Ketorolac-lubnipharm

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

Composition:

Active substance: ketorolac;

1 ml of solution contains ketorolac tromethamine 30 mg;

Excipients: ethanol (96%), sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear solution with a yellowish tint, practically free from particles.

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

ATC code M01AB15.

Pharmacological properties.

Pharmacodynamics.

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that demonstrates analgesic activity. The mechanism of action of ketorolac (as with other NSAIDs) is not completely understood but may involve inhibition of prostaglandin synthesis. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine has no sedative or anxiolytic properties.

The main difference between higher and lower doses of ketorolac lies in the duration of analgesia. The analgesic dose of ketorolac also exerts anti-inflammatory effects.

Pharmacokinetics.

Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with analgesic activity attributed to the S-form. After intramuscular administration, ketorolac is rapidly and completely absorbed. A mean peak plasma concentration of 2.2 µg/mL is achieved on average within 50 minutes after a single 30 mg dose.

Linear pharmacokinetics. In adults, following intramuscular administration of ketorolac tromethamine within the recommended dosage range, the clearance of the racemate does not change. This indicates that the pharmacokinetics of ketorolac tromethamine in adults after single or multiple intramuscular doses is linear. With higher recommended doses, a proportional increase in concentrations of both free and bound racemate is observed.

The drug poorly penetrates the blood-brain barrier. Ketorolac crosses the placenta and is excreted in small amounts into breast milk. More than 99% of ketorolac in plasma is protein-bound across a wide range of concentrations.

Table of approximate mean pharmacokinetic parameters

[mean value ± standard deviation (SD)]

Metabolism. Ketorolac tromethamine is largely metabolized in the liver. The metabolites are hydroxylated and conjugated forms of the parent drug. Metabolites and some unchanged drug are excreted in urine.

Excretion. The primary route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is recovered in urine: 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of the dose is excreted in feces. In a single-dose study of 10 mg ketorolac (n = 9), the S-enantiomer was eliminated twice as rapidly as the R-enantiomer, and clearance was independent of the route of administration. This indicates that the plasma concentration ratio of S-enantiomer to R-enantiomer decreases over time after each dose. Differences between S- and R-forms in humans are negligible or absent. The half-life (T½) of the S-enantiomer of ketorolac tromethamine is approximately 2.5 hours (SD ± 0.4), and that of the R-enantiomer is 5 hours (SD ± 1.7).

In other studies, the racemate half-life has been reported to be 5–6 hours.

Accumulation. Ketorolac tromethamine administered intravenously as a bolus every 6 hours for 5 days to healthy volunteers (n = 13) showed no significant differences between day 1 and day 5. Minimum levels averaged 0.29 µg/mL (SD ± 0.13) on day 1 and 0.55 µg/mL (SD ± 0.23) on day 6. Steady state was achieved after the fourth dose. Accumulation of ketorolac tromethamine in specific patient groups (elderly patients, children, patients with renal or hepatic impairment) has not been studied.

Pharmacokinetics in specific patient populations.

Elderly patients. Based solely on data obtained after single-dose administration, the half-life (T½) of racemic ketorolac tromethamine increased from 5 to 7 hours in elderly patients (65–78 years) compared to younger healthy volunteers (24–35 years).

Children. Pharmacokinetic data on intramuscular administration of ketorolac tromethamine in children are lacking.

Renal impairment. Based solely on data obtained after single-dose administration, the mean half-life (T½) of ketorolac tromethamine in patients with impaired renal function ranges from 6 to 19 hours and depends on the severity of impairment. There is almost no correlation between creatinine clearance and total clearance of ketorolac tromethamine in elderly patients and patients with renal dysfunction (r = 0.5). In patients with renal disease, the AUC8 of each enantiomer increases by nearly 100% compared to healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by one-fifth for the R-enantiomer. The increased volume of distribution of ketorolac tromethamine suggests an increased unbound fraction.

Hepatic impairment. T½, AUC8, and Cmax values in 7 patients with hepatic disease did not differ significantly from those in healthy volunteers.

