Instructions Sertofen solution for injection 50 mg/2 ml ampoule 2 ml No. 5
Composition
active ingredient: dexketoprofen;
1 ampoule (2 ml) of solution contains dexketoprofen (in the form of dexketoprofen trometamol) 50 mg;
1 ml of solution for injection contains dexketoprofen (in the form of dexketoprofen trometamol) 25 mg;
excipients: sodium chloride, sodium hydroxide, ethanol 96%, water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: transparent colorless solution.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. Propionic acid derivatives. Dexketoprofen. ATX code M01A E17.
Pharmacological properties
Pharmacodynamics.
Dexketoprofen trometamol is a propionic acid salt that has analgesic, anti-inflammatory, and antipyretic effects and belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).
The mechanism of action of NSAIDs is based on a decrease in prostaglandin synthesis by inhibiting the activity of cyclooxygenase. In particular, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2a, PGD2 are formed, as well as prostacyclin PGI2 and thromboxanes ThA2 and ThB2. In addition, inhibition of prostaglandin synthesis may affect other inflammatory mediators, such as kinins, which may also indirectly affect the main action of dexketoprofen. Its inhibitory effect on the activity of cyclooxygenase-1 and cyclooxygenase-2 has been found in laboratory animals and in humans.
Clinical studies in various types of pain have demonstrated that dexketoprofen has a pronounced analgesic effect. Its analgesic effect when administered intramuscularly and intravenously to patients with moderate to severe pain has been studied in various types of pain during surgical interventions (orthopedic and gynecological operations, abdominal operations), as well as in musculoskeletal pain (acute low back pain) and in renal colic. During the studies, the analgesic effect began quickly and reached a maximum within the first 45 minutes. The duration of the analgesic effect after the use of 50 mg of dexketoprofen is usually 8 hours. The use of dexketoprofen allows for a significant reduction in the dose of opiates when they are used simultaneously for the purpose of relieving postoperative pain. Patients treated with morphine (using a patient-controlled analgesia device) and dexketoprofen for postoperative pain relief required significantly less morphine (30–45%) than patients treated with placebo.
Pharmacokinetics.
Absorption
After intramuscular administration of dexketoprofen, its maximum concentration (Cmax) is reached after approximately 20 minutes (10–45 minutes). It has been proven that with a single intramuscular or intravenous administration of 25–50 mg, the area under the concentration-time curve (AUC) is proportional to the dose. Pharmacokinetic studies of multiple administration have shown that AUC and Cmax (mean maximum value) after the last intramuscular and intravenous administration do not differ from those after a single administration, which indicates the absence of cumulation of dexketoprofen.
Distribution
Similar to other drugs with a high degree of binding to plasma proteins (99%), the volume of distribution of dexketoprofen is on average 0.25 l/kg. The half-life is approximately 0.35 hours.
Metabolism
Dexketoprofen is mainly metabolized by conjugation with glucuronic acid and subsequent renal excretion. After administration of dexketoprofen, only the S-(+) optical isomer is detected in the urine, indicating that the drug is not transformed into the R-(-) optical isomer in humans.
Breeding
The half-life (T1/2) of dexketoprofen is 1–2.7 hours.
Elderly patients
After single and multiple doses of dexketoprofen, the exposure of healthy elderly volunteers (65 years and older) participating in the study was significantly higher (up to 55%) than in young volunteers, but there was no statistically significant difference in maximum concentration and time to reach it. The mean T1/2 increased (up to 48%), and the determined total clearance decreased.
Preclinical safety data.
Like all NSAIDs, dexketoprofen can cause embryo or fetal death in animals by directly affecting its development or indirectly by damaging the gastrointestinal tract of the mother.
Indication
Symptomatic treatment of acute pain of moderate to severe intensity in cases where oral dexketoprofen is inappropriate, for example, in postoperative pain, renal colic and low back pain.
Contraindication
Hypersensitivity to dexketoprofen, any other non-steroidal anti-inflammatory drug (NSAID) or to any of the excipients of the medicinal product.
