action
Esomeprazole is a weak base that transforms into an active form in the highly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa and inhibits the proton pump - the enzyme H + / K + -ATPase, thereby inhibiting both basal and stimulated secretion of hydrochloric acid.
Effect on the secretion of hydrochloric acid in the stomach
After oral administration of 20 mg or 40 mg, the effect of esomeprazole develops within 1 hour. When taking the drug daily for 5 days at a dose of 20 mg 1 time / day, the average Cmax of hydrochloric acid after stimulation with pentagastrin decreases by 90% (when measuring the acid concentration after 6 -7 hours after taking the drug on the 5th day of therapy).
In patients with GERD and the presence of clinical symptoms, after 5 days of daily oral esomeprazole at a dose of 20 mg or 40 mg, intragastric pH values above 4.0 were maintained for an average of 13 and 17 hours out of 24 hours. While taking esomeprazole at a dose of 20 mg /day, intragastric pH above 4.0 was maintained for at least 8, 12 and 16 hours in 76%, 54% and 24% of patients, respectively.
A correlation was found between the concentration of the drug in plasma and the inhibition of hydrochloric acid secretion (the AUC parameter was used to assess the concentration).
The therapeutic effect achieved by inhibiting the secretion of hydrochloric acid
When taking the drug at a dose of 40 mg, healing of reflux esophagitis occurs in approximately 78% of patients after 4 weeks of therapy and in 93% of patients after 8 weeks of therapy.
Treatment with esomeprazole at a dose of 20 mg 2 times a day in combination with appropriate antibiotics for one week leads to successful eradication of Helicobacter pylori in approximately 90% of patients.
Patients with uncomplicated peptic ulcer disease after a week-long eradication course do not require subsequent monotherapy with drugs that reduce the secretion of gastric glands to treat the ulcer and eliminate symptoms.
The effectiveness of esomeprazole in bleeding from peptic ulcers, confirmed endoscopically, has been shown.
Other effects associated with inhibition of hydrochloric acid secretion
During treatment with drugs that reduce the secretion of gastric glands, the concentration of gastrin in the plasma increases as a result of a decrease in the secretion of hydrochloric acid. Due to decreased secretion of hydrochloric acid, the concentration of chromogranin A (CgA) increases. Increased concentrations of CgA may affect the results of examinations for the detection of neuroendocrine tumors. To prevent this effect, it is necessary to temporarily stop taking esomeprazole 5 days before the CgA concentration test.
In patients receiving esomeprazole for a long time, an increase in the number of enterochromaffin-like cells was observed, probably associated with an increase in plasma gastrin concentrations.
Patients taking drugs that reduce the secretion of gastric glands for a long period of time are more likely to develop glandular cysts in the stomach. These phenomena are caused by physiological changes as a result of pronounced inhibition of hydrochloric acid secretion. Cysts are benign and undergo reverse development.
The use of medications that suppress the secretion of hydrochloric acid in the stomach, incl. proton pump inhibitors, is accompanied by an increase in the content of microbial flora in the stomach, normally present in the gastrointestinal tract. The use of proton pump inhibitors may lead to a slight increase in the risk of gastrointestinal infections caused by Salmonella spp. and Campylibacter spp. and probably Clostridium difficile in hospitalized patients.
In two comparative studies with ranitidine, esomeprazole showed superior efficacy in the treatment of gastric ulcers in patients receiving NSAIDs, including selective COX-2 inhibitors.
Drug interactions
Effect of esomeprazole on the pharmacokinetics of other drugs
A decrease in the secretion of hydrochloric acid in the stomach during treatment with esomeprazole and other proton pump inhibitors can lead to changes in the absorption of drugs, the absorption of which depends on the acidity of the environment. Like antacids and other drugs that reduce gastric acidity, the use of esomeprazole may lead to decreased absorption of ketoconazole, itraconazole and erlotinib, and increased absorption of drugs such as digoxin.
Simultaneous administration of esomeprazole at a dose of 20 mg 1 time / day and digoxin increases the bioavailability of digoxin by 10% (the bioavailability of digoxin increased by up to 30% in two out of 10 patients).
Esomeprazole is known to interact with some antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known. An increase in pH during esomeprazole therapy may affect the absorption of antiretroviral drugs. Interaction at the level of the CYP2C19 isoenzyme is also possible.
When esomeprazole is co-administered with certain antiretroviral drugs, such as atazanavir and nelfinavir, during esomeprazole therapy, a decrease in their serum concentrations is observed. Therefore, their simultaneous use is not recommended.