Clinical characteristics.

Indications. Management of moderate to severe postoperative pain for short-term use.

Contraindications.

• Hypersensitivity to the active substance or to any component of the medicinal product, or to other NSAIDs (nonsteroidal anti-inflammatory drugs).
• Active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer or gastrointestinal bleeding.
• Presence or suspected gastrointestinal bleeding.
• Allergic reactions such as bronchial asthma, rhinitis, angioedema, or urticaria induced by acetylsalicylic acid or other NSAIDs in the past (due to the possibility of severe anaphylactic reactions).
• History of bronchial asthma.
• Do not use as an analgesic before and during surgical procedures and interventions on coronary vessels, as it inhibits platelet aggregation and is also contraindicated during surgery due to increased risk of bleeding.
• Severe heart failure.
• Complete or partial syndrome of nasal polyps, Quincke's edema, or bronchospasm.
• Do not use in patients who have undergone surgery with high risk of bleeding or incomplete hemostasis, and in patients receiving anticoagulants, including low-dose heparin (2500–5000 IU every 12 hours).
• Severe hepatic or moderate to severe renal impairment (serum creatinine level >160 µmol/L).
• Suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding.
• Concomitant use with other NSAIDs (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid, or lithium salts.
• Hypovolemia, dehydration with risk of renal impairment due to reduced fluid volume.
• Pregnancy, labor, delivery, and breastfeeding period.
• Use in children under 16 years of age.
• Epidural or intrathecal administration of the drug is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Ketorolac is highly bound to plasma proteins (on average 99.2%). Ketorolac tromethamine does not alter the pharmacokinetics of other drugs via induction or inhibition of enzymes.

Should not be used concurrently with ketorolac.

Warfarin, digoxin, salicylates, and heparin. Ketorolac tromethamine slightly reduced the protein binding of warfarin in vitro and did not alter the protein binding of digoxin. In vitro studies indicate that at therapeutic concentrations of salicylates (300 µg/mL), the binding of ketorolac decreased from approximately 99.2% to 97.5%, suggesting a potential twofold increase in unbound ketorolac levels in plasma. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not alter the protein binding of ketorolac tromethamine. Concomitant use of ketorolac and prophylactic low-dose heparin (2500–5000 IU every 12 hours) has not been widely studied but may be associated with an increased risk of bleeding. Ketorolac should not be administered to patients receiving anticoagulants or low-dose heparin.

Antithrombotic agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding (see section "Special precautions").

Anticoagulants. Concomitant use with anticoagulants may potentiate bleeding. Concurrent use with anticoagulants (such as warfarin) is contraindicated.

Pentoxifylline. Concomitant use of ketorolac tromethamine and pentoxifylline increases the risk of bleeding.

Other NSAIDs and acetylsalicylic acid. When used with acetylsalicylic acid, the protein binding of ketorolac is reduced, although the clearance of free ketorolac remains unchanged. The clinical significance of this interaction is unknown; however, as with other NSAIDs, concomitant administration of ketorolac tromethamine with acetylsalicylic acid or other NSAIDs is not recommended due to the potential for increased frequency of adverse effects.

Diuretics. In some patients, ketorolac may reduce the natriuretic effect of furosemide and thiazides. During concomitant therapy with NSAIDs, patients should be closely monitored for signs of renal impairment and to ensure the effectiveness of diuretic therapy (see section "Special precautions"). In healthy volunteers with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%; therefore, special caution is required when prescribing ketorolac to patients with cardiac decompensation.

Probenecid. Concomitant use of ketorolac tromethamine and probenecid results in decreased clearance of ketorolac and significant increase in its plasma levels and half-life (T½). Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Oxpentifylline. Not recommended due to increased risk of hemorrhage.

Lithium. Concomitant use of NSAIDs and lithium preparations is contraindicated, as it may inhibit renal clearance of lithium, increase plasma lithium concentration, and lead to lithium toxicity.

