Ketanov

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETANOV (KETANOV)

Composition:

Active substance: ketorolac tromethamine;

One coated tablet contains 10 mg of ketorolac tromethamine;

Excipients: microcrystalline cellulose, corn starch, colloidal anhydrous silicon dioxide, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol 400, talc, titanium dioxide (E 171).

Pharmaceutical form. Coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex coated tablets with "KVT" imprint on one side.

Pharmacotherapeutic group.
Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AB15.

Pharmacological properties.

Pharmacodynamics.

Ketorolac tromethamine is an analgesic agent – a non-narcotic analgesic. It is a nonsteroidal anti-inflammatory drug exhibiting strong analgesic and anti-inflammatory effects, as well as mild antipyretic activity. Ketorolac tromethamine inhibits prostaglandin synthesis and is considered a peripherally-acting analgesic. It has no known effect on opioid receptors. In controlled clinical studies, no evidence of respiratory depression was observed following administration of ketorolac tromethamine. Ketorolac tromethamine does not cause miosis.

Pharmacokinetics.

Ketorolac tromethamine is rapidly and completely absorbed after oral administration, reaching a peak plasma concentration of 0.87 mg/kg within 45 minutes after a single 10 mg dose. In healthy volunteers, the mean terminal elimination half-life from plasma is 5.4 hours. In elderly individuals (mean age 72 years), it is 6.2 hours. More than 99% of ketorolac in plasma is protein-bound. Ketorolac poorly penetrates brain tissue. A negligible amount may be detected in breast milk. In healthy humans, less than 50% of the administered dose is metabolized. Major metabolites include glucuronide conjugates and 4-hydroxy-ketorolac, both of which are pharmacologically inactive. In humans, after single or multiple dosing, the pharmacokinetics of ketorolac are linear. Steady-state plasma concentrations are achieved within 1 day with administration four times daily. No changes were observed with prolonged dosing. In healthy volunteers, the terminal elimination half-life from plasma ranges from 4 to 6 hours (mean 5.4 hours). The plasma elimination half-life increases in patients with renal impairment and in elderly patients. After a single intravenous dose, the volume of distribution is 0.25 L/kg, the elimination half-life is 5 hours, and clearance is 0.55 mL/min/kg. The primary route of elimination for ketorolac and its metabolites (conjugates and p-hydroxymetabolites) is via urine (90%), with the remainder excreted in feces. A high-fat, difficult-to-digest meal reduces the rate, but not the extent, of absorption, whereas antacids do not affect ketorolac absorption.

Clinical characteristics.

Indications.

Short-term treatment of moderate-intensity pain, including postoperative pain.

Maximum duration of treatment – 5 days.

Contraindications.

• Hypersensitivity to ketorolac or to other NSAIDs or to any of the excipients;
  • hypersensitivity reactions such as bronchial asthma, rhinitis, angioedema, or urticaria in medical history caused by administration of acetylsalicylic acid or other NSAIDs (due to the possibility of severe anaphylactic reactions);
  • active or history of gastrointestinal bleeding or perforation associated with previous NSAID therapy;
  • active recurrent peptic ulcer/gastrointestinal bleeding (two or more episodes) in exacerbation phase or in medical history;
  • should not be used as an analgesic before and during surgical procedures and after manipulations on coronary vessels due to inhibition of platelet aggregation, which may cause bleeding;
  • suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding, as well as in the postoperative period if there is a high risk of bleeding or incomplete hemostasis;
  • complete or partial nasal polyps syndrome, Quincke's edema, or bronchospasm;
  • concomitant therapy with other nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, oxpentifylline, probenecid, or lithium salts, anticoagulants, including low-dose heparin (2500–5000 units every 12 hours);
  • hematopoiesis disorders of unknown etiology;
  • severe heart failure;
  • history of bronchial asthma;
  • hepatic or moderate to severe renal impairment (serum creatinine level > 160 µmol/L);
  • risk of developing renal failure due to reduced fluid volume;
  • hypovolemia, dehydration;
  • the drug is contraindicated during pregnancy, labor, delivery, and breastfeeding;
• not to be used in children and adolescents under 16 years of age.

