Ketorolac-sopharma

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

Composition:

Active substance: ketorolac tromethamine;

1 ml of injection solution (1 ampoule) contains ketorolac tromethamine 30 mg;

Excipients: ethanol 96%, sodium chloride, sodium hydroxide (1 mol/l), hydrochloric acid (1 mol/l), water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear liquid, practically free from particles.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances. Ketorolac.

ATC code M01A B15.

Pharmacological Properties

Pharmacodynamics

Ketorolac is a potent analgesic of the nonsteroidal anti-inflammatory drug (NSAID) class, possessing analgesic, anti-inflammatory, and antipyretic properties. Ketorolac inhibits the cyclooxygenase enzyme system and thereby suppresses prostaglandin synthesis. Ketorolac is a racemic mixture of [–]S and [+]R enantiomers, with the analgesic activity residing in the S-form. Ketorolac has no significant effect on the central nervous system (CNS) in animals and lacks sedative or anxiolytic properties.

Ketorolac is not an opioid and has no known effect on central opioid receptors. Ketorolac does not cause central respiratory depression and does not potentiate respiratory depression or sedation associated with opioids.

Pharmacokinetics

Absorption

Intramuscular (IM) administration. Ketorolac is rapidly and completely absorbed after IM administration in healthy young adult volunteers, with mean peak plasma concentrations of 2.2–3.0 mg/mL achieved on average within 50 minutes following a single 30 mg dose.

Intravenous (IV) bolus administration. After IV administration of a single 10 mg dose of ketorolac to healthy young adults, the mean peak plasma concentration was 2.4 mg/mL, reached on average within 5.4 minutes.

Continuous intravenous infusion. The mean peak plasma concentration is achieved approximately 5 minutes after completion of an initial 30 mg IV loading dose in healthy young adults, and a continuous infusion at a rate of 5 mg/hour subsequently maintains plasma concentrations within the same range as those achieved after IM administration of 30 mg every 6 hours.

Distribution

The pharmacokinetics of ketorolac are linear after single and repeated doses administered IV, IM, or orally in healthy young adult volunteers. After IV bolus administration every 6 hours to healthy young volunteers, steady-state plasma concentrations are achieved by the fourth dose.

Over 99% of ketorolac in plasma is protein-bound, with a mean volume of distribution of 0.15 L/kg after IV or IM administration of single 10 mg doses in healthy young volunteers. Plasma protein binding is independent of concentration. Since ketorolac is a highly potent drug present in plasma at low concentrations, significant displacement of other drugs is not expected.

Circulating metabolites in plasma consist almost entirely of ketorolac (96%) or p-hydroxyketorolac, which is pharmacologically inactive.

Ketorolac crosses the placenta to approximately 10%. Ketorolac has been detected in breast milk at low concentrations (see section "Special Warnings and Precautions for Use").

Metabolism

Ketorolac is extensively metabolized in the liver. The primary metabolic pathway in humans is conjugation with glucuronic acid. p-Hydroxylation is a minor pathway.

Elimination

The primary route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is recovered in urine, of which about 40% consists of metabolites and 60% is unchanged ketorolac. Approximately 6% of the dose is excreted in feces. The terminal half-life in plasma is approximately 5.3 hours, ranging from 2.4 to 9.2 hours, and total plasma clearance is approximately 0.023 L/h/kg in healthy young adults.

Pharmacokinetics in Special Populations

Elderly patients (≥ 65 years of age). The terminal half-life of ketorolac in plasma is longer in elderly individuals compared to healthy young volunteers, averaging 7 hours (range: 4.3–8.6 hours). Total plasma clearance may be lower than in healthy young volunteers, averaging 0.019 L/h/kg (see sections "Special Warnings and Precautions for Use" and "Dosage and Administration").

Renal impairment. Elimination of ketorolac is reduced in patients with renal impairment, as evidenced by a prolonged plasma half-life and lower total plasma clearance compared to healthy young adults. The volume of elimination of ketorolac decreases proportionally to the degree of renal impairment, except in patients with severe renal impairment, in whom plasma clearance is higher than predicted based solely on the degree of renal impairment (see sections "Contraindications" and "Dosage and Administration").

Hepatic impairment. Clinically significant pharmacokinetic changes of ketorolac have not been observed in patients with hepatic impairment, although a marked prolongation of time to peak and terminal half-life has been observed compared to healthy young volunteers.

