Medrolgin

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

Composition:

Active substance: ketorolac;

1 ml of solution contains 30 mg of ketorolac tromethamine;

Excipients: disodium edetate, ethanol 96%, sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless or pale yellow clear solution.

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

Pharmacological properties.

Pharmacodynamics.

Ketorolac is a potent nonsteroidal anti-inflammatory drug (NSAID) that demonstrates analgesic activity. It is not an opioid and does not exert effects on opioid receptors. The mechanism of action of ketorolac involves inhibition of the cyclooxygenase enzyme system, thereby suppressing prostaglandin synthesis. When administered at analgesic doses, it exhibits minimal anti-inflammatory effects.

Pharmacokinetics.

Intramuscular administration.

After intramuscular administration, ketorolac is rapidly and completely absorbed. The mean peak plasma concentration of 2.2 µg/mL is reached on average within 50 minutes following a single 30 mg dose. The effects of age, renal and hepatic function on the terminal half-life (t1/2) and mean total clearance are presented in the table below (evaluated after a single 30 mg intramuscular dose of ketorolac).

Intravenous administration.

After intravenous administration of ketorolac at a dose of 10 mg, the mean peak plasma concentration of 2.4 µg/mL is reached on average within 5.4 minutes. The terminal t_1/2 is 5.1 hours, the mean volume of distribution is 0.15 L/kg, and the total plasma clearance is 0.35 mL/min/kg.

The pharmacokinetics of ketorolac in humans after single or multiple doses is linear. Steady-state plasma concentrations are achieved after dosing every 6 hours over one day. With prolonged administration, clearance does not change. The main route of elimination of ketorolac and its metabolites is renal: 91.4% (on average) of the administered dose is recovered in urine and 6.1% (on average) is excreted in feces.

More than 99% of ketorolac is bound to plasma proteins over a wide concentration range.

Clinical characteristics.

Indications.

For the management of moderate to severe acute postoperative pain for short-term use only.

Treatment should be initiated only in hospitals. Maximum duration of treatment is 2 days.

Contraindications.

• Hypersensitivity to ketorolac, other NSAIDs, or to any of the excipients of the medicinal product.
• Allergic reactions to acetylsalicylic acid or other inhibitors of prostaglandin synthesis (in such patients severe anaphylactic reactions have been observed), manifested as asthma, rhinitis, angioedema, or urticaria.
• History of bronchial asthma.
• Active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer disease, gastrointestinal bleeding or perforation.
• Severe heart failure, hepatic failure, and renal failure.
• Moderate or severe renal function impairment (plasma creatinine > 160 µmol/L).
• Hypovolemia, dehydration with risk of renal failure due to reduced fluid volume.
• Prophylactic use prior to surgical procedures is contraindicated (due to platelet function inhibition) as well as use during surgery due to increased risk of bleeding.
• Should not be used in patients who have undergone surgical procedures with high risk of bleeding or incomplete hemostasis.
• Suspected or confirmed cerebrovascular bleeding, high risk of bleeding, e.g., hemorrhagic diathesis, including coagulation disorders (due to platelet function inhibition).
• Concomitant use with anticoagulants, including warfarin and low-dose heparin (2500–5000 units every 12 hours).
• Concomitant use with acetylsalicylic acid or other NSAIDs (including selective cyclooxygenase-2 inhibitors).
• Neuroaxial (epidural or intrathecal) administration is contraindicated, as the medicinal product contains ethanol.
• Concomitant use with pentoxifylline.
• Concomitant use with probenecid or lithium salts.
• Complete or partial syndrome of nasal polyps, angioedema, or bronchospasm.
• Should not be used during pregnancy, labor, delivery, or breastfeeding.
• Pediatric age under 16 years.

Interaction with other medicinal products and other forms of interaction.

Ketorolac is highly bound to plasma proteins (on average 99.2%), and its binding is concentration-dependent.