Interaction with other medicinal products and other forms of interactions.

Ketorolac is highly bound to plasma proteins (mean value 99.2%), and the degree of binding depends on concentration.

Should not be used concomitantly with ketorolac.

Ketorolac should not be used together with other NSAIDs, including selective cyclooxygenase-2 inhibitors, including in patients receiving acetylsalicylic acid, due to the risk of severe adverse reactions.

Ketorolac inhibits platelet aggregation, reduces thromboxane concentration, and prolongs bleeding time. Unlike the long-term effects of acetylsalicylic acid, platelet function recovers within 24–48 hours after discontinuation of ketorolac.

Anticoagulants. Although studies have not shown significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac and therapies affecting hemostasis, including therapeutic doses of anticoagulants (warfarin), low-dose prophylactic heparin (2500–5000 units every 12 hours), and dextrans, may increase the risk of bleeding. Concomitant use with anticoagulants (such as warfarin) is contraindicated.

Reduced renal clearance of lithium by some drugs that inhibit prostaglandin synthesis has led to increased plasma lithium concentration. Cases of increased plasma lithium concentration during ketorolac therapy have been reported.

Probenecid should not be administered concomitantly with ketorolac due to reduced plasma clearance and volume of distribution of ketorolac, increased plasma concentration of ketorolac, and prolonged elimination half-life.

NSAIDs should not be used within 8–12 days after mifepristone administration, as NSAIDs may reduce the effect of mifepristone.

When ketorolac is administered concomitantly with oxpentifylline, increased susceptibility to bleeding is observed.

Medicinal products that should be used with caution in combination with ketorolac.

As with all NSAIDs, corticosteroids should be used concomitantly with caution due to increased risk of gastrointestinal ulcers or bleeding. The risk of gastrointestinal bleeding is increased when NSAIDs are used in combination with antiplatelet agents and selective serotonin reuptake inhibitors.

Concomitant use of methotrexate is recommended with caution, as some prostaglandin synthesis inhibitors have been reported to reduce methotrexate clearance and thus possibly increase its toxicity.

In healthy individuals with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%. Concomitant administration with diuretics may lead to reduced diuretic efficacy and increased risk of NSAID nephrotoxicity.

Ketorolac should be used with caution when administered concomitantly with cyclosporine due to increased risk of nephrotoxicity.

There is a risk of nephrotoxicity when NSAIDs are used concomitantly with tacrolimus.

Particular caution is required when administering the drug to patients with cardiac decompensation. NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when administered concomitantly with cardiac glycosides.

Ketorolac and other nonsteroidal anti-inflammatory drugs may reduce the effect of antihypertensive agents. When ketorolac is used concomitantly with ACE inhibitors (angiotensin-converting enzyme inhibitors) or ARBs (angiotensin receptor blockers), there is an increased risk of impaired renal function (usually reversible), especially in patients with reduced blood volume or elderly patients. When such combination is used, careful monitoring of renal function is required at the beginning of treatment and periodically during therapy.

Opioid analgesics (e.g., morphine, pethidine) may be used concurrently; ketorolac does not affect binding of opioid drugs and does not enhance respiratory depression or sedative effects caused by opioids. It has been demonstrated that in cases of postoperative pain, concomitant use of ketorolac with opioid analgesics reduced the need for the latter.

Oral administration of ketorolac tablets after a high-fat meal results in reduced peak plasma concentration of ketorolac and increases the time to peak concentration by approximately 1 hour. Antacids do not affect the extent of absorption.

Patients taking NSAIDs and quinolones have an increased risk of seizures.