Opioid analgesics. The effect of opioid analgesics is enhanced, allowing for dose reduction in pain management.

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

Antithrombotic agents and selective serotonin reuptake inhibitors (SSRIs).

Increased risk of gastrointestinal bleeding (see section "Special precautions").

Thrombolytic agents.

Concomitant use with NSAIDs increases the risk of bleeding.

Methotrexate. Should be prescribed concomitantly with caution. Since NSAIDs may impair renal function, thereby reducing methotrexate clearance, increased methotrexate toxicity is possible.

ACE inhibitors. Concomitant use of angiotensin-converting enzyme (ACE) inhibitors increases the risk of renal function impairment, particularly in patients with reduced extracellular fluid volume.

NSAIDs may reduce the antihypertensive effect of ACE inhibitors. This interaction should be considered when prescribing NSAIDs together with ACE inhibitors.

β-blockers. Ketorolac and other NSAIDs reduce the antihypertensive effect of β-blockers.

Angiotensin-II receptor antagonists. Ketorolac and other NSAIDs reduce the antihypertensive effect of angiotensin-II receptor antagonists.

Anticonvulsants. Isolated cases of seizures have been reported during concomitant use of ketorolac tromethamine and anticonvulsants (phenytoin, carbamazepine).

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

Corticosteroids. As with all NSAIDs, corticosteroids should be used concomitantly with caution due to increased risk of gastrointestinal bleeding.

Quinolones. Patients taking quinolones have an increased risk of seizures.

Antidiabetic agents. NSAIDs may enhance the effect of sulfonylurea derivatives.

Antiviral agents. 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. Ritonavir may increase NSAID concentrations.

Tacrolimus. NSAIDs increase the risk of nephrotoxicity.

Garlic, onion, and Ginkgo biloba-containing preparations may enhance the effect of ketorolac and increase the risk of hemorrhagic complications.

Non-depolarizing muscle relaxants. No official studies on concomitant use of ketorolac tromethamine and muscle relaxants have been conducted. NSAIDs may reduce the excretion of baclofen (increasing the risk of toxicity). Animal and human studies have shown no evidence that ketorolac tromethamine induces or inhibits liver enzymes capable of metabolizing it or other drugs. Therefore, ketorolac is not expected to alter the pharmacokinetics of other drugs via enzyme induction or inhibition.

Cyclosporine. As with all NSAIDs, concomitant use with cyclosporine is contraindicated due to increased risk of nephrotoxic effects.

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

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

Ketorolac does not affect the protein binding of digoxin. In vitro studies show that at therapeutic concentrations (300 µg/mL) and higher concentrations of salicylates, the degree of protein binding of ketorolac decreases from 99.2% to 97.5%. Digoxin, warfarin, acetaminophen, phenytoin, and tolbutamide at therapeutic concentrations do not alter the protein binding of ketorolac. Since ketorolac is a potent drug and its plasma concentration is low, it is unlikely to significantly displace other drugs from plasma protein binding sites.

Effect on laboratory test results.

Ketorolac inhibits platelet aggregation and may prolong bleeding time.

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

Special precautions for use.

The likelihood of adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Physicians should be aware that in some patients, analgesia may only occur 30 minutes after parenteral administration.

Concomitant use of ketorolac and other NSAIDs, including selective cyclooxygenase-2 inhibitors, should be avoided (see section "Contraindications").

Combined intramuscular and oral administration of ketorolac tromethamine to adult patients should not exceed 2 days.

Careful monitoring of diuresis and renal function is required in patients with cardiac, renal, or hepatic insufficiency, patients on diuretics, and postoperative patients with hypovolemia.

Use in elderly patients.

In elderly patients (over 65 years of age), NSAIDs more frequently cause adverse reactions, especially gastrointestinal bleeding and perforation, including fatal outcomes (see section "Dosage and administration").

The increased risk associated with age is characteristic of all NSAIDs.

Compared to younger patients, elderly patients have a prolonged plasma half-life and reduced plasma clearance. Therefore, total daily doses exceeding 60 mg are not recommended in elderly patients (see section "Dosage and administration").

