Ketorolac-pharmak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOROLAC-FARMAK (Ketorolac-Farmak)

Composition:

Active substance: ketorolac;

1 ml of solution contains ketorolac tromethamine 30 mg;

Excipients: ethanol 96%, sodium chloride, diluted hydrochloric acid, sodium hydroxide, water for injections.

Medicinal form. Injection solution.

Main physicochemical characteristics: clear, colorless or slightly yellow liquid.

Pharmacotherapeutic group. Drugs affecting the musculoskeletal system. Anti-inflammatory and antirheumatic agents. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances. Ketorolac.

ATC code M01A B15.

Pharmacological Properties

Pharmacodynamics

Ketorolac tromethamine is a potent nonsteroidal anti-inflammatory drug (NSAID) that demonstrates analgesic activity. It is not an opioid and has no known effects on opioid receptors. Its mechanism of action involves inhibition of the cyclooxygenase enzyme system, thereby suppressing prostaglandin synthesis. At analgesic doses, ketorolac tromethamine exhibits only minimal anti-inflammatory activity.

Pharmacokinetics

Intramuscular administration. After intramuscular administration, ketorolac tromethamine 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 in plasma and mean total clearance are presented in the table below (evaluated after administration of a single 30 mg dose of ketorolac intramuscularly).

Category of patients	Total clearance (L/h/kg) mean value (range)	Terminal half-life (hours) mean value (range)
Typical patients (n = 54)	0.023 (0.010–0.046)	5.3 (3.5–9.2)
Patients with hepatic impairment (n = 7)	0.029 (0.013–0.066)	5.4 (2.2–6.9)
Patients with renal insufficiency (n = 25) (serum creatinine 160–430 µmol/L)	0.016 (0.005–0.043)	10.3 (5.9–19.2)
Patients on dialysis (n = 9)	0.016 (0.003–0.036)	13.6 (8.0–39.1)
Healthy elderly patients (n = 13) (mean age 72)	0.019 (0.013–0.034)	7.0 (4.7–8.6)

Intravenous administration. After intravenous administration of a single 10 mg dose of ketorolac tromethamine, the mean peak plasma concentration reached 2.4 µg/mL at an average of 5.4 minutes; the terminal half-life in plasma was 5.1 hours, the mean volume of distribution was 0.15 L/kg, and the total plasma clearance was 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 remains unchanged. The primary 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

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

Ketorolac-Farmak is contraindicated:

• in patients with a history of hypersensitivity reactions to ketorolac, any of the excipients, or other NSAIDs, and in patients with allergic reactions to aspirin or other inhibitors of prostaglandin synthesis (in these patients, severe anaphylactic reactions have been observed). Such reactions include asthma, rhinitis, angioedema, and urticaria;
• in patients with a history of bronchial asthma;
• in children under 16 years of age;
• in patients with active peptic ulcer, recent gastrointestinal bleeding, ulcerative disease, or perforation;
• in patients with severe heart failure, hepatic insufficiency, or renal insufficiency;
• in patients with moderate or severe renal impairment (serum creatinine level >160 μmol/L) or in patients at risk of developing renal failure due to reduced fluid volume or dehydration;
• during pregnancy, labor, delivery, and breastfeeding;
• as a prophylactic analgesic prior to surgery (due to inhibition of platelet aggregation) and during surgery (due to increased risk of bleeding);
• in patients with suspected or confirmed cerebrovascular hemorrhage, patients with incomplete hemostasis, and patients with a high risk of bleeding, such as hemorrhagic diatheses (including coagulation disorders) — due to inhibition of platelet function;
• in patients receiving anticoagulants, including warfarin and low-dose heparin (2500–5000 units every 12 hours);
• when used concomitantly with acetylsalicylic acid or other NSAIDs (including selective COX-2 inhibitors);
• for neuraxial (epidural or intrathecal) administration — due to ethanol content;
• in combination with oxpentifylline;
• when used concomitantly with probenecid or lithium salts;
• in patients with complete or partial nasal polyp syndrome, angioedema, or bronchospasm.