Co-administration of esomeprazole 40 mg once daily and atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (AUC, as well as Cmax and Cmin decreased by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of esomeprazole on the bioavailability of atazanavir.
Increased saquinavir serum concentrations were observed when esomeprazole and saquinavir were administered concomitantly; when used with some other antiretroviral drugs, their concentrations did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, co-administration of esomeprazole with antiretroviral drugs such as atazanavir and nelfinavir is not recommended.
Esomeprazole inhibits the CYP2C19 isoenzyme, the main enzyme involved in its metabolism. Accordingly, the combined use of esomeprazole with other drugs in the metabolism of which the CYP2C19 isoenzyme is involved, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to increased plasma concentrations of these drugs, which, in turn, may require dose reduction. This interaction is especially important to remember when prescribing Esomeprazole Canon in the “as needed” mode. When 30 mg of esomeprazole and diazepam, which is a substrate of the CYP2C19 isoenzyme, are taken together, a decrease in the clearance of diazepam by 45% is observed.
The administration of esomeprazole at a dose of 40 mg led to an increase in residual phenytoin concentrations in patients with epilepsy by 13%. In this regard, it is recommended to monitor plasma concentrations of phenytoin when starting treatment with esomeprazole and when discontinuing it.
Concomitant use of esomeprazole at a dose of 40 mg leads to an increase in plasma phenytoin concentrations in patients with epilepsy by 13%.
It is recommended to monitor plasma phenytonin concentrations when initiating esomeprazole therapy and when discontinuing it.
When using esomeprazole at a dose of 40 mg 1 time / day, the AUC and Tmax of voriconazole (CYP2C19 isoenzyme substrate) increases by 15% and 41%, respectively.
Co-administration of warfarin and 40 mg esomeprazole does not lead to a change in coagulation time in patients taking warfarin for a long time. However, several cases of clinically significant increases in the INR index have been reported with the combined use of warfarin and esomeprazole. It is recommended to monitor the INR at the beginning and at the end of the combined use of esomeprazole and warfarin or other coumarin derivatives.
Co-administration of cisapride with 40 mg of esomeprazole leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC by 18% and T1/2 by 26%; for one of the active metabolites of cytostazol, the increase was 29% and 69%, respectively. The simultaneous use of esomeprazole at a dose of 40 mg with cisapride leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC by 32% and T1/2 by 31%, but Cmax did not change significantly.
The slight prolongation of the QT interval that was observed with cisapride monotherapy was not increased by the addition of esomeprazole.
In some patients, an increase in the concentration of methotrexate in the blood serum was observed during simultaneous use of proton pump inhibitors. When using high doses of methotrexate, the possibility of temporary withdrawal of esomeprazole should be considered.
Esomeprazole does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.
Studies evaluating short-term co-administration of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.
The simultaneous short-term use of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.
In a clinical study, the interaction was studied when using clopidogrel (300 mg loading dose, then 75 mg/day) with esomeprazole (80 mg) simultaneously, at the same time, for 5 days. The activity of the thiol metabolite (active metabolite) of clopidogrel was reduced by 46% (day 1 of therapy) and 42% (day 5 of therapy) when clopidogrel and omeprazole were taken at the same time. When clopidogrel and esomeprazole were administered at the same time, mean inhibition of platelet aggregation (IRA) was reduced by 47% (within 24 hours of therapy) and 30% (day 5 of therapy).
According to the results of another study: esomeprazole, when used with clopidogrel not simultaneously, at different times, does not have an inhibitory effect on the CYP2C19 isoenzyme. Studies have reported conflicting data on the clinical manifestations of interactions with clopidogrel in the cardiovascular system.
When used concomitantly with tacrolimus, an increase in serum concentrations of tacrolimus is possible.
Effect of drugs on the pharmacokinetics of esomeprazole
The isoenzymes CYP2C19 and CYP3A4 are involved in the metabolism of esomeprazole.
Combined use of esomeprazole with clarithromycin (500 mg 2 times / day), which inhibits the isoenzyme AUC value of esomeprazole by 2 times.
Co-administration of esomeprazole and a combined CYP3A4 and CYP2C19 inhibitor, such as voriconazole, may result in a more than 2-fold increase in the AUC value for esomeprazole. As a rule, in such cases no dose adjustment of esomeprazole is required.