Clinical characteristics

Indications. Ketorolac is indicated for short-term management of moderate to severe postoperative acute pain. Treatment should be initiated only under hospital conditions. The maximum duration of treatment is 2 days.

Contraindications.

• Patients with previously confirmed hypersensitivity to ketorolac, to any of the excipients, or to other NSAIDs, as well as patients in whom acetylsalicylic acid or other inhibitors of prostaglandin synthesis induce allergic reactions, such as asthma, rhinitis, angioedema, or urticaria (severe anaphylactic reactions have been observed in such patients).
• Patients concurrently receiving acetylsalicylic acid or other NSAIDs (including selective cyclooxygenase-2 inhibitors).
• Patients with a history of asthma.
• Patients with severe hepatic insufficiency.
• For prophylactic analgesia before surgery due to inhibition of platelet aggregation, and during surgery—due to increased risk of bleeding.
• For neuraxial (epidural or intrathecal) administration due to the presence of ethanol in the solution.
• Patients with complete or partial nasal polyp syndrome, angioedema, or bronchospasm.
• Ketorolac inhibits platelet function and is therefore contraindicated in patients with suspected or confirmed cerebrovascular hemorrhage, patients who have undergone surgical procedures with high risk of hemorrhage or incomplete hemostasis, and patients with a high risk of bleeding, such as those with hemorrhagic diathesis, including coagulation disorders.
• Patients taking anticoagulants, including warfarin and low-dose heparin (2500–5000 units every 12 hours).
• Patients with active peptic ulcer or history of gastrointestinal bleeding, ulcer, or perforation.
• Severe heart failure.
• Patients with moderate or severe renal insufficiency (serum creatinine >160 µmol/L), as well as patients at risk of developing renal insufficiency due to hypovolemia or dehydration.
• Combination of ketorolac with oxpentifylline.
• Concomitant treatment with ketorolac and probenecid or lithium salts.
• During pregnancy, labor, delivery, and lactation (see section "Use in pregnancy or lactation").
• In children under 16 years of age.

Interaction with other medicinal products and other forms of interaction

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

Medicinal products that must not be used concomitantly with Ketorolac-Sofarma

Ketorolac-Sofarma should not be used with acetylsalicylic acid or other NSAIDs, including selective cyclooxygenase-2 inhibitors, as this increases the risk of serious adverse reactions associated with NSAIDs (see section "Contraindications").

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

Ketorolac is contraindicated in combination with anticoagulants such as warfarin, as concomitant use of NSAIDs and anticoagulants may enhance the anticoagulant effect (see section "Contraindications").

Although clinical studies have shown no significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac and therapies affecting hemostasis—including therapeutic doses of anticoagulants (warfarin), low prophylactic doses of heparin (2500–5000 units every 12 hours), and dextran—may be associated with an increased risk of hemorrhage.

During treatment with certain drugs that inhibit prostaglandin synthesis, reduced renal clearance of lithium has been observed, leading to increased lithium plasma concentrations. Several cases of elevated plasma lithium concentrations during ketorolac therapy have been reported.

Probenecid: should not be used concomitantly with ketorolac due to increased plasma concentrations and elimination half-life of ketorolac.

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

Concomitant use of ketorolac and oxpentifylline is associated with increased bleeding tendency.

Medicinal products that should be used with caution concomitantly with Ketorolac-Sofarma

Corticosteroids: caution should be exercised when using NSAIDs concomitantly with corticosteroids due to increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions").

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding when combined with NSAIDs (see section "Special precautions").

It has been reported that some prostaglandin synthesis inhibitors reduce the clearance of methotrexate and thus may increase its toxicity.

Ketorolac does not alter the protein binding of digoxin. In vitro studies have shown that at therapeutic concentrations of salicylate (300 µg/mL), binding to ketorolac decreases from approximately 99.2% to 97.5%, indicating a potential doubling of free ketorolac plasma concentration.

At therapeutic concentrations, digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not alter the protein binding of ketorolac.

Diuretics, angiotensin-converting enzyme inhibitors [ACE inhibitors], and angiotensin II antagonists: NSAIDs may reduce the efficacy of diuretics and antihypertensive agents. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients), concomitant use of ACE inhibitors and/or angiotensin II antagonists with NSAIDs may lead to further deterioration of renal function, with a possible increased risk of acute renal failure, which is usually reversible. The potential for such interactions should be considered when using ketorolac. Therefore, such combinations should be prescribed with caution, especially in elderly patients. Appropriate dose titration should be ensured, and monitoring of renal function after initiation and periodically thereafter should be considered.