Interaction with other medicinal products and other forms of interaction

Ketorolac is highly bound to plasma proteins (approximately 99.2%), and its binding is independent of concentration.

Medicinal products that must not be taken concurrently with ketorolac

Ketorolac should not be used concomitantly with products containing acetylsalicylic acid or other NSAIDs, including selective COX-2 inhibitors, as this increases the risk of serious adverse effects associated with NSAID use.

Ketorolac inhibits platelet aggregation, reduces thromboxane concentration, and prolongs bleeding time. Unlike aspirin, which has a prolonged effect on platelet function, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac.

Concomitant use of ketorolac with anticoagulants such as warfarin is not recommended, as combined use of NSAIDs and anticoagulants may enhance the anticoagulant effect.

Although studies do not indicate a significant 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.

Available data indicate that when certain prostaglandin synthesis inhibitors are used, lithium renal clearance is reduced, leading to increased plasma lithium concentrations. Cases of elevated plasma lithium concentrations have been reported during ketorolac therapy.

Concomitant use of ketorolac and probenecid leads to increased plasma levels and prolonged half-life (T½) of ketorolac. Therefore, concomitant use of ketorolac and probenecid is contraindicated.

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

Concomitant administration of ketorolac and oxpentifylline increases the risk of bleeding.

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

As with all other NSAIDs, ketorolac should be used cautiously concomitantly with corticosteroids due to an increased risk of gastrointestinal bleeding.

Concomitant use of NSAIDs with antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) increases the risk of gastrointestinal bleeding.

It has been reported that some prostaglandin synthesis inhibitors reduce renal clearance of methotrexate, thereby increasing its toxicity.

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

In studies conducted in healthy volunteers with normal blood volume, ketorolac reduced the diuretic effect of furosemide by approximately 20%. Therefore, special caution is required when prescribing ketorolac to patients with cardiac decompensation.

Concomitant use with diuretic agents may reduce diuretic efficacy and increase the risk of NSAID nephrotoxicity.

As with all other NSAIDs, ketorolac should be used cautiously concomitantly with cyclosporine due to an increased risk of nephrotoxic effects.

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

NSAIDs may attenuate the effects of diuretics and other antihypertensive agents. When angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists are used in combination with NSAIDs, the risk of acute renal failure, usually reversible, increases in some patients with impaired renal function (e.g., dehydrated patients or elderly patients). Therefore, such combinations should be prescribed with caution, especially in elderly patients. Appropriate dose titration and monitoring of renal function should be performed before initiating concomitant therapy and periodically thereafter.

NSAIDs may worsen heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when used concomitantly.

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

Experimental data indicate that NSAIDs increase the risk of seizures associated with quinolone use. Patients receiving both 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.

Studies in animals and humans have not provided evidence that ketorolac tromethamine induces or inhibits liver enzymes involved in the metabolism of ketorolac itself or other drugs. Therefore, it is unlikely that ketorolac will affect the pharmacokinetics of other drugs via enzyme induction or inhibition.

Special precautions for use

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

Physicians should be aware that analgesia may occur only 30 minutes after intravenous or intramuscular administration in some patients.

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

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

Gastrointestinal ulcers, bleeding, and perforation

Gastrointestinal bleeding, ulcers, or perforation have been reported with all NSAIDs, sometimes fatal, regardless of prior gastrointestinal symptoms or history of serious gastrointestinal events.

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

Elderly patients are at increased risk of adverse reactions associated with NSAID use, particularly gastrointestinal bleeding and perforation, sometimes fatal.