Concomitant use of NSAIDs with zidovudine increases the risk of hematological toxicity. There is an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia who are treated concomitantly with zidovudine and ibuprofen.

Unlikely that the following medicinal products interact with ketorolac.

Ketorolac did not affect protein binding of digoxin in plasma. In vitro studies indicate that at therapeutic concentrations of salicylate (300 µg/mL) and higher, ketorolac binding decreased from approximately 99.2% to 97.5%. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, paracetamol, phenytoin, and tolbutamide did not affect ketorolac binding to plasma proteins. Since ketorolac is a highly protein-bound drug and its plasma concentration is low, it is not expected to significantly displace other drugs bound to plasma proteins.

Studies in animals and humans have provided no evidence that ketorolac tromethamine induces or inhibits liver enzymes capable of metabolizing it or other drugs. Therefore, ketorolac is not expected to alter the pharmacokinetics of other drugs via enzyme induction or inhibition mechanisms.

Antiepileptic drugs.

Isolated cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).

Psychotropic agents.

Hallucinations have been reported during concomitant use of ketorolac and psychotropic agents (fluoxetine, tiotixene, alprazolam).

Effect on laboratory test results.

Ketorolac inhibits platelet aggregation and may prolong bleeding time.

Special precautions for use.

Epidemiological data suggest that ketorolac may be associated with a higher risk of gastrointestinal toxicity compared to other NSAIDs, especially when used outside the approved indications and/or for prolonged periods.

To minimize the risk of adverse effects, ketorolac treatment should be administered for the shortest possible duration and at the lowest effective dose required to control pain. The maximum duration of treatment should not exceed 5 days.

Gastrointestinal bleeding, ulceration, and perforation.

Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported during NSAID therapy at any time, with or without warning symptoms or a history of severe gastrointestinal disorders. The risk of serious gastrointestinal bleeding is dose-dependent. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including ketorolac, particularly in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. The risk of clinically significant bleeding episodes is dose-dependent. These patients should begin treatment with the lowest available dose. This is particularly relevant for elderly and debilitated patients receiving ketorolac at daily doses exceeding 60 mg. The majority of fatal cases associated with NSAID-related gastrointestinal adverse reactions have occurred in elderly or debilitated patients. Such patients should be warned to report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly during the initial stages of treatment. For these patients, as well as for those concurrently using low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, consideration should be given to concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors). Ketorolac should be used with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents like acetylsalicylic acid. NSAIDs, including ketorolac, should be used cautiously in patients with inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis). Ketorolac may be associated with an increased risk of gastrointestinal anastomotic dehiscence. Careful medical supervision and caution are recommended when using ketorolac after gastrointestinal surgery.

If gastrointestinal bleeding or ulceration occurs in patients receiving Ketorolac, treatment should be discontinued.

Hematological effects.

Ketorolac should not be prescribed to patients with coagulation disorders. Patients receiving anticoagulant therapy may have an increased risk of bleeding when ketorolac is used concomitantly (see Interaction with other medicinal products). Patients receiving other agents that may affect hemostasis should be closely monitored when ketorolac is prescribed. In controlled clinical trials, the incidence of significant postoperative bleeding was less than 1%. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal baseline bleeding time, bleeding time was prolonged but remained within the normal range of 2–11 minutes. Unlike the prolonged effect of acetylsalicylic acid, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac. Ketorolac should not be administered to patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis. Caution is advised when complete hemostasis is critical. Hypovolemia should be corrected before initiating ketorolac therapy.

Skin reactions.

Very rarely, severe skin reactions, sometimes fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with NSAID use (see Adverse reactions).

The risk of such reactions is higher at the beginning of treatment, with most cases occurring within the first month of therapy. Ketorolac should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity (see Adverse reactions).

Increasing the dose of ketorolac tablets above the daily dose of 40 mg does not enhance efficacy but increases the risk of adverse reactions.

Ketorolac does not cause dependence, and no withdrawal syndrome has been observed upon discontinuation.

