Ketorolac - zdorovya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOROLAC-ZDOROVYE (KETOROLAC-ZDOROVYE)

Composition:

Active substance: ketorolac;

1 tablet contains ketorolac tromethamine 10 mg;

Excipients: potato starch, celactose [a mixture of lactose monohydrate and powdered cellulose (75:25)], colloidal anhydrous silicon dioxide, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of white or white with creamish shade, flat cylindrical shape with bevelled edges.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01AB15.

Pharmacological properties.

Pharmacodynamics. Ketorolac tromethamine is a non-narcotic analgesic. It is a non-steroidal anti-inflammatory agent with anti-inflammatory and mild antipyretic activity. Ketorolac tromethamine inhibits prostaglandin synthesis and is considered a peripherally-acting analgesic. There is no evidence of its interaction with opioid receptors. Respiratory depression has not been observed after administration of ketorolac tromethamine. Ketorolac tromethamine does not cause pupillary constriction.

Pharmacokinetics. Ketorolac tromethamine is rapidly and completely absorbed after oral administration, reaching a C_max of 0.87 mg/kg in plasma within 50 minutes after a single 10 mg dose. The elimination half-life (T_½) from plasma averages 5.4 hours (6.2 hours in elderly individuals). Over 99% of ketorolac in plasma is protein-bound. 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 use. The primary route of elimination of ketorolac and its metabolites (conjugates and p-hydroxymetabolites) is via urine (91.4%), with the remainder excreted in feces. A high-fat diet reduces the rate of absorption but not the extent, whereas antacids do not affect ketorolac absorption.

Clinical characteristics.

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

Contraindications. Hypersensitivity to the components of the drug. Active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer or gastrointestinal bleeding. Bronchial asthma, rhinitis, angioedema, or urticaria induced by acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) (due to the possibility of severe anaphylactic reactions). History of bronchial asthma. Do not use as an analgesic before and during surgery and after procedures on coronary vessels. Severe heart failure. Complete or partial syndrome of nasal polyps, Quincke's edema, or bronchospasm. Do not use in patients who have undergone surgery with a high risk of bleeding or in whom bleeding has not been completely stopped, and in patients receiving anticoagulants, including low-dose heparin (2500–5000 units every 12 hours). Hepatic or moderate/severe renal impairment (serum creatinine concentration above 160 μmol/L). Suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding. Concomitant therapy with other NSAIDs (including selective cyclooxygenase (COX) inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid, or lithium salts. Hypovolemia, dehydration. Risk of developing renal failure due to reduced fluid volume.

Interaction with other medicinal products and other types of interactions.

Cannot be used simultaneously with ketorolac. Due to the possibility of adverse effects, ketorolac must not be prescribed with other NSAIDs, including selective COX-2 inhibitors, or to patients receiving acetylsalicylic acid, warfarin, lithium, probenecid, or cyclosporine. NSAIDs should not be prescribed within 8–12 days after administration of mifepristone, as the former may reduce the efficacy of mifepristone.

MEDICINAL PRODUCTS TO BE PRESCRIBED WITH CAUTION IN COMBINATION WITH KETOROLAC. In healthy individuals with normovolemia, ketorolac reduces the diuretic effect of furosemide by approximately 20%; therefore, the drug should be prescribed with particular caution to patients with cardiac decompensation. NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when administered concomitantly. Ketorolac and other NSAIDs may reduce the effectiveness of antihypertensive agents. When used concomitantly with angiotensin-converting enzyme (ACE) inhibitors, there is an increased risk of renal impairment, especially in patients with reduced intravascular volume. There is a risk of nephrotoxicity when NSAIDs are administered together with tacrolimus. Concomitant administration with diuretics may lead to reduced diuretic effect and increased risk of NSAID-induced nephrotoxicity. As with all NSAIDs, corticosteroids should be prescribed concomitantly with caution due to increased risk of gastrointestinal ulcers or bleeding. There is an increased risk of gastrointestinal bleeding when NSAIDs are prescribed in combination with antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Caution is recommended when prescribing methotrexate concomitantly, as some prostaglandin synthesis inhibitors have been reported to reduce methotrexate clearance and thus possibly increase its toxicity.

Patients taking NSAIDs and quinolones may 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.

It is unlikely that the following medicinal products interact with ketorolac. Ketorolac does not affect the plasma protein binding of digoxin. Therapeutic concentrations of digoxin, warfarin, paracetamol, phenytoin, and tolbutamide did not affect the plasma protein binding of ketorolac. Since ketorolac is a highly potent drug and its plasma concentration is low, it is not expected to significantly displace other drugs bound to plasma proteins. Ketorolac is not expected to alter the pharmacokinetics of other drugs through enzyme induction or inhibition.