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. The risk of clinically significant gastrointestinal bleeding is dose-dependent. These patients should start treatment, if possible, with the lowest dose. In such cases, and also when taking low-dose aspirin or other drugs that increase the risk of gastrointestinal disorders, consideration should be given to adding gastroprotective agents such as misoprostol or proton pump inhibitors. The age-related increase in the risk of gastrointestinal bleeding and perforation is characteristic of all NSAIDs. Compared to younger individuals, elderly patients have an increased plasma half-life and reduced plasma clearance of ketorolac. It is recommended to increase the interval between doses.

NSAIDs should be used with caution in patients with a history of inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated. Patients with a history of gastrointestinal disorders, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially in the early stages of treatment. If gastrointestinal bleeding or ulcers occur in a patient receiving intravenous ketorolac, treatment should be discontinued.

Particular caution is required in patients who are concurrently taking medications that may increase the risk of ulcers or bleeding, for example, oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs), or antithrombotic agents (such as aspirin).

Concomitant use with anticoagulants (such as warfarin) is contraindicated.

As with other NSAIDs, the frequency and severity of gastrointestinal complications may increase with higher doses and longer duration of intravenous ketorolac use. The risk of clinically significant gastrointestinal bleeding is dose-dependent. This is particularly relevant for elderly patients receiving an average daily intravenous dose of ketorolac exceeding 60 mg/day. A history of peptic ulcer disease increases the likelihood of developing serious gastrointestinal complications during ketorolac therapy.

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

Effect on hemostasis

Patients with coagulation disorders should not receive ketorolac therapy. The risk of bleeding increases when ketorolac is used concomitantly in patients receiving anticoagulant therapy. Detailed studies on the concomitant use of ketorolac with prophylactic low-dose heparin (2500–5000 units every 12 hours) and dextran have not been conducted, but such regimens may also increase the risk of bleeding. Patients already taking anticoagulants or requiring low-dose heparin should not receive ketorolac. Patients receiving other agents that adversely affect hemostasis should be closely monitored during ketorolac administration. 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, bleeding time increased but did not exceed the normal range of 2–11 minutes. Unlike the prolonged effect of aspirin on platelet function, 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, ketorolac should not be administered to patients who have undergone surgery with a high risk of bleeding or in whom bleeding has not been completely controlled. Caution should be exercised when stable hemostasis is critical, such as in cosmetic or ambulatory surgery, prostatectomy, or tonsillectomy. Hematomas and other signs of wound bleeding, as well as epistaxis, have been observed with ketorolac use. When prescribing ketorolac, its similarity to other NSAIDs that inhibit cyclooxygenase and the potential risk of bleeding, especially in elderly patients, should be considered.

Skin reactions

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

Systemic lupus erythematosus and mixed connective tissue disease

Patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease have an increased risk of developing aseptic meningitis.

Sodium/fluid retention in cardiovascular disease and peripheral edema

Caution is advised in patients with a history of hypertension and/or heart failure, as fluid retention and edema have been reported with NSAID use.

Fluid retention, hypertension, and edema have been observed in some patients taking NSAIDs, including ketorolac. Therefore, ketorolac should be used with caution in patients with decompensated heart failure, hypertension, or similar conditions.

Effect on the cardiovascular system and cerebral circulation

Patients with arterial hypertension and/or mild to moderate congestive heart failure should be closely monitored, as fluid retention and edema have been reported during NSAID therapy.

Clinical and epidemiological studies suggest that the use of coxibs and some NSAIDs (particularly at high doses) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Although no increase in thrombotic events such as myocardial infarction has been observed during ketorolac treatment, data are insufficient to exclude such a risk with ketorolac use.

Ketorolac should be prescribed to 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 such treatment. Similarly, the appropriateness of prescribing ketorolac to patients at risk of cardiovascular disease (e.g., patients with arterial hypertension, hyperlipidemia, diabetes mellitus, or smokers) should be considered.