Drugs that induce the isoenzymes CYP2C19 and CYP3A4, such as rifampicin and St. John's wort preparations, when used simultaneously with esomeprazole, may lead to a decrease in the concentration of esomeprazole in the blood plasma by accelerating the metabolism of esomeprazole.
Dosage regimen
Inside. The tablet should be swallowed whole, without chewing, with a sufficient amount of water.
Adults and children from 12 years old
Gastroesophageal reflux disease
Treatment of erosive reflux esophagitis:
40 mg 1 time/day for 4 weeks.
An additional 4-week course of treatment is recommended in cases where, after the first course, healing of esophagitis does not occur or symptoms persist.
Long-term maintenance treatment after healing of erosive reflux esophagitis, prevention of relapses:
20 mg 1 time/day.
Symptomatic treatment of GERD:
20 mg 1 time/day for patients without esophagitis. If symptoms do not disappear after 4 weeks of treatment, the patient should be further examined. After eliminating the symptoms, you can switch to the “as needed” regimen of the drug - 20 mg 1 time / day when symptoms return. For patients taking NSAIDs who are at risk of developing gastric or duodenal ulcers, treatment on an as-needed basis is not recommended.
Adults
Gastric ulcer and duodenal ulcer
As part of combination therapy for Helicobacter pylori eradication:
- treatment of duodenal ulcer associated with Helicobacter pylori: Esomeprazole Canon 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg. All drugs are taken 2 times a day for 1 week;
- prevention of relapse of peptic ulcer associated with Helicobacter pylori: Esomeprazole Canon 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg. All medications are taken 2 times a day for 1 week.
Long-term acid suppression therapy in patients who have suffered bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of gastric glands to prevent relapse):
Esomeprazole Canon 40 mg 1 time/day for 4 weeks after intravenous use of drugs that reduce the secretion of gastric glands.
Patients taking NSAIDs for a long time
Treatment of stomach ulcers caused by taking NSAIDs:
Esomeprazole Canon 20 mg 1 time/day; Duration of treatment is 4-8 weeks.
Prevention of gastric and duodenal ulcers caused by taking NSAIDs:
Esomeprazole Canon 20 mg 1 time/day.
Conditions characterized by pathological hypersecretion of the gastric glands, incl. Zollinger-Ellison syndrome and idiopathic hypersecretion:
The recommended initial dose of Esomeprazole Canon is 40 mg 2 times a day. Next, the dose is selected individually, the duration of treatment is determined by the clinical picture of the disease. There is experience with the use of 80 to 160 mg of esomeprazole per day; when taking the drug more than 80 mg/day, it is recommended to divide the required dose into 2 doses.
Kidney failure:
No dose adjustment is required for Esomeprazole Canon.
However, experience with the use of esomeprazole in patients with severe renal failure is limited; therefore, caution should be exercised when prescribing the drug to this category of patients. Liver failure:
For mild to moderate liver failure, no dose adjustment is required. For patients with severe liver failure, the maximum daily dose should not exceed 20 mg.
Elderly patients:
no dose adjustment is required.
Overdose
Currently, cases of overdose of the drug esomeprazole are described extremely rarely. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and gastrointestinal symptoms. A single dose of 80 mg of esomeprazole did not cause any negative effects.
Treatment:
a specific antidote is unknown. Hemodialysis is ineffective. In case of overdose, symptomatic and general supportive therapy is recommended.
Side effect
WHO classification of the incidence of side effects: very often - ≥1/10 prescriptions (>10%); often - from ≥1/100 to <1/10 prescriptions (>1% and <10%); infrequently - from ≥1/1000 to <1/100 prescriptions (>0.1% and <1%); rarely - from ≥1/10000 to <1/1000 prescriptions (>0.01% and <0.1%); very rarely - <1/10,000 prescriptions (<0.01%); frequency unknown—cannot be estimated from available data. Within each group, adverse effects are presented in order of decreasing severity.
Nervous system disorders
: often - headache; infrequently - drowsiness, insomnia, dizziness, paresthesia; rarely - agitation, confusion, depression; very rarely - aggressive behavior, hallucinations.
Respiratory system disorders:
rarely - bronchospasm.
Digestive system disorders:
often - abdominal pain, diarrhea, flatulence, nausea, vomiting, constipation; infrequently - dry mouth, increased activity of liver enzymes; rarely - stomatitis, gastrointestinal candidiasis, hepatitis (with or without jaundice); very rarely - liver failure, hepatic encephalopathy in patients with a history of liver disease, microscopic colitis.
Renal and urinary tract disorders:
very rarely - interstitial nephritis; frequency unknown - renal failure.
