Ketorol

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

Composition:

Active substance: ketorolac;

One film-coated tablet contains 10 mg of ketorolac tromethamine;

Excipients: microcrystalline cellulose, pregelatinized starch, corn starch, colloidal anhydrous silicon dioxide, magnesium stearate, film coating Opadry 03K51148 Green*.

*Qualitative composition of the film coating: hypromellose, titanium dioxide (E 171), triacetin, triacetate, yellow iron oxide (E 172), brilliant blue FCF (E 133).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, film-coated tablets of green color, with the monogram "S" on one side and smooth on the other.

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 agent that exhibits anti-inflammatory and weak 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 phenomena indicating respiratory depression. Ketorolac tromethamine does not cause miosis.

Pharmacokinetics.

Ketorolac tromethamine is rapidly and completely absorbed after oral administration, with a peak plasma concentration of 0.87 µg/mL achieved within 50 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. In humans, after administration of single or multiple doses, the pharmacokinetics of ketorolac are linear. Steady-state plasma levels are reached 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, the 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%); the remainder is 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 pain, including postoperative pain.

Contraindications.

• Hypersensitivity to ketorolac or to any component of the medicinal product;
• 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 (due to the possibility of severe anaphylactic reactions);
• History of bronchial asthma;
• Should not be used as an analgesic before and during surgery and after coronary 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 greater than 160 μmol/L);
• Suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding;
• Concomitant therapy with other nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid, or lithium salts;
• Hypovolemia, dehydration;
• Risk of renal impairment due to reduced fluid volume;
• Pregnancy, labor, delivery, and breastfeeding period;
• Pediatric age under 16 years.

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. Concomitant administration with food reduces the rate of absorption but does not affect the extent of ketorolac absorption.

Should not be used concomitantly with ketorolac.

Due to the possibility of adverse effects, ketorolac must not be prescribed together 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 mifepristone use, as NSAIDs may reduce the efficacy of mifepristone.

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

In healthy subjects 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 used concomitantly with cardiac glycosides. Ketorolac and other nonsteroidal anti-inflammatory drugs may attenuate the effect of antihypertensive agents. When ketorolac is used concomitantly with angiotensin-converting enzyme (ACE) inhibitors, there is an increased risk of renal dysfunction, especially in patients with reduced blood volume. There is a risk of nephrotoxicity when NSAIDs are administered together with tacrolimus. Concomitant use with diuretics may lead to reduced diuretic effect and increased risk of NSAID 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. 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.

Interaction with ketorolac unlikely.

Ketorolac did not affect the 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, paracetamol, phenytoin, and tolbutamide did not affect the protein binding of ketorolac in plasma. 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. Studies in animals and humans have not shown 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 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 drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for use in women who are attempting to conceive. For women who are unable to conceive or undergoing fertility investigations, discontinuation of ketorolac should be considered.

Gastrointestinal disorders.

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

Gastrointestinal bleeding, ulceration, and perforation.

Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been observed during NSAID therapy at any time, regardless of the presence of warning symptoms or a history of severe gastrointestinal disorders. The risk of developing severe gastrointestinal bleeding depends on the dosage of the drug. This is particularly relevant for elderly patients receiving ketorolac at daily doses exceeding 60 mg. For these 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). 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.

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

Respiratory function disorders.

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

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 kidney function. Patients with mild renal impairment should receive lower doses of ketorolac (not exceeding 60 mg per day intramuscularly or intravenously), and renal function should be closely monitored in such 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 after a single dose.

Cardiovascular, renal, and hepatic disorders.

The drug should be administered 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 these 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 carefully monitored until normovolemia is achieved. In patients undergoing renal dialysis, ketorolac clearance was reduced by approximately half compared to normal, and the terminal elimination half-life was prolonged by about threefold. Patients with hepatic impairment due to cirrhosis showed no clinically significant changes in ketorolac clearance or terminal elimination half-life. Mild 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 administered with caution to 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, hypertension, or similar conditions.

Cardiovascular and cerebrovascular effects.