Systemic lupus erythematosus and mixed connective tissue disorders.

Patients with systemic lupus erythematosus and mixed connective tissue disorders have an increased risk of developing aseptic meningitis.

Fluid and sodium retention and edema.

Fluid retention, hypertension, and edema have been reported during ketorolac therapy; therefore, the drug should be used with caution in patients with mild to moderate heart failure, arterial hypertension, or similar conditions.

Cardiovascular and cerebrovascular effects.

Patients with uncontrolled hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be under medical supervision, as the use of the drug may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Clinical trials and epidemiological data suggest that the use of COX-2 inhibitors and certain NSAIDs (particularly at high doses) may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Although ketorolac treatment has not demonstrated an increased frequency of thrombotic events such as myocardial infarction, data are insufficient to exclude such a risk for ketorolac tromethamine.

Cardiovascular, renal, and hepatic effects.

Ketorolac should be used with caution in patients with conditions leading to reduced blood volume and/or renal blood flow, where renal prostaglandins play a supportive role in maintaining renal perfusion. Renal function should be monitored in such patients. Hypovolemia should be corrected, and serum urea and creatinine levels and urine output should be closely monitored until normovolemia is achieved, as there is a risk of renal failure if these recommendations are not followed. In patients undergoing dialysis, creatinine clearance was approximately halved compared to normal, and the terminal elimination half-life was prolonged about threefold. Patients with hepatic impairment due to cirrhosis showed no clinically significant changes in ketorolac clearance or elimination half-life. Mild elevations in one or more liver function tests (ALT/AST) may occur. These abnormalities may be transient, remain unchanged, or progress with continued treatment. If clinical signs and symptoms suggest liver disease or if systemic manifestations occur, Ketorolac should be discontinued.

Ketorolac should be used with caution in patients with a history of cardiovascular disorders.

Renal effects.

Inhibitors of prostaglandin synthesis (including NSAIDs) have been reported to cause nephrotoxic effects. The drug should be used with caution in patients with renal, cardiac, or hepatic impairment, or a history of kidney disease, as NSAID use may worsen renal function due to inhibition of prostaglandin synthesis (see above). Since ketorolac tromethamine and its metabolites are primarily excreted by the kidneys, patients with moderate to severe renal impairment (serum creatinine > 160 µmol/L) should not receive Ketorolac. Patients with mild renal impairment should receive reduced doses of ketorolac (not exceeding 60 mg daily intramuscularly), and renal function should be closely monitored. As with other prostaglandin synthesis inhibitors, increases in serum urea, creatinine, and potassium have been reported during ketorolac tromethamine use, which may occur after a single dose. Discontinuation of the drug usually leads to recovery of renal function.

Respiratory function.

Caution is required when administering the drug to patients with bronchial asthma (or a history of asthma), as NSAIDs have been reported to trigger bronchospasm in such patients.

Anaphylactic reactions.

Anaphylactic/anaphylactoid reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) have occurred in patients with hypersensitivity to acetylsalicylic acid or any other NSAID, or with a history of intravenous ketorolac tromethamine administration. These reactions may also occur in individuals with angioedema, bronchospasm (e.g., asthma), or nasal polyps. Anaphylactoid reactions such as anaphylaxis may develop slowly. Therefore, ketorolac tromethamine is contraindicated in patients with a history of asthma and in those with complete or partial aspirin triad (nasal polyps, angioedema, and bronchospasm).

Effect on fertility.

The use of ketorolac, like any drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for women attempting to conceive. For women who are infertile or undergoing fertility investigations, consideration should be given to discontinuing ketorolac.

Use during pregnancy or breastfeeding.

The safety of ketorolac during human pregnancy has not been established. Approximately 10% of ketorolac crosses the placenta.

Therefore, the use of ketorolac tromethamine is contraindicated during pregnancy, labor, and delivery due to the known effects of NSAIDs on the fetal cardiovascular system.