Reproductive system disorders:
very rarely - gynecomastia.
Musculoskeletal disorders:
rarely - arthralgia, myalgia; very rarely - muscle weakness; frequency unknown - fractures of the femoral neck, wrist bones, vertebrae.
Skin disorders:
uncommon - itching, rash, urticaria, dermatitis, peripheral edema; rarely - alopecia, photosensitivity, malaise, excessive sweating; very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
Disorders of the hematopoietic organs:
rarely - leukopenia, thrombocytopenia; very rarely - agranulocytosis, pancytopenia.
Sensory organ disorders:
uncommon - blurred vision;
rarely - taste disturbance. Allergic reactions:
rarely - hypersensitivity reactions (for example, fever, angioedema, anaphylactic reaction/anaphylactic shock).
Laboratory and instrumental data:
rarely - hyponatremia; very rarely - hypomagnesemia, hypocalcemia due to severe hypomagnesemia, hypokalemia due to severe hypomagnesemia.
special instructions
If any alarming symptoms are present (eg, significant spontaneous weight loss, repeated vomiting, dysphagia, hematemesis, or melena), or if a gastric ulcer is present (or if a gastric ulcer is suspected), malignancy should be excluded because Treatment with esomeprazole may alleviate symptoms and delay diagnosis. Patients taking the drug for a long period (especially more than a year) should be under regular medical supervision. Patients taking esomeprazole "as needed" should be instructed to contact their physician if symptoms change. Taking into account fluctuations in the concentration of esomeprazole in plasma when prescribing therapy “as needed”, the interaction of the drug with other drugs should be taken into account (see section “Interaction with other drugs and other types of drug interactions”).
When using esomeprazole for Helicobacter pylori eradication, the possibility of drug interactions for all components of triple therapy should be taken into account. Clarithromycin is a potent inhibitor of the CYP3A4 isoenzyme, therefore, when using eradication therapy in patients receiving other drugs metabolized by the CYP3A4 isoenzyme (for example, cisapride), possible contraindications and interactions of clarithromycin with these drugs must be taken into account.
When using proton pump inhibitors, especially when used in large doses and over a long period (more than 1 year), there may be a risk of fracture of the femoral neck, wrist bones and vertebrae (especially in elderly patients).
The formation of glandular cysts in the stomach, decreased absorption of vitamin B12, and the development of hypomagnesemia are also noted. Effect on the ability to drive vehicles and machinery
During treatment, dizziness, blurred vision and drowsiness may occur, so care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Storage conditions
The drug should be stored in a dry place, protected from light and out of reach of children, at 25°C.
Best before date
Shelf life: 2 years.
Do not use after the expiration date.
Use during pregnancy and breastfeeding
Restrictions during pregnancy - With caution. Restrictions when breastfeeding - Contraindicated.
There is currently insufficient data on the use of esomeprazole during pregnancy. The results of epidemiological studies of esomeprazole, which is a racematic mixture, showed the absence of fetotoxic effects or impaired fetal development. Animal studies have not revealed any direct or indirect negative effects on the development of the embryo or fetus, either with the administration of esomeprazole or with the administration of a racematic mixture. The drug should be prescribed to pregnant women only if the expected benefit to the mother outweighs the potential risk to the fetus.
It is not known whether esomeprazole is excreted in breast milk, so the drug should not be used during breastfeeding.
Use for renal impairment
Restrictions for impaired renal function - With caution.
Use the drug with caution in patients with severe renal failure (experience is limited); dose adjustment of Esomeprazole Canon is not required.
Use for liver dysfunction
Restrictions for liver dysfunction - No restrictions.
Patients with mild to moderate hepatic impairment do not require dose adjustment.
For patients with severe liver failure, the maximum daily dose should not exceed 20 mg.
Use in elderly patients
Restrictions for elderly patients - No restrictions.
Elderly patients do not require dose adjustment.
Use in children
Restrictions for children - With caution.
The use of the drug in children under 12 years of age is contraindicated (due to the lack of data on the effectiveness and safety of the drug in this group of patients).
The use of the drug is contraindicated in children aged 12 to 18 years for all indications except GERD.
Terms of sale
The drug is available with a prescription.
