Ketalgin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETALGIN® (KETALGIN)

Composition:

Active substance: ketorolac;

1 tablet contains 0.01 g (10 mg) of ketorolac tromethamine;

Excipients: lactose monohydrate, potato starch, magnesium stearate, colloidal anhydrous silicon dioxide, microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: tablets of nearly white or white color with a yellowish tint.

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 nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory and 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, administration of ketorolac tromethamine did not result in any effects indicative of respiratory depression. Ketorolac tromethamine does not cause miosis.

Pharmacokinetics.

Ketorolac tromethamine is rapidly and completely absorbed after oral administration, reaching peak plasma concentration of 0.87 mg/kg at 50 minutes after a single 10 mg dose. In healthy volunteers, the terminal elimination half-life in plasma averages 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. In humans, after administration of single or multiple doses, the pharmacokinetics of ketorolac are linear. Steady-state plasma levels are achieved within 1 day with administration four times daily. No changes were observed with prolonged dosing. After a single intravenous dose, the volume of distribution is 0.25 L/kg, elimination half-life is 5 hours, and clearance is 0.55 mL/min/kg. 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 management of moderate-intensity pain, including postoperative pain.

Contraindications.

• Hypersensitivity to ketorolac or to any other component of the drug;
• Active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer disease or gastrointestinal bleeding;
• Bronchial asthma, rhinitis, angioedema, or urticaria induced by acetylsalicylic acid or other NSAIDs (due to the possibility of severe anaphylactic reactions);
• History of bronchial asthma;
• Should not be used as an analgesic before and during major surgery or after coronary artery procedures;
• Severe heart failure;
• Complete or partial syndrome of nasal polyps, Quincke's edema, or bronchospasm;
• Should not be used in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis, and in patients receiving anticoagulants, including low-dose heparin (2500–5000 units every 12 hours);
• Hepatic or moderate-to-severe renal impairment (serum creatinine clearance >160 μmol/L);
• Suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding;
• Concomitant use with other NSAIDs, including selective cyclooxygenase 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 forms of interaction.

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

Should not be used simultaneously with ketorolac.

Due to the risk of adverse effects, ketorolac must not be prescribed with other NSAIDs, including selective cyclooxygenase-2 inhibitors, or to patients receiving acetylsalicylic acid, warfarin, lithium, probenecid, or cyclosporine. NSAIDs should not be administered within 8–12 days after use of mifepristone, as NSAIDs may reduce the efficacy of mifepristone.

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

In healthy individuals with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%. The drug should be administered with particular caution in 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 NSAIDs may diminish the effect of antihypertensive agents. When ketorolac is used concomitantly with ACE inhibitors, there is an increased risk of renal dysfunction, especially in patients with reduced blood volume. There is a potential risk of nephrotoxicity when NSAIDs are administered together with tacrolimus. Concomitant use with diuretics may result in 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 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.

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

Concomitant use of NSAIDs with zidovudine increases the risk of hematologic 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 did not affect the protein binding of digoxin. In vitro studies indicate that at therapeutic salicylate concentrations (300 μg/mL) and higher, ketorolac binding decreased from approximately 99.2% to 97.5%. Therapeutic concentrations of digoxin, warfarin, paracetamol, phenytoin, and tolbutamide did not affect ketorolac protein binding. Since ketorolac is a highly potent drug and its plasma concentration is low, significant displacement of other protein-bound drugs is not expected. Studies in animals and humans have shown 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 agents.

Isolated cases of epileptic 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 drugs (fluoxetine, tiotixene, 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 drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for use in women attempting to conceive. For women who have difficulty conceiving or are 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 NSAID therapy at any time during treatment, with or without warning symptoms, and in patients with or without a history of serious gastrointestinal disorders. The risk of developing severe gastrointestinal bleeding is dose-dependent. This is particularly relevant for elderly patients receiving ketorolac at average daily doses exceeding 60 mg. 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 combination therapy with 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, or antiplatelet agents such as acetylsalicylic acid. If gastrointestinal bleeding or ulceration occurs in patients receiving Ketorolac®, treatment should be discontinued immediately.

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

Renal effects. Inhibitors of prostaglandin biosynthesis (including NSAIDs) have been reported to exert nephrotoxic effects. The drug should be used with caution in 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 (not exceeding 60 mg daily administered intramuscularly or intravenously), and renal function should be closely monitored in these patients. As with other drugs inhibiting prostaglandin synthesis, cases of increased serum urea, creatinine, and potassium levels have been reported during treatment with tromethamine ketorolac, which may occur even after a single dose.

Cardiovascular, renal, and hepatic effects. The drug 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. 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, creatinine clearance was approximately halved compared to normal, and terminal 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. Marginal elevations in one or more liver function tests 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.