Attacks of bronchial asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria or angioedema associated with previous use of substances with similar effects, for example, acetylsalicylic acid or other NSAIDs.
Photoallergic or phototoxic reactions associated with previous use of ketoprofen or other fibrates.
History of gastrointestinal bleeding or perforation associated with previous use of NSAIDs.
Active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers or perforation.
Chronic dyspepsia.
Crohn's disease or nonspecific ulcerative colitis.
Gastrointestinal bleeding, other bleeding in the active phase or increased bleeding.
Hemorrhagic diathesis and other blood clotting disorders.
Severe heart failure.
Moderate or severe renal impairment (creatinine clearance ≤59 ml/min).
Severe liver dysfunction (10–15 points on the Child-Pugh scale).
Severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake).
Third trimester of pregnancy.
Breastfeeding period.
Neuroaxial (intrathecal or epidural) administration of a drug (due to ethanol content).
Interaction with other medicinal products and other types of interactions
The simultaneous use of dexketoprofen with such agents is not recommended.
Other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day): the simultaneous use of dexketoprofen with these agents increases the risk of gastrointestinal ulcers and gastrointestinal bleeding due to their mutually reinforcing effect.
Anticoagulants: when used simultaneously with dexketoprofen, the effect of anticoagulants, for example, warfarin, is enhanced (due to the high degree of binding of dexketoprofen to blood plasma proteins, as well as inhibition of platelet function and damage to the gastric and duodenal mucosa). If the simultaneous use of these agents is necessary, careful medical supervision and monitoring of relevant laboratory parameters are necessary.
Heparins: the simultaneous use of dexketoprofen with these agents increases the risk of bleeding (due to dexketoprofen inhibition of platelet function and damage to the gastric and duodenal mucosa). If the simultaneous use of these agents is necessary, careful medical supervision and monitoring of relevant laboratory parameters are necessary.
Corticosteroids: Concomitant use of dexketoprofen with these agents increases the risk of gastrointestinal ulcers or bleeding.
Lithium: when used simultaneously with NSAIDs (there have been reports for several NSAIDs), the level of lithium in the blood plasma increases, which can lead to intoxication (reduced renal excretion of lithium). At the beginning of treatment with dexketoprofen, when adjusting the dose or discontinuing its use, the level of lithium in the blood plasma should be monitored.
Methotrexate in high doses (at least 15 mg per week): when used simultaneously with dexketoprofen, the renal clearance of methotrexate decreases and its overall negative effect on the blood system increases.
Hydantoin derivatives and sulfonamides: when used simultaneously with dexketoprofen, the toxicity of these agents increases.
Concomitant use of dexketoprofen with such agents should be carried out with caution.
Methotrexate in low doses (less than 15 mg per week): when used simultaneously with dexketoprofen, the renal clearance of methotrexate decreases and its negative effect on the blood system is generally increased. In the first weeks of simultaneous use of these drugs, blood tests should be performed weekly. Patients with even slight renal impairment, as well as elderly patients, require careful monitoring by a doctor.
Pentoxifylline: There is a risk of bleeding when dexketoprofen is used concomitantly with pentoxifylline. In case of concomitant use of these agents, monitoring and more frequent monitoring of bleeding time should be increased.
Zidovudine: When dexketoprofen is used concomitantly with zidovudine, there is a risk of increased erythrocyte toxicity due to the effect on reticulocytes, which leads to severe anemia after the first week of NSAID use. In the case of concomitant use of these agents for 1-2 weeks, a blood test should be performed and the reticulocyte count should be checked.
Sulfonylurea drugs: when used simultaneously with dexketoprofen, the hypoglycemic effect of these drugs is enhanced due to the displacement of sulfonylurea drugs in their compounds with blood plasma proteins.
When using dexketoprofen simultaneously with such agents, possible interactions should be taken into account.
Beta-blockers: when used simultaneously with dexketoprofen, the antihypertensive effect of beta-blockers may be weakened (due to inhibition of prostaglandin synthesis).