Gastrointestinal disorders. Epidemiological data suggest that, compared to some other NSAIDs, the use of ketorolac (especially off-label and/or for prolonged periods) may be associated with an increased risk of gastrointestinal complications. Ketorolac tromethamine can cause serious adverse effects in the gastrointestinal tract, such as bleeding, ulcers, and gastrointestinal perforation. These adverse effects may occur in patients taking ketorolac tromethamine at any time, with or without preceding symptoms, and may be fatal. The risk of clinically significant gastrointestinal bleeding is dose-dependent. However, adverse effects may occur even during short-term therapy. In addition to a history of peptic ulcer disease, particularly with bleeding or perforation, predisposing factors include concomitant use of oral corticosteroids, anticoagulants, prolonged NSAID therapy, smoking, alcohol consumption, advanced age, and poor general health. In such cases, careful consideration should be given to combining NSAIDs with gastroprotective agents, such as misoprostol or a proton pump inhibitor. Most spontaneous reports of gastrointestinal adverse events involved elderly or debilitated patients; therefore, special attention should be paid when treating such patients, and ketorolac should be discontinued if any suspicion arises. Alternative therapies not involving NSAIDs should be considered for patients at high risk. Patients (especially elderly) with a history of diagnosed gastrointestinal disorders (GI) should report any abdominal symptoms (particularly gastrointestinal bleeding). These symptoms should be closely monitored at the beginning of treatment.

If gastrointestinal bleeding or ulceration is diagnosed in a patient taking ketorolac, the drug should be discontinued.

NSAIDs, including ketorolac, should be used with caution in patients with a history of Crohn's disease or ulcerative colitis due to the potential for worsening of the disease.

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

Anaphylactic (anaphylactoid) reactions.

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

Hematological effects.

Ketorolac should not be administered to patients with coagulation disorders. The concomitant use of ketorolac tromethamine in patients receiving anticoagulant therapy increases the risk of bleeding. Detailed studies on the simultaneous use of ketorolac and prophylactic low-dose heparin (2500–5000 IU every 12 hours) have not been conducted. This regimen may also increase the risk of bleeding. Patients already taking anticoagulants or requiring low-dose heparin should not receive ketorolac tromethamine. Close monitoring is required for patients receiving other agents that negatively affect hemostasis during ketorolac tromethamine administration. Clinical studies have shown that the incidence of postoperative bleeding is less than 1%. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding time increased but did not exceed the normal range of 2–11 minutes. Unlike the prolonged effect after acetylsalicylic acid intake, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac. Ketorolac tromethamine should not be used in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis. Caution should be exercised when stable hemostasis is critical, such as in cosmetic or outpatient surgeries, prostatectomy, or tonsillectomy. Hematomas, other signs of wound bleeding, and epistaxis may occur 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. Ketorolac tromethamine is not an anesthetic and does not possess sedative or anxiolytic properties.

Use in patients with impaired renal function (see section "Contraindications"). Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have toxic effects on the kidneys (e.g., glomerulonephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, acute renal failure); therefore, it should be used with caution in patients with impaired renal function or a history of kidney disease. Risk groups include patients with impaired renal function, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Caution is advised in patients in whom disease may reduce blood volume and/or renal blood flow, where prostaglandins play an important role in maintaining perfusion. In such patients, NSAID use may cause dose-dependent inhibition of prostaglandin synthesis and renal failure.

Ketorolac may increase serum urea, creatinine, and potassium levels; deviations from normal may occur even after a single dose. After discontinuation of NSAID therapy, patients' condition usually normalizes.

Patients with mild renal impairment should receive lower doses of ketorolac (not exceeding 60 mg/day, intramuscularly). Close monitoring of renal function is required in these patients. Patients should be adequately hydrated before starting treatment. Inadequate fluid/blood transfusion during surgery followed by hypovolemia may cause renal dysfunction, which may be exacerbated by ketorolac administration. Correction of reduced extracellular fluid volume is necessary; careful monitoring of serum urea and creatinine levels and urine output is required until blood volume is normalized.