Ketorolac injection solution reduces the diuretic response to furosemide by approximately 20% in healthy volunteers; therefore, particular caution is required in patients with heart failure.

Concomitant use with diuretics may lead to reduced diuretic effect and increased risk of NSAID nephrotoxicity.

Cyclosporine: caution should be exercised when using NSAIDs concomitantly with cyclosporine due to increased risk of nephrotoxicity.

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

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

Ketorolac reduces the need for concomitant opioid analgesic therapy when used for postoperative pain relief.

Animal studies indicate that NSAIDs may increase the risk of seizures associated with quinolone antibiotics. Patients receiving NSAIDs and quinolones may have an increased risk of developing seizures.

Zidovudine: NSAIDs used concomitantly with zidovudine increase the risk of hematological toxicity. Data exist on increased risk of hemarthrosis and hematoma in HIV-positive patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.

Studies in animals and humans have not provided evidence that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing medicinal products. Therefore, Ketorolac-Sofarma is not expected to alter the pharmacokinetics of other medicinal products via enzyme induction or inhibition mechanisms.

Special precautions for use

Epidemiological data suggest that ketorolac may be associated with a higher risk of serious gastrointestinal toxicity compared to other NSAIDs, particularly when used outside the approved indications and/or for prolonged periods (see sections "Indications", "Contraindications", and "Dosage and administration").

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Dosage and administration" and information on gastrointestinal and cardiovascular risks below).

Concomitant use of ketorolac with other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, is contraindicated (see section "Contraindications").

Ketorolac should be used only for the approved therapeutic indications (see section "Indications") and at the recommended dose (see section "Dosage and administration").

Clinicians should be aware that in some patients, pain relief may occur only after 30 minutes following intravenous or intramuscular administration.

Gastrointestinal bleeding, ulceration, and perforation

Gastrointestinal bleeding, potentially fatal ulcers, and gastrointestinal tract perforation have been reported with all NSAIDs, including ketorolac, occurring at various stages of treatment and not always associated with warning symptoms or a history of serious gastrointestinal disease.

In a hospital-based non-randomized post-marketing study, an increased frequency of clinically significant gastrointestinal bleeding was observed in patients under 65 years of age receiving an average daily dose of >90 mg ketorolac intramuscularly compared to patients receiving parenteral opioids.

In elderly patients, the frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, is increased and may be fatal (see section "Dosage and administration").

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

The risk of bleeding, ulceration, or perforation is higher when higher doses of NSAIDs are used, particularly with intravenous ketorolac, in patients with a history of peptic ulcer disease, especially if complicated by bleeding or perforation (see section "Contraindications"), and in elderly patients. Patients should inform their physician about abdominal symptoms and gastrointestinal bleeding, particularly in the early stages of treatment.

In patients at risk of gastrointestinal complications, treatment should be initiated at the lowest possible dose. Consideration should be given to concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors) for these patients, as well as for those requiring concomitant low-dose acetylsalicylic acid or other agents that increase the risk of gastrointestinal ulceration or bleeding, such as corticosteroids, selective serotonin reuptake inhibitors, or antiplatelet agents (see section "Interaction with other medicinal products and other forms of interaction"). Use in patients taking anticoagulants such as warfarin is contraindicated (see section "Contraindications").

The age-related risk of gastrointestinal bleeding and perforation described is characteristic of all NSAIDs. Compared to younger individuals, elderly people have reduced plasma half-life and clearance of ketorolac. A longer interval between doses is recommended (see section "Dosage and administration").

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

NSAIDs 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 toxicity, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly in the early stages of treatment. If gastrointestinal bleeding or ulceration occurs in patients receiving intravenous ketorolac, treatment should be discontinued.

Hematological effects

Ketorolac-Sofarma should not be used in patients with coagulation disorders.

Ketorolac inhibits platelet aggregation, reduces thromboxane concentration, and prolongs bleeding time. In patients with normal platelet function, bleeding time was prolonged but remained within the normal range of 2 to 11 minutes. Unlike the prolonged effect of acetylsalicylic acid, the inhibitory effect on platelet function disappears within 24–48 hours after discontinuation of ketorolac.