Cyclosporine, tacrolimus: when used simultaneously with dexketoprofen, the nephrotoxicity of these drugs may be increased (due to the effect of dexketoprofen on renal prostaglandins). In case of simultaneous use of these drugs, renal function should be monitored.
Thrombolytic agents: the risk of bleeding increases when dexketoprofen is used simultaneously with these agents.
Antiplatelet agents and selective serotonin reuptake inhibitors: the risk of gastrointestinal bleeding increases when dexketoprofen is used concomitantly with these agents.
Probenecid: Concomitant use of probenecid may increase plasma levels of dexketoprofen, probably due to inhibition of its renal tubular secretion and conjugation with glucuronic acid. In case of concomitant use of these agents, the dose of dexketoprofen should be adjusted.
Cardiac glycosides: when used simultaneously with dexketoprofen, an increase in the level of glycosides in the blood plasma is possible.
Mifepristone: There is a theoretical risk that the efficacy of mifepristone may be altered by prostaglandin synthetase inhibitors. Limited data suggest that co-administration of NSAIDs on the same day as a prostaglandin does not adversely affect the efficacy of mifepristone or prostaglandin in cervical ripening or contractility, nor does it reduce the clinical efficacy of medical abortion.
Quinoline antibiotics: animal studies have shown that the risk of seizures is increased when quinolone derivatives are used in high doses with NSAIDs.
Tenofovir: Concomitant use with dexketoprofen may increase blood urea nitrogen and creatinine levels. Renal function should be monitored during concomitant use.
Deferasirox: Concomitant use of dexketoprofen with deferasirox may increase the risk of gastrointestinal toxicity. Careful patient monitoring is required when these agents are used concomitantly.
Pemetrexed: Concomitant use with dexketoprofen may result in decreased excretion of pemetrexed. Special caution should be exercised when these agents are used concomitantly (especially with high doses of dexketoprofen). In patients with mild to moderate renal impairment (creatinine clearance 45 to 79 ml/min), concomitant use of pemetrexed with dexketoprofen should be avoided for 2 days before and 2 days after pemetrexed administration.
Application features
The drug should be used with caution in patients with a history of allergic conditions.
Concomitant use of the drug with other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided.
Adverse drug reactions can be minimized by using the lowest effective dose for the shortest time necessary to improve the condition.
Gastrointestinal effects
Gastrointestinal bleeding, ulceration or perforation, in some cases fatal, has been observed with all NSAIDs at various stages of treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal disease.
If gastrointestinal bleeding or ulceration develops, the drug should be discontinued.
Elderly patients are more likely to experience adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, sometimes fatal. Treatment of such patients should be started at the lowest possible dose.
As with all NSAIDs, patients with a history of esophagitis, gastritis and/or peptic ulcer disease should be ensured that these diseases are in remission.
When using the drug in patients with existing symptoms of digestive tract pathology and with a history of digestive tract diseases, the condition of the digestive tract should be monitored for possible disorders, especially gastrointestinal bleeding.
The drug should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as there is a risk of their exacerbation. The use of NSAIDs can lead to relapses of nonspecific ulcerative colitis, as well as Crohn's disease in patients who are in remission. For such patients and patients who use acetylsalicylic acid in low doses or other agents that increase the risk of adverse reactions from the digestive tract, the possibility of combination therapy with protective drugs, for example, misoprostol or proton pump inhibitors, should be considered.
Patients, especially the elderly, who have a history of adverse reactions from the digestive tract should inform their doctor about all unusual symptoms related to the digestive system, in particular gastrointestinal bleeding, especially in the initial stages of treatment.
The drug should be used with caution in patients who are concomitantly taking agents that may increase the risk of ulceration or bleeding, namely oral corticosteroids, anticoagulants (e.g. warfarin), selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid.
Kidney effects
The drug should be used with caution in patients with impaired renal function, since the use of NSAIDs may worsen renal function, fluid retention and edema. Due to the increased risk of nephrotoxicity, the drug should be used with caution in patients who are simultaneously taking diuretics, as well as in patients who may develop hypovolemia.