In patients undergoing hemodialysis, ketorolac clearance was reduced by approximately half compared to normal rates, and terminal half-life increased nearly threefold.

Effects on the cardiovascular system and cerebral vessels. Reports indicate an association between NSAID use and fluid retention and edema. Therefore, close monitoring is required in patients with arterial hypertension and/or a history of mild to moderate heart failure.

To minimize the potential risk of cardiovascular complications in patients using NSAIDs, the lowest effective dose should be used for the shortest possible duration. Ketorolac tromethamine may be prescribed to patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful consideration of the benefits and risks of such treatment. Similarly, the appropriateness of prescribing ketorolac should be evaluated before initiating long-term treatment in patients at risk for cardiovascular diseases (e.g., those with arterial hypertension, hyperlipidemia, diabetes mellitus, or smokers).

Clinical studies and epidemiological data suggest that the use of some NSAIDs, particularly at high doses and for prolonged periods, may be associated with a slight increase in the risk of arterial thromboembolic complications, such as myocardial infarction or stroke. Such a risk cannot be excluded for ketorolac.

Use in patients with impaired hepatic function. Ketorolac tromethamine should be used with caution in patients with impaired hepatic function or a history of liver disease. In patients with hepatic dysfunction due to cirrhosis, ketorolac clearance and terminal half-life are not clinically significantly altered.

Elevation of one or more liver function tests may occur. Significant increases (more than three times the upper limit of normal) in serum ALT and AST were observed in less than 1% of patients. Additionally, there have been reports of isolated cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, sometimes fatal. Ketorolac should be discontinued if clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash) develop.

Respiratory system. The patient's condition should be monitored for the potential development of bronchospasm.

Systemic lupus erythematosus and mixed connective tissue diseases.

The risk of aseptic meningitis is increased in patients with systemic lupus erythematosus and various mixed connective tissue diseases.

Dermatological. Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and Lyell's syndrome have been reported very rarely with NSAID use. The highest risk of these reactions occurs at the beginning of treatment, with most cases appearing within the first month of therapy. Patients should discontinue treatment at the first sign of rash, mucosal lesions, or other signs of hypersensitivity.

Fluid retention and edema. Fluid retention and edema have been reported during ketorolac use; therefore, it should be used with caution in patients with cardiac decompensation, arterial hypertension, or similar conditions.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

This medicinal product contains a small amount of ethanol (alcohol), less than 100 mg/dose.

Use during pregnancy or breastfeeding.

The use of ketorolac tromethamine is contraindicated during pregnancy, labor, and delivery due to the known effects of NSAIDs on the fetal cardiovascular system.

Pregnancy.

Safety during pregnancy has not been established. It has been demonstrated that ketorolac crosses the placental barrier and reaches the fetus. Therefore, ketorolac tromethamine is contraindicated during pregnancy and labor.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of spontaneous abortion, cardiac malformations, and gastroschisis following the use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. This risk is believed to increase with higher doses and longer duration of therapy. Animal studies have shown that prostaglandin synthesis inhibitors lead to increased loss of fertilized ova before implantation and interruption of pregnancy after implantation, as well as increased embryonic and fetal mortality. Furthermore, reports indicate a higher incidence of various malformations, including cardiovascular malformations, in animals treated with a prostaglandin synthesis inhibitor during organogenesis.

From the 20th week of pregnancy, the use of ketorolac tromethamine may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after the start of treatment and is usually reversible upon discontinuation of therapy.

During pregnancy, all prostaglandin synthesis inhibitors may cause in the fetus:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function, which may progress to renal failure with the development of oligohydramnios (reduced amniotic fluid volume) (see above).

At the end of pregnancy, these drugs may cause in the mother and newborn:

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

Therefore, the use of ketorolac is contraindicated throughout pregnancy.

Breastfeeding.

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

Fertility.