Patients receiving anticoagulant therapy have an increased risk of bleeding if ketorolac is used concomitantly. Patients already taking anticoagulants or requiring low-dose heparin should not take ketorolac. Ketorolac should be used with caution and under strict monitoring in patients with coagulation disorders. Although clinical studies have not shown a significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac with treatments affecting hemostasis, low prophylactic doses of heparin (2500–5000 units every 12 hours), and dextran may increase the risk of hemorrhage. In controlled clinical trials, the incidence of clinically significant postoperative bleeding was less than 1%.

Post-marketing use of ketorolac has been associated with hematoma at surgical incision sites and other signs of bleeding related to ketorolac use in the postoperative period. Therefore, ketorolac should not be used in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis. Clinicians should be aware of the potential bleeding risk when hemostasis is critical, such as in prostatectomy, tonsillectomy, aesthetic surgery, day surgery, or other conditions (see section "Contraindications").

Hematomas, other signs of wound bleeding, and epistaxis have been reported with ketorolac use. Clinicians should be aware of the pharmacological similarity of ketorolac to other cyclooxygenase-inhibiting NSAIDs and the risk of bleeding, especially in elderly patients.

Cardiovascular and cerebrovascular effects

There have been reports of fluid retention and edema associated with NSAID therapy. Therefore, ketorolac should be used with caution in patients with a history of arterial hypertension and/or mild to moderate congestive heart failure: such patients should be adequately monitored and advised.

Clinical trials and epidemiological data suggest that the use of coxibs and certain NSAIDs (particularly at high doses) slightly increases the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). There are insufficient data to exclude the risk of such effects with ketorolac use.

Ketorolac should be used in patients with uncontrolled severe hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful evaluation. The same precautions should be taken before initiating treatment in patients with cardiovascular risk factors (e.g., arterial hypertension, hyperlipidemia, diabetes mellitus, smoking).

Sodium/fluid retention in cardiovascular disease and peripheral edema

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

Fluid retention, arterial hypertension, and peripheral edema have been observed in some patients taking NSAIDs, including ketorolac; therefore, it should be used with caution in patients with cardiac decompensation, arterial hypertension, or similar conditions.

Cardiovascular, renal, and hepatic disorders

Caution is advised when treating patients with conditions leading to reduced blood volume and/or renal blood flow, where renal prostaglandins play a supportive role in maintaining renal perfusion. In these patients, NSAID use may cause dose-dependent reduction in renal prostaglandin production and may trigger overt renal failure. The greatest risk for this reaction is in patients with reduced blood volume due to blood loss or severe dehydration, patients with impaired renal function, heart failure, hepatic dysfunction, elderly patients, and those taking diuretics. Renal function should be monitored in these patients. Discontinuation of NSAID therapy is usually followed by recovery to the pre-treatment state. Inadequate fluid/blood replacement during surgery, leading to hypovolemia, may result in renal dysfunction, which may be exacerbated by ketorolac use. Therefore, blood volume deficit should be corrected, and close monitoring of serum urea and creatinine levels and diuresis is recommended until normovolemia is established. In patients undergoing renal dialysis, ketorolac clearance is reduced to about half the normal level, and terminal half-life is increased approximately threefold (see section "Contraindications").

Renal effects

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. Since renal toxicity has been observed with ketorolac and other NSAIDs, caution is recommended when using ketorolac in patients with conditions causing reduced blood volume and/or renal blood flow, as in these situations renal prostaglandins play a supportive role in maintaining renal perfusion. In these patients, use of ketorolac or other NSAIDs may reduce, in a dose-dependent manner, prostaglandin synthesis in the kidneys and trigger decompensation or renal failure. Patients at increased risk of this reaction include those with impaired renal function, hypovolemia, heart failure, hepatic insufficiency, patients taking diuretics, and elderly patients (see section "Contraindications").

Recovery to the pre-treatment state usually occurs after discontinuation of ketorolac or another NSAID.

Elevations in serum urea, creatinine, and potassium levels have been reported with drugs that inhibit prostaglandin synthesis, including ketorolac tromethamine, and may occur after a single dose.

Patients with impaired renal function: Since ketorolac tromethamine and its metabolites are primarily excreted by the kidneys, ketorolac should not be used in patients with moderate to severe renal impairment (serum creatinine level >160 µmol/L). Patients with mild renal insufficiency require a reduced dose of ketorolac (not exceeding 60 mg/day intramuscularly or intravenously) and careful monitoring of renal function.