While using the drug, the patient should receive sufficient fluids to avoid dehydration, which can lead to increased toxic effects on the kidneys.
Like all NSAIDs, dexketoprofen may increase the concentration of urea nitrogen and creatinine in blood plasma.
Like other prostaglandin synthesis inhibitors, its use may be accompanied by renal adverse reactions, leading to glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Most renal dysfunction occurs in elderly patients.
Liver effects
The drug should be used with caution in patients with impaired liver function. Like other NSAIDs, dexketoprofen may cause a temporary and slight increase in the values of some liver parameters, as well as a pronounced increase in the activity of AST and ALT. If these parameters increase, the drug should be discontinued.
Most liver dysfunction occurs in elderly patients.
Effects on the cardiovascular system and cerebral circulation
When using the drug, patients with arterial hypertension and/or mild to moderate heart failure should be under close medical supervision.
The drug should be used with extreme caution in patients with a history of heart disease, in particular with previous episodes of heart failure (the risk of developing heart failure increases with the use of dexketoprofen), since fluid retention in the tissues and the formation of edema have been observed during treatment with NSAIDs. Clinical studies and epidemiological data suggest that the risk of arterial thrombosis (for example, myocardial infarction or stroke) may be slightly increased with the use of some NSAIDs (especially in high doses and for a long time). There is insufficient data to exclude such a risk with the use of dexketoprofen.
The drug should only be used after careful assessment in patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease. The same careful assessment should be performed before long-term use of the drug in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidemia, diabetes mellitus, smoking).
However, during the use of the drug, patients taking drugs that affect hemostasis, such as warfarin, other coumarin drugs or heparins, should be under close medical supervision. Cardiovascular system dysfunction is most common in elderly patients.
Skin effects
Very rare cases of serious skin reactions (some fatal), including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with NSAIDs. Patients appear to be at greatest risk at the start of treatment, with most patients experiencing these reactions within the first month of treatment. The drug should be discontinued if skin rash, signs of mucosal involvement or other signs of hypersensitivity occur.
Masking the symptoms of underlying infections
Dexketoprofen may mask the symptoms of infections, which may prevent diagnosis and timely treatment and, thereby, worsen the consequences of the infection. Such cases have been observed with bacterial pneumonia and bacterial complications of varicella. When the drug is used to relieve pain associated with an infectious process, monitoring of the infectious process is recommended. In outpatient settings, the patient should consult a doctor if symptoms persist or worsen.
Other caveats
The drug should be used with extreme caution in patients with hereditary disorders of porphyrin metabolism (e.g., acute intermittent porphyria), dehydration, and immediately after major surgery.
In case of prolonged use of the drug, liver and kidney function and blood cell counts should be regularly monitored.
Severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed in very rare cases with the use of dexketoprofen. At the first signs of severe hypersensitivity reactions, the use of the medicinal product should be discontinued. Depending on the symptoms, any treatment required in such cases should be carried out under medical supervision.
Patients with asthma in combination with chronic rhinitis, chronic sinusitis and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs than other patients. The use of the drug may cause asthma attacks or bronchospasm, especially in patients with allergy to acetylsalicylic acid or NSAIDs.
Severe infectious complications of the skin and soft tissues may develop in association with chickenpox. To date, there is no evidence to rule out the role of NSAIDs in aggravating this infectious process. Therefore, the use of the drug in chickenpox is not recommended.
The drug should be used with caution in patients with hematopoietic disorders, systemic lupus erythematosus, and mixed connective tissue diseases.
Like other NSAIDs, dexketoprofen may mask the symptoms of infectious diseases during its use. In isolated cases, there have been reports of the activation of infectious processes localized in soft tissues during the use of NSAIDs. In case of development or worsening of symptoms of bacterial infection, you should immediately consult a doctor.
Each ampoule of the medicinal product contains 12.35 vol.% ethanol, i.e. up to 200 mg per dose, which is equivalent to 5 ml of beer or 2.08 glasses of wine per dose. The medicinal product may have a negative effect on people suffering from alcoholism. The ethanol content should be taken into account when using it in pregnant and lactating women, children, patients at risk, for example, with liver diseases, as well as patients with epilepsy.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
Use during pregnancy or breastfeeding
The drug is contraindicated for use in the third trimester of pregnancy and during breastfeeding.