Side effects
From the senses and central nervous system: hallucinations, confusion, decreased speed of thought processes, dizziness, drowsiness. From the heart and blood vessels: congestive heart failure, arterial hypertension, disorders of cerebral and coronary blood flow. From the digestive tract: nausea, heartburn, diarrhea, discomfort and pain in the upper third of the abdomen (epigastric region), dyspepsia, vomiting, the appearance of ulcers on the oral mucosa (aphthous stomatitis). From the urinary system: decreased renal function (usually reversible), renal failure. Allergic reactions: angioedema, urticaria, itching, rash. Other: increased levels of AlAt, AsAt, the occurrence of edema of the lower extremities.
Interaction with other drugs
When taking Denebol simultaneously with ACE inhibitors, the effectiveness of antihypertensive therapy is significantly reduced. Rofecoxib should not be used in combination with drugs or products containing caffeine (it increases blood pressure). The use of Denebol during anticoagulant therapy may increase prothrombin time. Rofecoxib increases plasma concentrations of methotrexate. Some antibiotics (rifampicin, rifamycin) can reduce the plasma concentration of rofecoxib by half. Denebol does not affect the pharmacokinetics of drugs such as prednisolone, digoxin, oral contraceptives (norethindrol, ethinyl estradiol), antacids, ketoconazole, cimetidine.
Rofecoxib in the family of non-steroidal anti-inflammatory drugs
Rofecoxib is a specific inhibitor of COX-2, has the highest selectivity coefficient (IC50COX-1/IC50COX-2 according to Warner et al.) - 0.004, which is explained by the peculiarities of the stereometric structure of its molecule: the presence of a rigid side chain capable of penetrating into the hydrophilic side cavity molecules of COX-2 and thereby non-competitively block the active center of this isoenzyme [7]. For celecoxib this figure is 0.1, for nimesulide - 0.15, ibuprofen - 10, indomethacin - 33, naproxen - 100. Another important aspect is the fact that the selectivity of rofecoxib is practically independent of the concentration of the drug, which distinguishes it favorably from classic NSAIDs.
Rofecoxib has a pronounced analgesic and anti-inflammatory effect that is superior to traditional NSAIDs. Thus, in a study by Jokhio et al. The analgesic efficacy of rofecoxib and ketoprofen was compared. 165 patients with damage to the ligamentous apparatus, dislocations of the joints of the upper and lower extremities were divided into two equal groups. Group 1 (82 patients) received rofecoxib 25 mg per day orally, group 2 (83 patients) took ketoprofen 200 mg per day. The duration of therapy was 7 days. The effectiveness was assessed taking into account the speed of onset of pain relief and the degree of its severity. The study found that in the group receiving rofecoxib therapy, an analgesic effect was achieved more quickly, which persisted for 24 hours and did not require additional analgesia, in contrast to the group taking ketoprofen, where additional analgesia was required in 7.8% of cases.
A similar study was conducted by M. Petri et al. It involved 306 patients with post-traumatic glenohumeral periarthritis and subacromial bursitis. All patients were divided into 3 groups (102 patients each). Group 1 received rofecoxib at a dose of 25 mg/day, group 2 received naproxen at a dose of 1000 mg/day, and group 3 received placebo. Treatment was carried out for 14 days. At the end of the observation period, only with the use of rofecoxib there was a significantly significant (compared to placebo) reduction in pain severity - on average by 35.0 mm according to VAS. However, the effectiveness of naproxen was not superior to placebo.
A prospective, randomized, double-blind study conducted by M. Broggini (2003) involving 30 patients compared the effectiveness of nimesulide (100 mg), celecoxib (200 mg) and rofecoxib (25 mg) in the symptomatic treatment of osteoarthritis of the knee joint for 7 days [10 ]. Its results demonstrated a faster onset of analgesic action with a pronounced and long-lasting effect in the group of patients taking rofecoxib.
K. Malmstrom et al. [11] conducted a large-scale RCT that examined the comparative effectiveness of a single dose of rofecoxib 50 mg, celecoxib 200 and 400 mg, ibuprofen 400 mg, or placebo in 482 patients who had undergone extraction of at least 2 teeth (3 molars). For the primary outcome measure of total pain relief (TOTPAR) at 8 and 12 hours, all three NSAIDs were superior to placebo, but the advantage in pain relief was in the rofecoxib group.
Thus, according to a number of studies, rofecoxib is superior in its analgesic and anti-inflammatory activity to both classical NSAIDs and coxibs. To date, there are no comparative studies of rofecoxib and etoricoxib, but the undoubted advantage of rofecoxib is the presence of several dosage forms: ampoules, tablets, gel, suppositories, which allows for stepwise therapy, and therefore better control of pain in patients.