Patients with cardiovascular, renal, and 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, NSAID use may cause dose-dependent reduction in prostaglandin production and trigger acute renal failure. The risk of this reaction is highest in patients with fluid imbalance due to blood loss or severe dehydration, patients with impaired renal or hepatic function, heart failure, elderly patients, and those taking diuretics. Renal function should be monitored in these patients. Usually, after discontinuation of NSAID therapy, the patient's condition returns to the pre-treatment state. Inadequate correction of fluid/blood loss during surgery, leading to hypovolemia, may cause renal dysfunction, which may be exacerbated by ketorolac use. Correction of reduced extracellular fluid volume is necessary; careful monitoring of serum urea and creatinine levels and observation of urine output are required until blood volume is normalized. In patients undergoing renal dialysis, the clearance of ketorolac is approximately two times lower than normal, and the terminal half-life is increased by about three times.

Effect on kidneys

As with other NSAIDs, ketorolac 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. Caution is required, as nephrotoxicity has been observed with ketorolac and other NSAIDs 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, the use of NSAIDs, including ketorolac, may cause dose-dependent reduction in prostaglandin production and trigger acute renal failure. Patients at risk include those with impaired renal function, hypovolemia, heart failure, hepatic impairment, those taking diuretics, and elderly patients. Usually, after discontinuation of ketorolac or other NSAIDs, the patient's condition returns to the pre-treatment state.

During treatment with ketorolac tromethamine, as with other prostaglandin synthesis inhibitors, increased serum urea, creatinine, and potassium levels have been reported, even after a single dose.

Use in patients with renal impairment: Since ketorolac tromethamine and its metabolites are primarily excreted by the kidneys, ketorolac should not be administered to patients with moderate to severe renal impairment (serum creatinine >160 µmol/L). Patients with mild renal impairment should receive lower doses (not exceeding 60 mg/day intramuscularly or intravenously) and renal function should be monitored periodically.

Use in patients with hepatic disease: In patients with hepatic impairment due to cirrhosis, the clearance of ketorolac and terminal half-life are not clinically significantly altered.

Elevation of one or more liver function parameters 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] (more than three times the upper limit of normal). If clinical symptoms indicating hepatic dysfunction or systemic manifestations appear, ketorolac 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 prior hypersensitivity to aspirin, other NSAIDs, or intravenous ketorolac, as well as in those without prior hypersensitivity reactions. These reactions may occur in individuals with angioneurotic edema, a history of bronchospastic reactions (e.g., asthma), or nasal polyps. Such anaphylactoid reactions, including anaphylaxis, may be fatal. Therefore, ketorolac should not be used in patients with a history of asthma, nasal polyps (complete or partial syndrome), angioedema, or bronchospasm.

Safety measures related to fertility

Like other inhibitors of cyclooxygenase/prostaglandin synthesis, ketorolac may negatively affect fertility. The drug is not recommended for women planning to become pregnant. Women with fertility problems or undergoing infertility evaluation should discontinue ketorolac use.

Fluid retention and edema

Fluid retention, hypertension, and edema have been observed in some patients taking ketorolac. Therefore, ketorolac should be used with caution in patients with decompensated heart failure, hypertension, or similar conditions.

Caution is recommended when using ketorolac concomitantly with drugs that inhibit prostaglandin synthesis, such as methotrexate, as they may reduce renal clearance of methotrexate and thereby increase its toxicity.

Abuse and dependence

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

This product contains 10 vol.% ethanol (alcohol), i.e., 100 mg/mL, equivalent to 3 mL of beer or 1.25 mL of wine per dose. It is harmful for patients with alcoholism. Caution is advised when using in pregnant women, breastfeeding women, children, patients with liver disease, and patients with epilepsy.

1 mL of injectable ketorolac tromethamine solution contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding

Due to the proven effects of NSAIDs on the fetal cardiovascular system (early closure of the ductus arteriosus), ketorolac is contraindicated during pregnancy, labor, delivery, and breastfeeding.