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

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

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

Dermatological effects. Ketorolac® should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Hematological effects. Ketorolac® should not be administered to patients with coagulation disorders. Patients receiving anticoagulant therapy may have an increased risk of bleeding when ketorolac is used concomitantly. Patients receiving other drugs 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 bleeding time, bleeding duration increased 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 definitive hemostasis is critical. Ketorolac® is not an anesthetic agent and lacks sedative or anxiolytic properties; therefore, it is not recommended as a premedication for anesthesia.

Hypovolemia should be corrected before initiating ketorolac therapy.

The product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

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

Use during pregnancy or breastfeeding.

The safety of ketorolac use during human pregnancy has not been established.

Starting from the 20th week of pregnancy, ketorolac use may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there have been reports of ductus arteriosus constriction following second-trimester treatment, which in most cases resolved after stopping the drug.

Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable after exposure to ketorolac for several days starting from the 20th gestational week.

Due to the known effects of NSAIDs on the fetal cardiovascular system (risk of premature constriction/closure of the ductus arteriosus), ketorolac is contraindicated during pregnancy, labor, and delivery. Onset of labor may be delayed, and labor duration prolonged, with an increased tendency for bleeding in both mother and child.

Ketorolac passes into breast milk in low 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, or depression when using ketorolac. If patients experience these or similar effects, they should refrain from driving or operating machinery.

Method of Administration and Dosage

Tablets should be taken during or after a meal. The drug is recommended for short-term use only (up to 5 days). To minimize adverse effects, the drug should be used at the lowest effective dose for the shortest duration necessary to control symptoms. Normovolemia should be achieved before initiating treatment. For adults, administer Ketaldgin® 10 mg every 4–6 hours as needed. Doses exceeding 40 mg per day are not recommended. Opioid analgesics (e.g., morphine, meperidine) may be used concomitantly; ketorolac does not affect the binding of opioid drugs and does not enhance respiratory depression or sedation caused by opioids. It has been demonstrated that in cases of postoperative pain, the concomitant use of ketorolac with opioid analgesics reduces the need for opioids. For patients receiving parenteral ketorolac and who are 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 with body weight less than 50 kg), and the dosage of the oral formulation must not exceed 40 mg per day when switching dosage forms. Patients should be switched to oral administration of the drug as early as possible.

Elderly patients

In elderly patients, there is a higher risk of developing severe complications, particularly involving the gastrointestinal tract. During treatment with NSAIDs, patients should be monitored regularly, and a longer interval between doses is generally recommended, e.g., 6–8 hours.

Children

Do not use in children under 16 years of age.

Overdose

Symptoms: headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding; rarely – diarrhea, disorientation, agitation, coma, drowsiness, dizziness, tinnitus, loss of consciousness, and 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 amount. 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. Dialysis does not remove ketorolac from the bloodstream.

Adverse Reactions

Gastrointestinal system: Peptic ulcer, gastrointestinal perforation or bleeding, sometimes fatal (especially in elderly patients), nausea, dyspepsia, abdominal pain, abdominal discomfort, hematemesis, epigastric spasm or burning sensation, vomiting with blood, gastritis, esophagitis, diarrhea, belching, constipation, flatulence, bloating, melena, rectal bleeding, ulcerative stomatitis, vomiting, hemorrhages, perforation, pancreatitis, exacerbation of colitis and Crohn's disease.

Central nervous system: Anxiety, drowsiness, dizziness, headache, nervousness, paresthesia, functional disturbances, depression, euphoria, seizures, inability to concentrate, insomnia, malaise, increased fatigue, excitement, vertigo, unusual dreams, confusion, hallucinations, hyperkinesia, aseptic meningitis with corresponding symptoms, psychotic reactions, disturbances in thinking.

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

Ear disorders: Hearing loss, tinnitus.

Urinary system: Increased frequency of urination, oliguria, acute renal failure, hyponatremia, hyperkalemia, 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: Female infertility.

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

Cardiovascular system: Flushing, bradycardia, pallor, arterial hypertension, 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).

Respiratory system: Dyspnea, asthma, pulmonary edema.

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

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

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).

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

Other: Postoperative wound bleeding, hematoma, epistaxis, prolonged bleeding time, asthenia, edema, weight gain, elevated body temperature, increased sweating, dry mouth, excessive thirst, taste disturbances, myalgia.

Shelf life. 3 years.

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

Packaging. 10 tablets per blister, 1 or 2 blisters per carton.

Prescription category. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv". PJSC "Tekhnolog".

Manufacturer's address and location of business activity.

Ukraine, 61115, Kharkiv region, Kharkiv, Severina Pototskogo St., 36.

Ukraine, 20300, Cherkasy region, Uman, Stara Prorizna St., 8.