Patients with impaired hepatic function: In patients with hepatic impairment due to cirrhosis, no clinically significant changes in ketorolac clearance or terminal half-life have been observed.

Mild elevations in one or more liver function parameters may occur. These abnormalities may be transient, remain unchanged, or progress with continued therapy. Marked elevations (more than three times the upper limit of normal) in serum glutamate-pyruvate transaminase (SGPT/ALT) or serum glutamate-oxaloacetate transaminase (SGOT/AST) were observed in less than 1% of patients in controlled clinical trials. If clinical signs and symptoms of liver disease develop or systemic manifestations occur, ketorolac should be discontinued.

Anaphylactic (anaphylactoid) reactions

Anaphylactic (anaphylactoid) reactions (anaphylaxis, bronchospasm, flushing, exanthema, hypotension, laryngeal edema, angioedema, etc.) may occur in patients regardless of a history of hypersensitivity to acetylsalicylic acid, other NSAIDs, or intravenous ketorolac. These reactions may also occur in individuals with a history of angioedema, bronchospastic reactions (e.g., asthma), and nasal polyps. Anaphylactoid reactions such as anaphylaxis may be fatal. Therefore, ketorolac should not be used in patients with a history of asthma or in patients with partial or complete nasal polyp syndrome, angioedema, and bronchospasm (see section "Contraindications").

Skin reactions

Very rarely, severe skin reactions, sometimes fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and toxic epidermal necrolysis, have been reported with NSAID use (see section "Adverse reactions"). The risk of these reactions is highest at the beginning of treatment, and in most cases, these reactions occur 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 (SLE) and mixed connective tissue diseases

Patients with SLE and mixed connective tissue diseases have an increased risk of aseptic meningitis (see section "Adverse reactions").

Fertility-related warnings

Use of ketorolac, like any cyclooxygenase/prostaglandin synthetase inhibitor, may impair fertility and is not recommended for women attempting to conceive.

Consideration should be given to discontinuing ketorolac treatment in women experiencing difficulty conceiving or undergoing infertility evaluation.

Abuse of psychoactive substances / dependence

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

Caution is advised when using ketorolac concomitantly with methotrexate, as some prostaglandin synthesis inhibitors are known to reduce methotrexate clearance, potentially increasing its toxicity (see section "Interaction with other medicinal products and other forms of interaction").

The medicinal product contains 100 mg of ethanol (alcohol) per 1 ml of injection solution, i.e., 100 mg/dose, equivalent to 2.54 ml of beer and 1.06 ml of wine per dose. Harmful for patients with alcoholism. Caution is advised when used in pregnant women, nursing mothers, children, patients with liver disease, and patients with epilepsy.

The medicinal product contains less than 1 mmol (23 mg)/dose (1 ml of injection solution) of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. Due to the known effects of NSAIDs on the fetal cardiovascular system (risk of arterial duct closure), ketorolac is contraindicated during pregnancy, labor, and delivery (see section "Contraindications").

The safety of ketorolac during pregnancy has not been established. No evidence of teratogenicity was found in rats and rabbits administered ketorolac at maternally toxic doses. In rats, prolonged gestation and/or delayed delivery were observed. Congenital anomalies have been reported in association with NSAID use in humans, although they are rare and do not show a clear pattern.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryofetal development. Epidemiological data suggest an increased risk of miscarriage, cardiac malformations, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformations increased from less than 1% to approximately 1.5%. It is assumed that the risk increases with increasing dose and duration of treatment. Administration of prostaglandin synthesis inhibitors to animals results in increased pre- and post-implantation loss and embryofetal mortality. Furthermore, in animals receiving prostaglandin synthesis inhibitors during the organogenetic period, an increased frequency of various developmental abnormalities, including cardiovascular, has been reported.

Approximately 10% of ketorolac crosses the placental barrier.

Oligohydramnios / renal dysfunction in newborns

From the 20th week of pregnancy, use of ketorolac may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible upon discontinuation of treatment. Additionally, reports of arterial duct constriction after second-trimester treatment have been reported, which in most cases resolved after treatment cessation.

Therefore, ketorolac is contraindicated during pregnancy, labor, delivery, and lactation.

If a woman attempting to conceive takes ketorolac, the dose should be as low as possible and the duration of treatment as short as possible.