There is no evidence from animal or human studies that ketorolac induces or inhibits liver enzymes involved in the metabolism of ketorolac itself or other medicinal products. Therefore, it is unlikely that ketorolac may alter the pharmacokinetics of other drugs via enzyme induction or inhibition mechanisms.

Concomitant use of ketorolac with the following agents is contraindicated.

Acetylsalicylic acid and other NSAIDs, including selective cyclooxygenase-2 inhibitors.

Concomitant use with ketorolac increases the risk of developing serious adverse reactions associated with NSAID use. Concomitant use is contraindicated.

Ketorolac inhibits platelet aggregation, reduces thromboxane concentration, and prolongs bleeding time. Unlike the prolonged effect after acetylsalicylic acid administration, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac.

Anticoagulants (such as warfarin, heparin).

Concomitant use with ketorolac may enhance the anticoagulant effect.

Although studies do not indicate a significant degree of interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac with therapeutic agents affecting hemostasis, including therapeutic doses of anticoagulants (warfarin), prophylactic low doses of heparin (2500–5000 units every 12 hours), and dextrans, may be associated with an increased risk of bleeding. Concomitant use is contraindicated.

Lithium.

When using some prostaglandin synthesis inhibitors, decreased renal clearance of lithium has been observed, leading to increased plasma lithium concentrations. Cases of elevated plasma lithium concentrations have been reported during ketorolac use. Concomitant use is contraindicated.

Probenecid.

Concomitant use with ketorolac increases plasma levels and prolongs the elimination half-life of ketorolac. Concomitant use is contraindicated.

Mifepristone.

Ketorolac should not be used within 8–12 days after mifepristone administration, as it may reduce the efficacy of mifepristone.

Pentoxifylline.

Concomitant use with ketorolac increases the risk of bleeding. Concomitant use is contraindicated.

Ketorolac should be used with caution when administered concomitantly with the following agents.

Corticosteroids.

Concomitant use with ketorolac increases the risk of gastrointestinal bleeding.

Antiplatelet agents, selective serotonin reuptake inhibitors (SSRIs).

Concomitant use with ketorolac increases the risk of gastrointestinal bleeding.

Methotrexate.

Some prostaglandin synthesis inhibitors reduce renal clearance of methotrexate and thereby increase its toxicity.

Digoxin.

Ketorolac does not alter protein binding of digoxin in plasma. In vitro studies indicate that at therapeutic salicylate concentrations (300 µg/mL), ketorolac binding decreased from approximately 99.2% to 97.5%, demonstrating a potential twofold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not alter ketorolac binding to plasma proteins.

Diuretics.

Concomitant use with ketorolac may reduce diuretic effect and increase the risk of nephrotoxicity. Caution should be exercised when used concomitantly.

In healthy volunteers with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%. Therefore, special attention is required when ketorolac is used concomitantly in patients with cardiac decompensation.

Cyclosporine.

Concomitant use with ketorolac increases the risk of nephrotoxicity. Caution should be exercised when used concomitantly.

Tacrolimus.

Concomitant use with ketorolac increases the risk of nephrotoxicity.

Antihypertensive agents (β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists).

Concomitant use with ketorolac may attenuate the antihypertensive effect.

When ACE inhibitors and/or angiotensin II receptor antagonists are used in combination with NSAIDs, the risk of acute, usually reversible, renal failure may be increased in certain patients with impaired renal function (e.g., dehydrated patients or elderly patients). Caution should be exercised, particularly in elderly patients. Appropriate titration and monitoring of renal function, with periodic follow-up, should be performed before initiating combination therapy.

Cardiac glycosides.

Concomitant use with ketorolac may worsen heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides.

Quinolones.

Experimental data indicate that NSAIDs increase the risk of seizures associated with quinolone use. Patients taking ketorolac and quinolones may have an increased risk of developing seizures.

Zidovudine.

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

Opioid analgesics.

When ketorolac is used to alleviate postoperative pain, the need for concomitant use of opioid analgesics is reduced.

Special precautions for use.