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

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from potentially hazardous activities requiring heightened attention and rapid psychomotor reactions due to the possible development of nervous system adverse reactions. Some patients may experience dizziness, fatigue, somnolence, vertigo, visual disturbances, insomnia, and depression during ketorolac therapy.

Method of Administration and Dosage.

It is recommended to use in a hospital setting.

After intramuscular administration, analgesic effect occurs approximately within 30 minutes; maximum pain relief is achieved within 1–2 hours. Overall, the average duration of analgesia is 4–6 hours. The dose should be adjusted depending on the severity of pain and the patient's response to treatment. Continuous 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 the majority of patients are either switched to oral administration of the drug or no longer require analgesic therapy after the intramuscular administration period. The risk of adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The medicinal product must not be administered epidurally or intraspinally.

Adults. The recommended initial dose of ketorolac tromethamine is 10 mg (0.3 ml of the solution), followed by doses of 10–30 mg (0.3–1 ml of the solution) every 4–6 hours (as needed). In the initial postoperative period, ketorolac tromethamine may be administered every 2 hours if necessary. The lowest effective dose should be prescribed. The total daily dose must not exceed 90 mg (3 ml of the solution) for younger patients, and 60 mg (2 ml of the solution) for elderly patients, patients with renal insufficiency, and patients weighing less than 50 kg. The maximum duration of treatment must not exceed 2 days. The dose must be reduced in patients weighing less than 50 kg.

Concomitant use of opioid analgesics (morphine, meperidine) is possible. Ketorolac has no negative effect on opioid receptor binding and does not potentiate respiratory depression or sedative effects of opioid drugs.

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

Elderly patients. For patients aged 65 years and older, the lowest dose within the recommended range should be prescribed. The total daily dose must not exceed 60 mg.

Patients with renal impairment. Ketorolac is contraindicated in moderate to severe renal impairment. In mild to moderate renal dysfunction, dosage reduction is required (not exceeding 60 mg/day intramuscularly).

Children.

Not to be used in children under 16 years of age.

Overdose.

Symptoms: depressed state, lethargy, somnolence, nausea, vomiting, epigastric pain, gastrointestinal bleeding, arterial hypertension, acute renal failure, respiratory depression and coma, seizures. Anaphylactoid reactions have been reported.

Single overdoses of ketorolac at various times have led to abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and impaired renal function, which resolved after discontinuation of the drug.

Following intramuscular administration of 360 mg of ketorolac over 5 days, abdominal pain and peptic ulcers were observed, which resolved after discontinuation of the drug. Overdose may also present with nausea, headache, dizziness, disorientation, tinnitus, and hyperventilation. Suicide attempts have been reported. After intentional overdose, metabolic acidosis was observed.

Treatment: symptomatic and supportive therapy. There is no specific antidote. For patients presenting with overdose symptoms or after a large overdose (oral dose 5–10 times higher than usual), emesis should be induced within 4 hours of drug intake, and activated charcoal (60–100 g for adults) and/or an osmotic laxative should be administered. Forced diuresis, urine alkalinization, hemodialysis, or blood transfusion are ineffective due to the high plasma protein binding of the drug. Close monitoring of the patient is required, with regular assessment of liver and kidney function. For prolonged seizures, intravenous diazepam is recommended.

Adverse Reactions

Adverse reactions reported more frequently than isolated cases are classified by organ systems and frequency as follows: very common (> 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Gastrointestinal system: The most common adverse reactions observed are gastrointestinal disorders. Erosive and ulcerative lesions of the gastrointestinal tract, ulcer perforation, and gastrointestinal bleeding (hematemesis, melena) may occur, sometimes with fatal outcomes (especially in elderly patients) (see section "Special precautions"). Reported adverse effects include nausea, vomiting, dyspepsia, abdominal discomfort, abdominal pain, spasm or burning sensation in the epigastric region, taste disturbances, diarrhea, dry mouth, thirst, flatulence, constipation, acute pancreatitis, gastric fullness, esophagitis, belching, exacerbation of colitis and Crohn's disease, ulcerative stomatitis; uncommon: gastritis.