During pregnancy, all prostaglandin synthesis inhibitors may cause risks:

for the fetus:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction (see above);

for the mother at the end of pregnancy and for the newborn:

• possible prolongation of bleeding time, antiaggregant effect, which may occur even at very low doses;
• inhibition of uterine contractions, leading to delayed or prolonged labor.

Labor and delivery. Ketorolac is contraindicated during labor and delivery because, due to its inhibitory effect on prostaglandin synthesis, it may negatively affect fetal circulation and inhibit uterine contractions, increasing the risk of uterine bleeding.

Increased bleeding tendency may occur in both mother and child (see section "Contraindications").

Breastfeeding. Ketorolac and its metabolites cross the placenta and are excreted in animal milk. Ketorolac has also been detected at low concentrations in human breast milk; therefore, it is contraindicated in nursing mothers.

Fertility. Warnings regarding female fertility are provided in the "Special precautions for use" section.

Ability to affect reaction speed when driving vehicles or operating machinery. In some patients, use of ketorolac may be associated with somnolence, dizziness, vertigo, headache, fatigue, visual disturbances, insomnia, or depression. If a patient experiences such or similar adverse effects, they should not drive a vehicle or operate machinery.

Method of Administration and Dosage

Dosing

The time to onset of analgesic effect is the same for both intravenous (IV) and intramuscular (IM) administration and is approximately 30 minutes, with maximum analgesia occurring within 1–2 hours. The average duration of analgesia is typically 4 to 6 hours.

Dosage should be adjusted according to the severity of pain and the patient's response.

Continuous multiple-dose administration of ketorolac via IM or IV route should not exceed two days, as adverse effects may increase with prolonged use. Experience with long-term use of the drug is limited, since the majority of patients either switch to oral medications or no longer require analgesic therapy after this period.

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Adults

The recommended initial dose of Ketorolac-Sofarma is 10 mg, followed by 10–30 mg every 4–6 hours as needed. In the immediate postoperative period, Ketorolac-Sofarma may be administered every 2 hours if necessary. The smallest effective dose should be used. The total daily dose must not exceed 90 mg. For elderly patients, patients with impaired renal function, and patients with body weight less than 50 kg, the total daily dose must not exceed 60 mg. The maximum duration of treatment is 2 days.

Opioid analgesics (e.g., morphine, pethidine) may be used concomitantly and may be required to achieve optimal analgesia in the early postoperative period when pain is most intense. Ketorolac does not interfere with opioid binding and does not potentiate opioid-induced respiratory depression or sedation. When used concomitantly with Ketorolac-Sofarma via IV or IM administration, a lower daily dose of opioid is usually required. However, opioid-related adverse effects should still be considered, especially in the setting of same-day surgery.

Elderly Patients

Elderly individuals are at increased risk of serious adverse reactions. If NSAIDs are considered necessary, the lowest effective dose should be used for the shortest possible duration. Patients should be monitored regularly for gastrointestinal bleeding during NSAID therapy. The total daily dose must not exceed 60 mg (see section "Special Warnings and Precautions for Use").

Pediatric Population

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

Renal Impairment

The drug is contraindicated in moderate to severe renal impairment; in mild renal impairment, the dose should be reduced (not exceeding 60 mg/day via IV or IM) (see section "Contraindications").

Method of Administration

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

Children. The drug is contraindicated in children under 16 years of age, as safety and efficacy in children have not been established.

Overdose

Symptoms. Acute overdose of ketorolac is associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcer and/or erosive gastritis, and renal dysfunction, which resolve after discontinuation of the drug.

Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression, and coma may occur after NSAID overdose, but are rare.

Other symptoms include headache, epigastric pain, disorientation, agitation, drowsiness, dizziness, tinnitus, and loss of consciousness.

Rare cases of diarrhea and accidental seizures have also been reported.

Anaphylactoid reactions associated with therapeutic use of NSAIDs may also occur in overdose.

Treatment. Symptomatic and supportive treatment should be provided following NSAID overdose. There are no specific antidotes. Dialysis does not significantly remove ketorolac from the blood.

Within one hour after ingestion of a potentially toxic amount of the drug orally (swallowed), administration of activated charcoal may be beneficial. In addition, gastric lavage should be considered in adults within one hour after ingestion of a potentially life-threatening dose.

Adequate urinary output should be maintained. Renal and hepatic function must be closely monitored.