Epidemiological data indicate that ketorolac treatment is associated with a high risk of serious gastrointestinal toxicity compared to some other NSAIDs, particularly when used off-label and/or for prolonged periods.

Clinicians should be aware that analgesia may not occur until 30 minutes after intravenous or intramuscular administration of ketorolac.

Concomitant use of ketorolac with NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided.

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

Gastrointestinal ulcers, bleeding, and perforation.

Gastrointestinal bleeding, ulcers, or perforation have been observed with the use of all NSAIDs, in some cases resulting in fatal outcomes, both in patients with and without prior warning signs or serious gastrointestinal history, particularly in elderly patients.

In a non-randomized, post-marketing observational inpatient study, increased rates of clinically significant gastrointestinal bleeding were observed in patients under 65 years of age receiving a mean daily intramuscular dose of ketorolac exceeding 90 mg, compared to patients receiving parenteral opioids.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including intravenous ketorolac. The risk is also increased in patients with a history of peptic ulcer, especially with complications (bleeding or perforation), and in elderly patients. These patients should be initiated on the lowest possible dose. In such cases, and in patients taking low-dose acetylsalicylic acid or other medications that increase gastrointestinal risk, concomitant use of gastroprotective agents such as misoprostol or proton pump inhibitors may be advisable.

Increased risk of gastrointestinal bleeding and perforation in elderly patients has been observed with all NSAIDs. Compared to younger individuals, elderly patients have a prolonged plasma half-life and reduced plasma clearance of ketorolac. Dosage intervals should be extended (see section "Administration and dosage").

The drug should be used with caution in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated (see section "Adverse reactions"). Patients with a history of gastrointestinal disorders, especially the elderly, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding), particularly during the initial stages of treatment. If gastrointestinal bleeding or ulceration is diagnosed in a patient taking ketorolac, the drug should be discontinued.

The drug should be used with particular caution in patients concurrently taking medications that increase the risk of ulceration or bleeding, such as corticosteroids, selective serotonin reuptake inhibitors (SSRIs), or antithrombotic agents (acetylsalicylic acid) (see section "Interaction with other medicinal products and other forms of interaction").

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

Concomitant use of the drug with anticoagulants (such as warfarin) is contraindicated (see section "Contraindications").

The frequency and severity of gastrointestinal complications increase with higher doses and longer duration of ketorolac treatment. This is particularly relevant for elderly patients receiving intravenous ketorolac at average daily doses exceeding 60 mg/day. A history of peptic ulcer disease increases the likelihood of developing serious gastrointestinal complications during ketorolac therapy.

Effect on hemostasis.

The drug should not be used in patients with coagulation disorders. Concomitant use of ketorolac in patients receiving anticoagulant therapy increases the risk of bleeding. Detailed studies on the concomitant use of ketorolac with prophylactic low-dose heparin (2500–5000 units every 12 hours) and dextrans have not been conducted, so an increased risk of bleeding cannot be excluded. The drug should not be used in patients already taking anticoagulants or those requiring low-dose heparin administration. Close monitoring is required in patients taking other agents that negatively affect hemostasis. In controlled clinical trials, the incidence of clinically significant postoperative bleeding was less than 1%.

Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal coagulation parameters, bleeding time 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.

Post-marketing reports have described bleeding from postoperative wounds associated with immediate parenteral intravenous or intramuscular administration of ketorolac during surgery. Therefore, the drug should not be used in patients who have undergone surgery with a high risk of bleeding or in whom hemostasis is incomplete. Caution should be exercised when stable hemostasis is critical, such as in cosmetic or outpatient procedures, prostatectomy, or tonsillectomy. Hematomas, other signs of wound bleeding, and epistaxis may occur with ketorolac use. The potential risk of bleeding, particularly in elderly patients, should be considered due to its similarity to other cyclooxygenase-inhibiting NSAIDs.

Skin reactions.

Serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with NSAIDs, sometimes with fatal outcomes. The highest risk of these reactions occurs early in the course of treatment, with initial manifestations appearing in most cases within the first month of therapy. The drug should be discontinued at the first signs of skin rash, mucosal lesions, or other signs of hypersensitivity.