The safety of ketorolac use in pregnant women has not been established. In studies in rats and rabbits, no teratogenic effects were observed when the drug was administered at doses toxic to the mother. In rats, prolongation of gestation and/or delayed delivery were observed. Congenital anomalies have been reported in humans after NSAID use, but their 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 malformations, and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increases from less than 1% to about 1.5%. The risk is considered to increase with higher doses and longer duration of treatment. Animal studies have shown that prostaglandin synthesis inhibitors lead to pre- and post-implantation losses and embryonic and fetal death. Additionally, increased numbers of congenital malformations, particularly cardiovascular defects, have been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

From the 20th week of pregnancy, ketorolac use may cause oligohydramnios due to fetal renal dysfunction. This effect may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, constriction of the ductus arteriosus has been reported after use of prostaglandin synthesis inhibitors in the second trimester, which usually resolves after discontinuation of treatment. Therefore, ketorolac should not be prescribed during the first and second trimesters of pregnancy unless clearly necessary.

If ketorolac is used in women attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

After several days of ketorolac use starting from the 20th week of pregnancy, consideration should be given to antenatal monitoring for oligohydramnios and ductus arteriosus constriction. If oligohydramnios or ductus arteriosus constriction is detected, ketorolac use should be discontinued.

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

in the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the patent ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

in the mother towards the end of pregnancy and in the newborn:

• prolonged bleeding time (since anti-aggregatory effects may occur even at low doses);
• inhibition of uterine contractility, which may lead to delayed or prolonged labor.

Therefore, ketorolac is contraindicated during the third trimester of pregnancy (see section "Contraindications").

Breastfeeding

Studies have shown that ketorolac and its metabolites pass to the fetus and into milk in animals. Low concentrations of ketorolac have been detected in human breast milk; therefore, this medicinal product is contraindicated for breastfeeding mothers.

Ability to affect reaction speed when driving or operating machinery

Some patients may experience dizziness, somnolence, fatigue, visual disturbances, headache, vertigo, insomnia, or depression after ketorolac administration. If such disorders occur, patients should not drive or operate machinery.

Method of Administration and Dosage

Ketorolac-Farmak is intended for intramuscular or bolus intravenous injection. Bolus intravenous doses should be administered over at least 15 seconds. Ketorolac-Farmak should not be used for epidural or spinal administration.

Analgesic effect begins approximately 30 minutes after injection and reaches maximum intensity within 1–2 hours. The average duration of analgesia is 4–6 hours.

Dosage should be selected and adjusted according to the intensity of pain and the patient's response to treatment.

Continuous intramuscular or intravenous 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 either switch to oral medication or no longer require analgesic therapy.

The likelihood of adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Adults

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

During the early postoperative period, when pain is most severe, concomitant use of opioid analgesics (morphine, pethidine) may be considered for optimal analgesic effect. 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 opioid dose is generally lower than usual. However, opioid-related adverse effects should be considered, especially in surgical patients.

Elderly Patients

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

Renal Impairment

The drug is contraindicated in cases of moderate to severe renal impairment. In milder forms of renal dysfunction, the dose should be reduced (not more than 60 mg/day intravenously or intramuscularly).

Children

Safety and efficacy in children have not been established. Therefore, ketorolac is not recommended for use in children under 16 years of age.

Overdose

Symptoms

Acute overdose of ketorolac has in various cases led to abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers, erosive gastritis, and transient renal dysfunction.

Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression, and coma may also occur after NSAID overdose, although such symptoms are rare.

In addition, headache, epigastric pain, confusion, agitation, 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 NSAID overdose, symptomatic therapy and measures to support vital functions should be administered. There is no specific antidote. Dialysis does not provide significant removal of ketorolac from blood due to extensive protein binding.

In life-threatening overdose, activated charcoal or gastric lavage may be used as therapy in adult patients within the first hour after ingestion.

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

Side effects

The following adverse effects have been observed during the post-marketing period in patients receiving intravenous ketorolac. The frequency of adverse reactions is unknown, as the data are based on voluntary reports and the patient population size is undefined.