Patients should be observed for at least 4 hours after ingestion of a potentially toxic amount of the drug. Frequent or prolonged seizures should be treated with intravenous diazepam. Other interventions may be indicated depending on the patient's clinical condition.

Adverse Reactions

Below is a list of adverse reactions that may occur in patients receiving intravenous ketorolac; the frequency of occurrence is unknown, as reports of adverse reactions were voluntarily submitted by consumers, and the number of such reports is undefined.

Gastrointestinal disorders: Gastrointestinal adverse reactions are the most commonly observed: peptic ulcer, ulceration, perforation, or gastrointestinal hemorrhage (sometimes fatal), particularly in elderly patients (see section "Special Warnings and Precautions for Use"). Nausea, dyspepsia, vomiting, hematemesis, eructation, esophagitis, gastrointestinal ulceration, abdominal pain, diarrhea, constipation, melena, stomatitis, ulcerative stomatitis, rectal bleeding, pancreatitis, dry mouth, flatulence, and exacerbation of colitis or Crohn's disease have been reported following administration of this medicinal product (see section "Special Warnings and Precautions for Use"). Gastritis has been observed less frequently.

Hepatobiliary disorders: Hepatitis, cholestatic jaundice, hepatic failure.

Renal and urinary 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). As with other medicinal products that inhibit prostaglandin synthesis in the kidneys, single intravenous administration of ketorolac may be associated with signs of renal impairment, including elevated serum creatinine and potassium levels.

Reproductive system and breast disorders: Female infertility.

Metabolism and nutrition disorders: Anorexia, hyperkalemia, hyponatremia.

Blood and lymphatic system disorders: Thrombocytopenia. Purpura, neutropenia, agranulocytosis, aplastic anemia, and hemolytic anemia have also been observed.

Immune system disorders: Anaphylaxis, anaphylactoid reactions. Anaphylactoid reactions, such as anaphylaxis, may be fatal. Hypersensitivity reactions, for example: bronchospasm attacks, skin rash, hypotension, laryngeal edema. These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g., asthma and nasal polyps).

Skin and subcutaneous tissue disorders: Exfoliative dermatitis, maculopapular rash, pruritus, urticaria, purpura, angioedema, sweating. Bullous reactions, including Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and toxic epidermal necrolysis (very rare). In addition, cases of erythema multiforme and photosensitivity have been observed.

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

Cardiac disorders: Palpitations, bradycardia, heart failure.

Vascular disorders: Arterial hypertension, hypotension, hematoma, hyperemia, pallor, postoperative wound bleeding.

Clinical studies and epidemiological data suggest that the use of selective COX-2 inhibitors (coxibs) and certain NSAIDs (particularly at high doses) may be associated with a slightly increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Although ketorolac has not demonstrated an increased incidence of thrombotic complications such as myocardial infarction, there is insufficient data to exclude this risk with ketorolac use.

Aural and labyrinthine disorders: Tinnitus, hearing loss, vertigo.

Eye disorders: Visual disturbances, visual disorders, optic neuritis.

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

Psychiatric disorders: Cognitive disturbances, depression, insomnia, anxiety, restlessness, psychotic reactions, unusual dreams, hallucinations, euphoria, difficulty concentrating, somnolence. Confusion and excitement have also been observed.

Musculoskeletal and connective tissue disorders: Myalgia, functional disorders.

Infections: Aseptic meningitis (particularly in patients with autoimmune disorders such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as nuchal rigidity, headache, nausea, vomiting, fever, or disorientation (see section "Special Warnings and Precautions for Use").

General disorders and administration site conditions: Intense thirst, asthenia, edema, injection site reactions and pain, fever, chest pain. Malaise, fatigue, and weight gain have also been observed.

Laboratory investigations: Prolonged bleeding time, increased serum urea nitrogen, elevated creatinine levels, liver function test abnormalities.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions. Keep out of reach and sight of children.

This medicinal product does not require special storage conditions.

Incompatibilities. Ketorolac injection solution is compatible with 0.9% sodium chloride solution, 5% glucose solution, Ringer's lactate solution, Ringer's solution, and Plasmalyte solution.

Packaging. 1 ml of injection solution in a vial made of brown glass.

5 or 10 vials per PVC blister; 1 blister per cardboard pack.

Prescription status. Prescription only.

Manufacturer. JSC "Sofarma".

Manufacturer’s address and location of business activity

16 Iliensko Shose Str., Sofia, 1220, Bulgaria.