Pregnancy.

The safety of use during pregnancy has not been proven. It has been demonstrated that ketorolac crosses the placental barrier and enters the fetal circulation. Therefore, ketorolac tromethamine is contraindicated during pregnancy and labor.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of spontaneous abortion, cardiac malformations, and gastroschisis following the use of prostaglandin synthesis inhibitors during early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. This risk is believed to increase with higher doses and longer duration of therapy. Animal studies have shown that prostaglandin synthesis inhibitors lead to increased pre-implantation loss of fertilized ova, post-implantation pregnancy loss, and increased embryonic and fetal mortality. Additionally, increased incidence of various malformations, including cardiovascular malformations, has been reported in animals exposed to prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, the use of ketorolac tromethamine may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction after second-trimester treatment, which was mostly reversible after stopping the drug.

Furthermore, during pregnancy, all prostaglandin synthesis inhibitors may cause in the fetus:

• cardiopulmonary toxicity (due to premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with the development of oligohydramnios (reduced amniotic fluid volume) (see above).

In late pregnancy, these drugs may affect both the mother and the newborn by:

• prolonging bleeding time due to antiplatelet effects, which may occur even with very low doses;
• inhibiting uterine contractions, potentially leading to delayed or prolonged labor.

Therefore, the use of ketorolac is contraindicated throughout pregnancy.

If a pregnant woman has taken the drug, antenatal monitoring for oligohydramnios after exposure to ketorolac for several days starting from the 20th week of pregnancy may be advisable. Ketorolac use should be discontinued.

Breastfeeding.

Ketorolac passes into breast milk in small amounts; therefore, Ketorolac is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Some patients may experience somnolence, dizziness, vertigo, insomnia, increased fatigue, visual disturbances, headache, or depression when using ketorolac. If patients experience any of these or similar effects, they should not drive or operate machinery.

Administration and Dosage

It is advisable to take tablets during or after a meal.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The total duration of treatment (parenteral administration followed by oral administration) should not exceed 5 days.

Adults.

The usual recommended dose is 10 mg every 4 or 6 hours. A daily dose exceeding 40 mg is not recommended.

If treatment follows parenteral administration:

• For patients aged 16 to 64 years, with body weight of at least 50 kg and normal renal function – initially administer 20 mg, followed by 10 mg each time, up to 4 times daily, with intervals of 4 to 6 hours;
• For patients weighing less than 50 kg, elderly patients, or patients with impaired renal function – 10 mg, up to 4 times daily, with intervals of 4 to 6 hours.

For patients who have received ketorolac parenterally and then switched to oral administration, the combined total dose of ketorolac should not exceed 90 mg in adults and 60 mg in elderly patients with impaired renal function or patients weighing less than 50 kg.

Patients should be switched to oral administration as early as possible.

Elderly Patients.

Elderly patients have a higher risk of developing severe complications, particularly gastrointestinal complications. During treatment with NSAIDs, patients should be monitored regularly, and a longer dosing interval is generally recommended, for example, every 6–8 hours.

Children.

Do not use in children under 16 years of age.

Overdose.

Symptoms: headache, nausea, vomiting, epigastric pain, peptic ulcers, erosive gastritis, gastrointestinal bleeding; hyperventilation, hypertension, rarely – diarrhea, disorientation, excitement, coma, drowsiness, dizziness, tinnitus, loss of consciousness, seizures. In cases of severe poisoning, acute renal failure and hepatic injury are possible.

Treatment: gastric lavage, administration of activated charcoal. Adequate diuresis should be maintained. Renal and hepatic functions should be closely monitored. Patients should be observed for at least 4 hours after ingestion of a potentially toxic dose. Frequent or prolonged seizures should be treated by intravenous administration of diazepam. Other measures may be implemented depending on the patient's clinical condition. Treatment is symptomatic. There is no specific antidote. Dialysis does not remove ketorolac from the bloodstream.