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

Psychotropic agents. Hallucinations have been reported with concomitant use of ketorolac and psychotropic agents (fluoxetine, thiothixene, alprazolam).

Effect on laboratory test results. Ketorolac inhibits platelet aggregation and may prolong bleeding time.

Special precautions for use.

The maximum duration of treatment should not exceed 5 days.

Effect on fertility. The use of ketorolac, as with any other drug that inhibits cyclooxygenase (COX)/prostaglandin synthesis, may impair fertility and is not recommended for women attempting to conceive. If a woman experiences difficulty becoming pregnant or is undergoing fertility investigations, discontinuation of ketorolac should be considered.

Gastrointestinal bleeding, ulceration, and perforation. Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported during the use of NSAIDs at any time during treatment, regardless of the presence of warning symptoms or a history of serious gastrointestinal disorders. The risk of developing severe gastrointestinal bleeding depends on the dosage of the drug. This particularly applies to elderly patients receiving ketorolac at daily doses exceeding 60 mg. For such patients, as well as for patients concurrently using low-dose acetylsalicylic acid or other agents that may increase gastrointestinal risk, consideration should be given to combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors). The drug should be used with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, SSRIs, or antiplatelet agents, excluding acetylsalicylic acid. If gastrointestinal bleeding or ulceration occurs in patients receiving the drug, treatment should be discontinued.

NSAIDs, including ketorolac, may be associated with an increased risk of gastrointestinal anastomotic dehiscence. Careful medical supervision and caution are recommended when using ketorolac following gastrointestinal surgery.

Respiratory effects. NSAIDs have been reported to provoke bronchospasm in patients with bronchial asthma (or a history of asthma).

Renal effects. Inhibitors of prostaglandin biosynthesis (including NSAIDs) have been reported to have nephrotoxic effects. The drug should be administered with caution to patients with impaired renal, cardiac, or hepatic function, as NSAID use may lead to worsening of renal function. Patients with mild renal impairment should receive lower doses of ketorolac, and renal function should be closely monitored in such patients. As with other drugs that inhibit prostaglandin synthesis, increases in serum urea, creatinine, and potassium levels have been reported during ketorolac administration, which may occur after a single dose.

Cardiovascular, renal, and hepatic effects. The drug should be administered with caution to patients with conditions leading to reduced blood volume and/or renal blood flow, where renal prostaglandins play a supportive role in maintaining renal perfusion. In such patients, renal function should be monitored. Reduced blood volume should be corrected, and serum urea and creatinine levels, as well as urine output, should be closely monitored until normovolemia is achieved. In patients undergoing renal dialysis, ketorolac clearance was approximately halved compared to normal, and the terminal half-life was prolonged about threefold. Patients with hepatic impairment due to cirrhosis showed no clinically significant changes in ketorolac clearance or terminal half-life. Mild elevations in liver function tests may occur. These abnormalities may be transient, remain unchanged, or progress with continued treatment. If clinical symptoms suggest liver disease or systemic manifestations occur, the drug should be discontinued. Ketorolac should be used with caution in patients with a history of cardiovascular disorders.

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

Cardiovascular and cerebrovascular effects. There is currently insufficient information to assess this risk specifically for ketorolac. Patients with uncontrolled hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be under medical supervision.

Systemic lupus erythematosus and mixed connective tissue diseases. Patients with these conditions have an increased risk of developing aseptic meningitis.

Cutaneous effects. The drug should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Hematological effects. The drug should not be administered to patients with coagulation disorders. Patients receiving anticoagulant therapy may have an increased risk of bleeding when using ketorolac concomitantly. Close monitoring is required when prescribing ketorolac to patients receiving other agents that may affect hemostasis. Ketorolac inhibits platelet aggregation and prolongs bleeding time. 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 high-bleeding-risk surgery or in whom complete hemostasis has not been achieved. Caution is advised when definitive hemostasis is critical. Hypovolemia should be corrected before initiating ketorolac therapy.

Increasing the dose of ketorolac tablets beyond 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 of the drug.

The medicinal product contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

Use during pregnancy or breastfeeding. The safety of ketorolac during pregnancy has not been established. Due to the effects of NSAIDs on the fetal cardiovascular system (risk of premature closure of the ductus arteriosus), ketorolac is contraindicated during pregnancy, labor, and delivery. Onset of labor may be delayed, duration prolonged, and the risk of bleeding increased in both mother and child.