Hepatobiliary system: uncommon: cholestatic jaundice, hepatitis; frequency not known: liver function abnormalities, hepatomegaly, increased hepatic transaminase activity, liver failure.

Nervous system: uncommon: somnolence, psychotic reactions, headache, difficulty concentrating, pathological thinking, vertigo, aseptic meningitis (particularly in patients with autoimmune diseases such as systemic lupus erythematosus, with symptoms including fever, severe headache, seizures, neck and/or back stiffness), hyperactivity (mood changes, restlessness), nervousness, hallucinations, depression, psychosis, loss of consciousness; frequency not known: insomnia, euphoria, dizziness, anxiety, asthenic syndrome, paresthesia, functional disturbances, malaise, fatigue, excitement, irritability, unusual dreams, confusion, disorientation, hyperkinesia.

Cardiovascular system: common: pallor; uncommon: tachycardia, palpitations, chest pain; frequency not known: bradycardia, flushing. Cases of edema, hypertension or hypotension, and heart failure associated with NSAID use (especially at high doses and prolonged treatment) have been reported. Increased risk of arterial thromboembolic complications such as myocardial infarction or stroke (see section "Special precautions").

Hematopoietic system: frequency not known: aplastic anemia, hemolytic anemia, purpura, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, neutropenia.

Respiratory system: uncommon: bronchial asthma, exacerbation of bronchial asthma, pulmonary edema; frequency not known: bronchospasm, dyspnea, laryngeal edema.

Urinary system: uncommon: hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), acute renal failure; frequency not known: nephrotoxicity, including increased urinary frequency, oliguria, flank pain (with or without hematuria), interstitial nephritis, urinary retention, nephrotic syndrome, dysuria, hyponatremia, hyperkalemia, increased creatinine and urea levels, papillary necrosis, back pain, hematuria, azotemia. Administration of ketorolac (even after a single intravenous dose), like other drugs that inhibit renal prostaglandin synthesis, may lead to signs of renal impairment, not limited to elevated blood creatinine and potassium levels.

Skin: common: pruritus, purpura; uncommon: exfoliative dermatitis (erythema, skin induration or desquamation, enlargement and/or tenderness of palatine tonsils); frequency not known: photosensitivity, skin rashes (including maculopapular eruptions), bullous reactions, erythema multiforme.

Hemostatic system: uncommon: postoperative wound bleeding, epistaxis, rectal bleeding, subcutaneous hemorrhage, reduced blood clotting speed; frequency not known: prolonged bleeding time, bruising.

Reproductive system: frequency not known: female infertility.

Immune system: allergic reactions, including uncommon – anaphylaxis (which may be fatal) or anaphylactoid reactions (facial skin discoloration, skin rashes, urticaria, pruritus, tachypnea or dyspnea, eyelid swelling, periorbital edema, shortness of breath, difficulty breathing, chest tightness, wheezing); very rare: severe exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), angioneurotic edema. Such reactions may occur in individuals with a history of angioneurotic edema and bronchospastic reactions (e.g., asthma or nasal polyps).

Sensory organs: uncommon: hearing loss, deafness, tinnitus, visual disturbances, blurred vision; frequency not known: optic neuritis.

General disorders: frequency not known: myalgia, increased sweating; rare: pain, injection site reactions.

Other: common: facial, ankle, finger, foot, and tongue edema, weight gain, anorexia, increased perspiration, fever with or without chills, sepsis.

Laboratory test abnormalities: frequency not known: deviations from normal in liver function tests.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

1 ml in a vial; 5 vials in a blister pack made of film, 1 or 2 blisters per carton.

1 ml in a vial; 10 vials in a cardboard carton with cardboard dividers.

Prescription category. Prescription only.

Manufacturer. JSC "Lubnipharm".

Manufacturer's address and location of business activity.

16 Barvinkova St., Lubny, Poltava region, 37500, Ukraine.