Gastrointestinal disorders. The most commonly observed adverse reactions are of gastrointestinal origin. Peptic ulcer, ulceration, perforation, or gastrointestinal bleeding, sometimes fatal, may occur, particularly in elderly patients. Nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain/discomfort, melena, hematemesis, stomatitis, ulcerative stomatitis, eructation, flatulence, esophagitis, gastrointestinal ulceration, rectal bleeding, pancreatitis, dry mouth, bloating, exacerbation of ulcerative colitis and Crohn's disease have been reported. Gastritis has been observed less frequently.

Infections. Aseptic meningitis (particularly in patients with autoimmune disorders such as SLE, mixed connective tissue disease), with symptoms such as neck stiffness, headache, nausea, vomiting, fever, or disorientation.

Blood and lymphatic system disorders. Thrombocytopenia. In addition, purpura, neutropenia, agranulocytosis, aplastic anemia, and hemolytic anemia have been observed.

Immune system disorders. Anaphylaxis, anaphylactoid reactions similar to anaphylaxis, which may be fatal; hypersensitivity reactions such as bronchospasm, flushing, rash, hypotension, laryngeal edema.

These reactions may occur in individuals with a history of angioedema or bronchospastic reactions (e.g., asthma or nasal polyps).

Metabolism and nutrition disorders. Anorexia, hyperkalemia, hyponatremia.

Psychiatric disorders. Pathological thinking, depression, insomnia, restlessness, nervousness, psychotic reactions, unusual dreams, hallucinations, euphoria, difficulty concentrating, drowsiness.

Confusion and excitation have also been observed.

Nervous system disorders. Headache, dizziness, seizures, paresthesia, hyperkinesia, taste disturbances.

Eye disorders. Visual disturbances, blurred vision, 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, with or without azotemia). As with other prostaglandin synthesis inhibitors, signs of renal impairment, including elevated creatinine and potassium levels, have been reported during ketorolac use and may occur after intravenous administration of a single dose.

Cardiac disorders. Palpitations, bradycardia, heart failure.

Vascular disorders. Hypertension, hypotension, hematoma, flushing, pallor, postoperative wound bleeding.

Clinical and epidemiological studies have shown that the use of coxibs and certain NSAIDs (particularly at high doses) may be 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 during ketorolac treatment, data are insufficient to exclude such a risk.

Reproductive system and breast disorders. Female infertility.

Respiratory, thoracic and mediastinal disorders. Asthma, dyspnea, pulmonary edema. In addition, epistaxis has been observed.

Hepatobiliary disorders. Hepatitis, cholestatic jaundice, hepatic failure.

Skin and subcutaneous tissue disorders. Exfoliative dermatitis, maculopapular rash, pruritus, urticaria, purpura, angioedema, sweating, bullous dermatitis, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).

In addition, polymorphic erythema and increased photosensitivity of the skin have been observed.

Musculoskeletal and connective tissue disorders. Myalgia, functional disorders.

General disorders and administration site conditions. Excessive thirst, asthenia, edema, injection site reactions and pain, fever, chest pain.

Malaise, increased fatigue, and weight gain have also been reported.

Investigations. Prolonged bleeding time, elevated serum urea nitrogen, elevated creatinine levels, liver function test abnormalities.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions

Store in the original packaging. No special storage conditions required. Keep out of reach of children.

Incompatibility

Ketorolac should not be mixed in the same syringe with the following medicinal products: morphine sulfate, meperidine hydrochloride, promethazine hydrochloride, hydroxyzine hydrochloride — as ketorolac will precipitate.

Ketorolac is compatible with normal saline, 5% dextrose solution, Ringer's solution, Ringer's lactate solution, and "Plasmalyte" solution.

Compatibility of ketorolac with other medicinal products is unknown.

Packaging. 1 ml in an ampoule. 5 ampoules per blister; 1 or 2 blisters per pack.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of its business activities.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.