From the 20th week of pregnancy, NSAID use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible upon discontinuation of therapy. Additionally, there have been reports of fetal ductus arteriosus constriction following NSAID treatment in the second trimester, which in most cases resolved after treatment cessation.

A certain amount of ketorolac passes into breast milk; therefore, the drug is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery. In some patients, the use of ketorolac may cause drowsiness, dizziness, vertigo, insomnia, increased fatigue, visual disturbances, or depression. If patients experience any of these or similar effects, they should refrain from driving or operating machinery.

Dosage and Administration

Tablets should be taken during or after meals. The drug is recommended for short-term use only (up to 5 days).

To minimize adverse effects, the drug should be administered at the lowest effective dose for the shortest duration necessary to control symptoms. Normovolemia should be achieved before initiating treatment.

The recommended dose is 10 mg every 4–6 hours as needed. Daily doses exceeding 40 mg are not recommended. Opioid analgesics (e.g., morphine, meperidine) may be used concomitantly: ketorolac does not affect the binding of opioids and does not potentiate respiratory depression or sedative effects caused by opioids. For patients receiving parenteral ketorolac and those being switched to oral ketorolac tablets, the total combined daily dose must not exceed 90 mg (60 mg for elderly patients, patients with impaired renal function, and patients weighing less than 50 kg), and the oral dose must not exceed 40 mg per day. Patients should be switched to oral ketorolac as soon as possible.

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

Children. The efficacy and safety of ketorolac in children under 16 years of age have not been established; therefore, the drug should not be prescribed to this patient group.

Overdose. Symptoms: headache, epigastric pain, nausea, vomiting, gastrointestinal bleeding; rarely – diarrhea, confusion, agitation, coma, drowsiness, dizziness, tinnitus, loss of consciousness, seizures. In severe poisoning, acute renal failure and hepatic injury may occur.

Treatment: gastric lavage, administration of activated charcoal. Adequate diuresis should be maintained. Renal and hepatic functions must be closely monitored. Patients should be observed for at least 4 hours after ingestion of a potentially toxic dose of ketorolac. Frequent or prolonged seizures should be treated with intravenous diazepam. Other measures may be implemented depending on the patient's clinical condition. Treatment is symptomatic. Ketorolac is not eliminated from the bloodstream by dialysis.

Side effects.

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

Nervous system: headache, drowsiness, dizziness, anxiety, dry mouth, increased thirst, nervousness, paresthesia, functional disturbances, depression, euphoria, convulsions, inability to concentrate, insomnia, unusual dreams, malaise, increased fatigue, excitement, vertigo, myalgia, confusion, hallucinations, hyperkinesia, aseptic meningitis with corresponding symptoms, psychotic reactions, disturbances in thinking.

Sensory organs: hearing loss, tinnitus, optic neuritis, visual disturbances, blurred vision, taste disturbances.

Urinary and reproductive system: increased frequency of urination, oliguria, renal failure (including acute), hyponatremia, hyperkalemia, hemolytic uremic syndrome, flank pain (with or without hematuria), elevated serum urea and creatinine levels, interstitial nephritis, urinary retention, nephrotic syndrome, female infertility.

Hepatobiliary system: liver function abnormalities, hepatitis, jaundice and liver failure, hepatomegaly.

Cardiovascular system: flushing, bradycardia, pallor, arterial hypertension, palpitations, chest pain, development of edema, heart failure.

Use of some NSAIDs, especially at high doses and for prolonged periods, may be associated with an increased risk of arterial thromboembolic complications (myocardial infarction or stroke).

Respiratory system: dyspnea, asthma, pulmonary edema.

Blood system: purpura, thrombocytopenia, neutropenia, agranulocytosis, aplastic and hemolytic anemia, eosinophilia.

Skin: pruritus, urticaria, photosensitization, bullous reactions including Stevens-Johnson syndrome and Lyell's syndrome (very rare), exfoliative dermatitis, rash (including maculopapular).

Hypersensitivity: hypersensitivity reactions have been reported, including non-specific allergic reactions and 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, purpura, angioedema, and in isolated cases—exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme).

These reactions may occur in patients with hypersensitivity to ketorolac or other NSAIDs, as well as in those without such history. They may also occur in individuals with a history of angioedema or bronchospastic reactivity (e.g., bronchial asthma and nasal polyps). Anaphylactoid reactions such as anaphylaxis may be fatal.

Other: postoperative wound bleeding, hematoma, nasal bleeding, prolonged bleeding time, asthenia, edema, weight gain, increased sweating, elevated body temperature.

Shelf life. 3 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. Tablets № 10, № 10×2 in blisters in a box; № 30 in a container in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and location of business activity. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(Limited Liability Company "FARMEKS GROUP")