Systemic lupus erythematosus (SLE) and mixed connective tissue disease.

Patients with SLE and mixed connective tissue disease have an increased risk of developing aseptic meningitis.

Sodium/water retention in cardiovascular disease and peripheral edema.

The drug should be used with caution in patients with a history of arterial hypertension and/or heart failure, as fluid retention and edema have been reported with NSAID use.

Fluid retention, hypertension, and peripheral edema have been reported in some patients during treatment with NSAIDs, including ketorolac; therefore, the drug should be used cautiously in patients with cardiac decompensation, arterial hypertension, or similar conditions.

Effect on the cardiovascular system and cerebral circulation.

Clinical and epidemiological studies indicate that the use of coxibs and certain NSAIDs (particularly at high doses) is associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Although an increase in thrombotic events such as myocardial infarction has not been observed with ketorolac treatment, data are insufficient to exclude this risk.

The drug should be used in patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful assessment of the benefits and risks of treatment. Similarly, the appropriateness of prescribing ketorolac should be considered in patients at risk for cardiovascular disease (e.g., those with arterial hypertension, hyperlipidemia, diabetes mellitus, or smokers).

To minimize the potential risk of cardiovascular complications in patients taking NSAIDs, the lowest effective dose of ketorolac should be used for the shortest possible duration.

Patients with cardiovascular, renal, or hepatic impairment.

The drug should be used with caution in patients with conditions that may lead to reduced blood volume and/or renal blood flow, where renal prostaglandins play a compensatory role in maintaining renal perfusion. In such cases, use of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause dose-dependent reduction in prostaglandin synthesis and precipitate overt renal failure. The risk is highest in patients with fluid imbalance due to blood loss or severe dehydration, those with impaired renal or hepatic function, heart failure, the elderly, and patients taking diuretics. Renal function should be monitored in these patients. Typically, the patient's condition returns to pre-treatment levels after discontinuation of NSAIDs. Inadequate correction of fluid/blood loss during surgery, leading to hypovolemia, may result in renal dysfunction, which may be exacerbated by ketorolac use. Correction of reduced extracellular fluid volume is required; careful monitoring of plasma urea and creatinine levels and urine output is necessary until blood volume is normalized. In patients undergoing renal dialysis, ketorolac clearance is approximately half the normal value, and the terminal half-life is increased approximately threefold.

As with other NSAIDs, the drug should be used with caution in patients with impaired renal function or a history of kidney disease, as it is a potent inhibitor of prostaglandin synthesis.

Elevations in plasma levels of urea, creatinine, and potassium have been observed with prostaglandin synthesis inhibitors, including ketorolac, even after a single dose.

Use in patients with renal impairment.

Since ketorolac and its metabolites are primarily excreted by the kidneys, the drug should not be used in patients with moderate to severe renal impairment (plasma creatinine >160 µmol/L). Patients with mild renal impairment should receive reduced doses (not exceeding 60 mg daily by intramuscular or intravenous route) and renal function should be monitored periodically.

Use in patients with hepatic disease.

In patients with hepatic impairment due to cirrhosis, ketorolac clearance and terminal half-life are not clinically significantly altered.

Elevation of one or more liver function tests may occur. These abnormalities may be transient, remain unchanged, or progress if treatment continues. In controlled clinical trials, less than 1% of patients experienced elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels (more than three times the upper limit of normal). Additionally, isolated cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some fatal, have been reported. The drug should be used cautiously in patients with impaired liver function or a history of liver disease. If clinical signs of liver dysfunction or systemic manifestations appear, the drug should be discontinued.

Anaphylactic (anaphylactoid) reactions.