Pregnancy
Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. Epidemiological studies have shown that the use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage, fetal heart defects and anterior abdominal wall nonunion. Thus, the absolute risk of developing cardiovascular anomalies increased from <1% to approximately 1.5%. It is believed that the risk of such phenomena increases with increasing dexketoprofen dose and duration of therapy. The use of prostaglandin synthesis inhibitors in animals caused an increase in pre- and post-implantation losses and increased embryo-fetal lethality. In addition, in animals treated with prostaglandin synthesis inhibitors during organogenesis, the incidence of fetal malformations, including cardiovascular anomalies, increased. However, studies of dexketoprofen trometamol in animals have not revealed any toxicity to reproductive organs.
In the first and second trimesters of pregnancy, the use of the drug is possible only if absolutely necessary.
When using the drug in women planning pregnancy or in the first and second trimesters of pregnancy, the lowest possible effective dose should be used for the shortest possible duration of treatment.
Antenatal monitoring for oligohydramnios and narrowing of the ductus arteriosus should be considered after exposure to dexketoprofen for several days, starting from the 20th week of gestation. The drug should be discontinued if oligohydramnios is detected.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors cause:
risks to the fetus:
cardiopulmonary toxic syndrome (with obstruction of the ductus arteriosus and pulmonary hypertension);
impaired renal function, which may progress to renal failure with the development of oligohydramnios (see above);
for mother and child at the end of pregnancy:
prolongation of bleeding time (effect of inhibiting platelet aggregation), which is possible even when using low doses;
Delayed uterine contractions with corresponding delayed labor and prolonged labor.
Breastfeeding period
There is no data on the penetration of dexketoprofen into breast milk. The use of the drug is contraindicated during breastfeeding.
Fertility
As with all NSAIDs, dexketoprofen may impair female fertility and is therefore not recommended in women attempting to conceive. Women who have difficulty conceiving or are undergoing investigation of infertility should consider discontinuing the drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
When using dexketoprofen, dizziness, visual disturbances or drowsiness may occur. In such cases, the ability to react quickly, navigate the road situation and drive vehicles or other mechanisms may be impaired.
Method of administration and doses
Dosage
Adults
The recommended dose is 50 mg every 8–12 hours.
If necessary, administer a second dose after 6 hours.
The maximum daily dose should not exceed 150 mg.
The medication is intended for short-term use, so it should only be used during acute pain (no longer than 2 days).
Patients should be switched to oral analgesics if possible.
Adverse reactions can be reduced by using the lowest effective dose for the shortest time necessary to improve the condition.
For moderate or severe postoperative pain, the drug can be used according to indications in the same recommended doses in combination with opioid analgesics.
Elderly patients
Dose adjustment is usually not required in such patients. However, due to physiologically decreased renal function, a lower dose of the drug is recommended, namely, the maximum daily dose is 50 mg in mild renal impairment.
Patients with renal impairment
In patients with mild renal impairment (creatinine clearance 60–89 ml/min), the maximum daily dose should be reduced to 50 mg. In patients with moderate or severe renal impairment (creatinine clearance <59 ml/min), the use of the medicinal product is contraindicated.
Patients with liver dysfunction
Patients with mild or moderate hepatic impairment (Child-Pugh score 5-9) should reduce the maximum daily dose to 50 mg and monitor liver function closely. The drug is contraindicated in patients with severe hepatic impairment (Child-Pugh score 10-15).
Method of application
Intramuscular injection
The contents of the ampoule (2 ml of solution for injection) should be slowly injected deep into the muscle.
Intravenous infusion
The contents of the ampoule (2 ml of solution for injection) should be diluted in 30–100 ml of 0.9% sodium chloride solution, glucose solution or Ringer-lactate solution.
The solution for infusion should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution should be clear.
The infusion should be administered intravenously slowly over 10–30 minutes.