Adverse Reactions

Gastrointestinal disorders: Peptic ulcer, perforation or gastrointestinal hemorrhage, sometimes fatal (especially in elderly patients), nausea, dry mouth, dyspepsia, abdominal pain, discomfort in the abdomen, spasm or burning sensation in the epigastric region, vomiting with blood, gastritis, esophagitis, diarrhea, belching, constipation, flatulence, feeling of stomach fullness, melena, rectal bleeding, stomatitis, ulcerative stomatitis, vomiting, hemorrhages, perforation, pancreatitis, exacerbation of colitis and Crohn's disease.

Blood and lymphatic system disorders: Purpura, thrombocytopenia, neutropenia, agranulocytosis, aplastic and hemolytic anemia, eosinophilia.

Immune system disorders (hypersensitivity): Cases of hypersensitivity reactions have been reported, including non-specific allergic reactions and anaphylactoid reactions such as anaphylaxis, respiratory tract reactivity including asthma, worsening of asthma, bronchospasm, laryngeal edema or dyspnea, as well as various skin disorders including rashes of different types, pruritus, urticaria, flushing, purpura, angioedema, hypotension, and in isolated cases – exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme).

Such reactions may occur in patients with or without known hypersensitivity to ketorolac or other nonsteroidal anti-inflammatory drugs (NSAIDs). They may also occur in individuals with a history of angioedema or bronchospastic reactivity (e.g., asthma and nasal polyps). Anaphylactic reactions may be fatal.

Metabolic and nutritional disorders: Hyponatremia, hyperkalemia, anorexia.

Central nervous system and psychiatric disorders: Dizziness, headache, hyperkinesia, nervousness, paresthesia, functional disturbances, depression, euphoria, seizures, inability to concentrate, insomnia, malaise, anxiety, somnolence, increased fatigue, excitement, unusual dreams, confusion, hallucinations, dysgeusia, aseptic meningitis with corresponding symptoms (neck stiffness, headache, nausea, vomiting, fever, or disorientation), psychotic reactions, disturbances in thinking.

Eye disorders: Visual disturbances, blurred vision, optic neuritis.

Ear and labyrinth disorders: Hearing loss, tinnitus, vertigo.

Cardiovascular disorders: Hot flushes, bradycardia, pallor, arterial hypertension, hypotension, palpitations, chest pain, development of edema, heart failure. Clinical and epidemiological data suggest that the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with an increased risk of arterial thromboembolic complications (myocardial infarction or stroke). Although such reactions have not been observed with ketorolac, the risk of their occurrence cannot be ruled out.

Respiratory system disorders: Dyspnea, asthma, pulmonary edema.

Hepatobiliary disorders: Liver function abnormalities, hepatitis, jaundice and liver failure, hepatomegaly, abnormalities in liver function laboratory tests.

Skin disorders: Pruritus, urticaria, sweating, photosensitivity, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), exfoliative dermatitis, maculopapular rashes.

Musculoskeletal and connective tissue disorders: Myalgia, functional disorders.

Renal and urinary disorders: Increased frequency of urination, oliguria, acute renal failure, hemolytic uremic syndrome, flank pain (with or without hematuria), elevated serum urea and creatinine levels, interstitial nephritis, urinary retention, nephrotic syndrome, renal failure.

Reproductive system disorders: Female infertility.

Other: Postoperative wound bleeding, hematoma, epistaxis, prolonged bleeding time, asthenia, malaise, anorexia, weight gain, edema, elevated body temperature, increased thirst.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Packaging.

10 tablets in a blister; 1, 2, or 10 blisters per cardboard package.

Prescription category.

Prescription only.

Manufacturer.

Terapia A.T. / Terapia S.A.

Manufacturer's address and place of business.

Strada Fabriciei 124, 400632, Cluj-Napoca, Cluj County, Romania.