Anaphylactic (anaphylactoid) reactions (such as anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioneurotic edema) may occur in patients with previously diagnosed hypersensitivity to acetylsalicylic acid, other NSAIDs, including ketorolac, as well as in those without prior history of hypersensitivity reactions. These reactions may occur in individuals with angioneurotic edema, bronchospastic reactions (e.g., asthma), or nasal polyps. Such anaphylactoid reactions, including anaphylaxis, may be fatal. Therefore, the drug is contraindicated in patients with a history of asthma, nasal polyps (complete or partial syndrome), angioedema, or bronchospasm (see section "Contraindications").

Effect on fertility.

Like other inhibitors of cyclooxygenase/prostaglandin synthesis, ketorolac may adversely affect fertility. The drug is not recommended for women who are planning to become pregnant. Women experiencing infertility or undergoing fertility investigations should discontinue use of the drug.

Interaction with other agents.

Caution should be exercised when using the drug concomitantly with methotrexate, as ketorolac reduces renal clearance of methotrexate, thereby increasing its toxicity.

Abuse and dependence.

Ketorolac does not cause dependence. No withdrawal symptoms have been observed after abrupt discontinuation of intravenous ketorolac.

Precautions regarding excipients.

The drug contains a small amount of ethanol (alcohol), less than 100 mg per dose.

1 mL of the drug solution contains less than 1 mmol (23 mg) of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

Due to the proven effects of NSAIDs on the fetal cardiovascular system (premature closure of the ductus arteriosus), the drug is contraindicated during pregnancy, labor, or delivery.

The safety of ketorolac use in pregnant women has not been established. Teratogenic effects were not observed in rats and rabbits at maternally toxic doses of ketorolac. In rats, prolonged gestation and/or delayed delivery were noted. Congenital anomalies have been reported in humans following NSAID use, although the frequency is low and no clear trend has been observed.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic and fetal development. Epidemiological data suggest an increased risk of miscarriage, cardiac defects, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to approximately 1.5%. The risk is believed to increase with higher doses and longer duration of treatment. Animal studies show that prostaglandin synthesis inhibitors lead to pre- and post-implantation losses and embryo-fetal death. Additionally, increased numbers of congenital malformations, including cardiovascular defects, have been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Oligohydramnios/renal failure in newborns.

NSAID use from approximately the 20th week of pregnancy has been associated with impaired fetal renal function leading to oligohydramnios and, in some cases, neonatal renal failure. These adverse effects typically occur after several days or weeks of treatment, although oligohydramnios has been reported as early as 48 hours after initiation of NSAID therapy. Oligohydramnios is often, but not always, reversible upon discontinuation of treatment. Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. Post-marketing reports have described cases of neonatal renal dysfunction requiring invasive procedures such as exchange transfusion or dialysis.

Additionally, reports of ductus arteriosus constriction following second-trimester treatment have been documented, which in most cases resolved after discontinuation of therapy.

During pregnancy, all prostaglandin synthesis inhibitors may contribute to fetal adverse effects such as:

• cardiopulmonary toxicity (premature constriction/closure of the patent ductus arteriosus and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with oligohydramnios (see above);

in the mother near term and in the newborn:

• prolonged bleeding time, as anti-aggregatory effects may occur even at low doses;
• inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Approximately 10% of ketorolac crosses the placenta.

Labor and delivery.

The use of the drug is contraindicated during labor and delivery because its inhibitory effect on prostaglandin synthesis may adversely affect fetal hemostasis and inhibit uterine contractions, thereby increasing the risk of bleeding.

There is an increased risk of bleeding in both mother and child.

Lactation period.

Ketorolac and its metabolites have been shown to pass into the fetus and milk in animals. Ketorolac has been detected in human breast milk at low concentrations; therefore, the drug is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

During ketorolac use, some patients may experience dizziness, somnolence, fatigue, visual disturbances, headache, vertigo, insomnia, or depression. If such symptoms occur, patients should not drive or operate machinery.

Administration and Dosage

Administration.

The medicinal product is intended for intramuscular or bolus intravenous administration.

Intravenous bolus injection should last no less than 15 seconds.

The medicinal product should not be used for epidural or spinal administration.