Do not allow the prepared solution to be exposed to natural daylight.
The drug, diluted in 100 ml of 0.9% sodium chloride solution or in glucose solution, can be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine and theophylline.
The drug should not be mixed in an infusion solution with promethazine and pentazocine.
Intravenous injection (bolus administration).
The contents of the ampoule (2 ml of solution for injection) should be administered intravenously slowly over at least 15 seconds.
The drug can be mixed in small volumes (e.g., in a syringe) with injectable solutions of heparin, lidocaine, morphine, and theophylline.
The drug should not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, and hydroxyzine because a white precipitate is formed.
Diluted infusion solutions should not be mixed with promethazine or pentazocine.
For intramuscular or intravenous bolus administration, the drug should be administered immediately after withdrawal from the ampoule. The solution for intravenous infusion should be used immediately after preparation.
When storing diluted drug solutions in polyethylene bags or in products made of ethyl vinyl acetate, cellulose propionate, low-density polyethylene, and polyvinyl chloride designed for administration, no changes in the content of the active substance due to sorption were observed.
The medicine is intended for single use, therefore any remaining solution should be discarded.
Before administration, the solution should be visually inspected to ensure that it is clear and colorless. Solutions containing particulate matter should not be used.
Children
The medicine should not be used in children and adolescents due to a lack of data on its efficacy and safety.
Overdose
Symptoms of overdose are unknown. Similar drugs cause disorders of the digestive tract (vomiting, anorexia, abdominal pain) and the nervous system (drowsiness, dizziness, disorientation, headache).
In case of accidental overdose, symptomatic treatment should be initiated immediately according to the patient's condition. Dexketoprofen is removed from the body by dialysis.
Side effects
The following are listed by organ system and frequency of occurrence, adverse reactions considered at least possibly related to dexketoprofen based on available clinical studies, as well as adverse reactions reported during post-marketing experience. The criteria for assessing the frequency of adverse reactions are: common (≥ 1/100 < 1/10); uncommon (≥ 1/1000 < 1/100); rare (≥ 1/10000 < 1/1000); very rare (<1/10000).
Blood/lymphatic system disorders:
infrequently - anemia; very rarely - neutropenia, thrombocytopenia.
On the part of the immune system:
Rarely - laryngeal edema; very rarely - anaphylactic reactions, including anaphylactic shock.
Nutritional and metabolic:
rarely - hyperglycemia, hypoglycemia, hypertriglyceridemia, anorexia, lack of appetite.
From the psyche:
infrequently - insomnia, anxiety.
From the nervous system:
infrequently - headache, dizziness, drowsiness; rarely - paresthesia, fainting.
On the part of the organs of vision:
infrequently - blurred vision.
On the part of the hearing organs:
infrequently - vertigo; rarely - tinnitus.
From the heart:
infrequently - palpitation; rarely - extrasystole, tachycardia.
From the vascular system:
infrequently - arterial hypotension, hot flashes; rarely - arterial hypertension, superficial vein thrombophlebitis.
Respiratory, thoracic and mediastinal disorders:
rarely - bradypnea; very rarely - bronchospasm, shortness of breath.
From the digestive tract:
often - nausea, vomiting; infrequently - abdominal pain, dyspepsia, diarrhea, constipation, vomiting with blood, dry mouth; rarely - peptic ulcer, bleeding or perforation; very rarely - pancreatitis.
From the hepatobiliary system:
rarely – hepatocellular pathology.
Skin and subcutaneous tissue disorders:
infrequently - dermatitis, itching, rash, increased sweating; rarely - urticaria, acne; very rarely - Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), angioedema, facial edema, photosensitivity.
Musculoskeletal and connective tissue disorders:
rarely - muscle rigidity, joint stiffness, muscle cramps, back pain.
From the kidneys and urinary tract:
Rare: acute renal failure, polyuria, renal pain, ketonuria, proteinuria; very rare: nephritis, nephrotic syndrome.
From the reproductive system and mammary glands:
rarely - menstrual disorders, prostate dysfunction