There is currently insufficient information to assess the risk associated with the use of tromethamine 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 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 medications 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 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.

Use during pregnancy or breastfeeding.

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

Due to the known 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, and its duration prolonged, with an increased tendency for bleeding in both mother and child.

Starting from the 20th week of pregnancy, the use of ketorolac may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation of the drug.

Prenatal monitoring for oligohydramnios should be considered after drug exposure for several days starting from the 20th week of pregnancy.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• Cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• Renal dysfunction.

Risks to the mother at the end of pregnancy and to the newborn:

• Possible prolongation of bleeding time, anti-aggregatory effect, which may occur even at very low doses;
• Inhibition of uterine contractions, leading to delayed or prolonged labor.

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

Ability to affect reaction speed when driving or operating machinery.
Some patients may experience drowsiness, dizziness, vertigo, insomnia, increased fatigue, visual disturbances, or depression when using ketorolac. If patients experience these or similar adverse effects, they should not drive or operate machinery.

Dosage and Administration

It is recommended to take the tablets during or after meals. The medicinal product is intended 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 starting treatment. Adults should be administered 10 mg every 4–6 hours as needed. The daily dose should not exceed 40 mg. Opioid analgesics (e.g., morphine, pethidine) may be used concomitantly; ketorolac does not affect the binding of opioid drugs and does not enhance respiratory depression or sedative effects caused by opioids. For patients receiving parenteral ketorolac and those switched to oral ketorolac tablets, the total combined daily dose must not exceed 90 mg (60 mg for elderly patients, patients with renal impairment, and patients weighing less than 50 kg), and the oral dosage should 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

Elderly patients are at increased risk of developing severe complications, particularly gastrointestinal adverse events. During treatment with NSAIDs, patients should be monitored regularly, and a longer interval between doses 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, gastrointestinal bleeding; rarely – diarrhea, disorientation, excitement, coma, drowsiness, dizziness, tinnitus, loss of consciousness, and occasionally seizures. In severe poisoning, acute renal failure and hepatic injury may occur. Metabolic acidosis has been observed following intentional overdose.

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 instituted depending on the patient's clinical condition. Treatment is symptomatic. Dialysis does not remove ketorolac from the bloodstream.

Adverse Reactions

Gastrointestinal system: peptic ulcer, perforation or gastrointestinal bleeding, sometimes fatal (especially in elderly patients), nausea, dyspepsia, abdominal pain, discomfort in the abdomen, hematemesis, 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, increased sweating, dry mouth, nervousness, paresthesia, functional disturbances, depression, euphoria, seizures, increased thirst, difficulty concentrating, insomnia, malaise, increased fatigue, excitement, vertigo, taste and vision disturbances, myalgia, unusual dreams, confusion, hallucinations, hyperkinesia, aseptic meningitis with corresponding symptoms, psychotic reactions, thinking disturbances.

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

Auditory system: 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, infertility, renal failure.

Hepatic 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, bronchial asthma, pulmonary edema.

Blood system: purpura, thrombocytopenia, neutropenia, agranulocytosis, aplastic and hemolytic anemia, hematoma, prolonged bleeding time.

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 bronchial asthma, worsening of bronchial asthma, bronchospasm, laryngeal edema or dyspnea, as well as skin reactions including various types of rashes, 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 nonsteroidal anti-inflammatory drugs. 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, epistaxis, prolonged bleeding time, asthenia, edema, weight gain, increased body temperature.

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals, pharmacists, as well as patients or their legal representatives should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

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 in an aluminum-aluminum (Alu-Alu) blister. 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Ltd, FTO – II.

Manufacturer’s address and place of business.
Plot Nos. 42R, 43, 44R, 45R, 46R, 53, 54, 83, Bachupally, Bachupally Mandal, Medchal Malkajgiri District – 500090, Telangana State, India.

To report an adverse reaction or lack of efficacy during use of the medicinal product, please call:
+380 44 207 51 97 or +380 50 414 39 39; or send an email to: [email protected] (24/7).