After intramuscular or intravenous administration, analgesic effect is observed approximately within 30 minutes, and maximum pain relief occurs within 1–2 hours. Overall, the average duration of analgesia is 4–6 hours. The dose should be adjusted according to the severity of pain and the patient's response to treatment.

Repeated intramuscular administration of multiple daily doses of ketorolac should not exceed 2 days, as prolonged use increases the risk of adverse reactions. Experience with long-term use is limited, since most patients are either switched to oral medication or no longer require analgesic therapy.

The likelihood of adverse reactions can be minimized by using the lowest effective dose of ketorolac for the shortest duration necessary to control symptoms (see section "Special precautions").

Dosage.

Adults.

The recommended initial dose of ketorolac is 10 mg, followed by 10–30 mg every 4–6 hours (as needed). In the initial postoperative period, ketorolac may be administered every 2 hours, if necessary.

The lowest effective dose should be used. The total daily dose should not exceed 90 mg in younger patients, and 60 mg in elderly patients, patients with renal impairment, and patients weighing less than 50 kg. The maximum duration of treatment should not exceed 2 days.

For patients weighing less than 50 kg, the dose should be reduced.

Concomitant use of opioid analgesics (morphine, pethidine) may be considered for optimal analgesic effect in the early postoperative period when pain is most severe. Ketorolac has no negative effect on opioid receptor binding and does not potentiate respiratory depression or sedative effects of opioid drugs. When used in combination with intramuscular/intravenous ketorolac, the daily dose of opioids is generally lower than usual. However, adverse effects of opioids should be considered, especially in surgical settings.

For patients receiving parenteral ketorolac who are being switched to oral ketorolac tromethamine (tablets), the total combined daily dose should not exceed 90 mg (60 mg for elderly patients, patients with renal impairment, and patients weighing less than 50 kg). On the day of switching formulations, the dose of the oral component should not exceed 40 mg. Patients should be switched to the oral form as soon as possible.

Elderly patients.

In elderly patients, the risk of serious adverse effects is increased. If NSAID use is considered necessary, the lowest effective dose should be used for the shortest possible duration. Patients should be monitored for gastrointestinal bleeding during NSAID therapy. The total daily dose should not exceed 60 mg.

Patients with renal impairment.

The medicinal product is contraindicated in moderate to severe renal impairment. In mild renal impairment, dosage reduction is required (not exceeding 60 mg/day intravenously or intramuscularly).

Children.

The safety and efficacy of ketorolac have not been established. The medicinal product is contraindicated in children under 16 years of age.

Overdose.

Symptoms.

Acute overdose of ketorolac has resulted in abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction, all of which resolved after discontinuation of ketorolac.

Gastrointestinal bleeding may occur.

After NSAID administration, arterial hypertension, acute renal failure, respiratory depression, and coma may occur, although such symptoms are rare.

In addition, headache, epigastric pain, confusion, excitement, drowsiness, dizziness, tinnitus, and loss of consciousness may occur, as well as rare cases of diarrhea or isolated seizures.

Anaphylactoid reactions have been reported with therapeutic doses of NSAIDs and may also occur in cases of overdose.

Treatment.

In case of overdose, symptomatic and supportive therapy should be administered. There is no specific antidote. Dialysis does not lead to significant removal of ketorolac from blood due to its high protein binding.

Adequate diuresis should be maintained. Liver and kidney function should also be monitored, and the patient should remain under observation for at least 4 hours after administration of a toxic dose of ketorolac. In case of recurrent or prolonged seizures, diazepam should be administered. Other therapeutic measures may also be required depending on the patient's clinical condition.

Adverse reactions.

Infections and infestations:

aseptic meningitis (particularly in patients with autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, with symptoms such as neck stiffness, headache, nausea, vomiting, fever, disorientation (see section "Special precautions")).

Blood and lymphatic system disorders:

thrombocytopenia, purpura, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Immune system disorders:

hypersensitivity reactions, including anaphylaxis (which may be fatal) or anaphylactoid reactions, bronchospasm, flushing, rash, hypotension, laryngeal edema.

Metabolism and nutrition disorders:

anorexia, hyperkalemia, hyponatremia.

Psychiatric disorders:

abnormal thinking, depression, insomnia, anxiety, restlessness, psychotic reactions, unusual dreams, hallucinations, euphoria, somnolence, difficulty concentrating, confusion, agitation.

Nervous system disorders:

headache, dizziness, convulsions, paresthesia, hyperkinesia, taste disturbances.

Eye disorders:

visual disturbances, disturbances of visual perception, optic neuritis.

Ear and labyrinth disorders:

tinnitus, hearing loss, vertigo.

Renal and urinary system disorders:

acute renal failure, increased frequency of urination, interstitial nephritis, nephrotic syndrome, urinary retention, oliguria, hemolytic-uremic syndrome, flank pain (with or without hematuria + azotemia).

The use of ketorolac (even after a single intravenous dose), as with other drugs that inhibit renal prostaglandin synthesis, may lead to signs of renal impairment, not limited to elevated blood creatinine and potassium levels.

Cardiac disorders:

palpitations, bradycardia, heart failure.

Vascular disorders:

hypertension, hypotension, hematoma, flushing, pallor, postoperative wound bleeding.

According to clinical and epidemiological studies, the use of coxibs and certain NSAIDs (especially at high doses) is associated with a small increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Although increased incidence of thrombotic events such as myocardial infarction has not been observed during ketorolac treatment, data are insufficient to exclude this risk.

Gastrointestinal disorders:

gastrointestinal adverse reactions are the most common. Possible peptic ulcers, ulcer perforation, gastrointestinal bleeding, sometimes fatal (especially in elderly patients) (see section "Special precautions"), nausea, vomiting, dyspepsia, abdominal discomfort, abdominal pain, melena, hematemesis, diarrhea, dry mouth, flatulence, pancreatitis, feeling of stomach fullness, esophagitis, belching, exacerbation of colitis and Crohn’s disease (see section "Special precautions"), gastritis, ulcerative stomatitis, stomatitis, gastrointestinal ulcer, rectal bleeding.

Reproductive system and breast disorders:

female infertility.

Respiratory, thoracic and mediastinal disorders:

bronchial asthma, pulmonary edema, dyspnea. In addition, epistaxis may occur.

Hepatobiliary disorders:

hepatitis, cholestatic jaundice, liver failure, hepatomegaly.

Skin and subcutaneous tissue disorders:

pruritus, purpura, exfoliative dermatitis, photosensitization, skin rashes (including maculopapular), erythema multiforme, urticaria, angioneurotic edema, sweating, bullous reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome) (very rare).

Musculoskeletal and connective tissue disorders:

myalgia, functional disorders.

General disorders and administration site conditions:

intense thirst, asthenia, edema, injection site reactions and pain, fever, chest pain.

Investigations:

prolonged bleeding time, elevated plasma urea levels, elevated creatinine levels, impaired liver function tests.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine registration is very important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

5 years.

Storage conditions.

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

Incompatibility.

The medicinal product should not be mixed in the same container with morphine sulfate, meperidine hydrochloride, promethazine, and hydroxyzine due to precipitate formation.

Compatible with saline solution, 5% dextrose solution, Ringer’s solution, Ringer’s solution with lactate, or plasmalyte.

Compatibility of ketorolac with other drugs is unknown.

Packaging.

1 ml of solution in a brown glass ampoule, 5 ampoules in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICINE ILAC SAN. VE TIDJ. A.S./
WORLD MEDICINE IILAC SAN. VE TIC. A.S.

Manufacturer's address and place of business.

OPZCH, G.O. Pasha district, 6th street, No. 30, Cerkezkoy/Tekirdag, Turkey./
COSB G.O. Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.

Marketing authorization holder.

LLC "WORLD MEDICINE", Ukraine/
WORLD MEDICINE, LLC, Ukraine.