Thoro

INSTRUCTIONS for medical use of the medicinal product TORO (TORO)

Composition:

Active substance: ketorolac;

1 ml of solution contains ketorolac tromethamine 30 mg;

Excipients: sodium chloride; citric acid monohydrate; anhydrous ethanol; water for injections.

Pharmaceutical form. Solution for injection.

Main physical and chemical properties: clear, light yellow solution.

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

ATC code: M01A B15.

Pharmacological Properties.

Pharmacodynamics.

Ketorolac is a potent analgesic agent belonging to the group of nonsteroidal anti-inflammatory drugs (NSAIDs). It is not an opioid and therefore does not affect opioid receptors. The analgesic action of ketorolac is based on its ability to inhibit the synthesis of the enzyme cyclooxygenase, thereby preventing the formation of prostaglandins in body tissues, which contribute to the development of inflammation, fever, and pain. The analgesic dose of ketorolac also exerts anti-inflammatory effects.

Pharmacokinetics.

After intramuscular (i.m.) administration, ketorolac is rapidly and completely absorbed. The mean maximum plasma concentration (Cmax) is 2.2 μg/mL, achieved on average 50 minutes after a single 30 mg dose.

An overview of data on the influence of age, renal and hepatic function on the terminal elimination half-life from plasma and mean total clearance is presented in the table below (obtained after a single i.m. dose of ketorolac 30 mg):

After intravenous (i.v.) administration of 10 mg, the mean maximum plasma concentration of ketorolac (Cmax) is 2.4 µg/mL, which is reached on average 5.4 minutes after administration. The terminal elimination half-life from plasma (t½) is 5.1 hours, the mean volume of distribution is 0.15 L/kg, and the total plasma clearance is 0.35 mL/min/kg.

The pharmacokinetics of ketorolac in adults after single or multiple doses is linear. Steady-state plasma concentrations are achieved within 1 day with administration every 6 hours. Following repeated dosing, clearance remains unchanged. The primary route of excretion of ketorolac and its metabolites is renal: on average, 91.4% of the administered dose is excreted in urine and 6.1% in feces.

More than 99% of ketorolac in plasma is protein-bound over a wide concentration range.

Clinical characteristics.

Indications.

To be used short-term for moderate to severe postoperative pain.

Treatment should only be initiated in a hospital setting. The maximum duration of use is 2 days.

Contraindications.

Ketorolac is contraindicated:

• in patients with a history of hypersensitivity reactions to ketorolac, any of its excipients, or NSAIDs, and in patients with allergic reactions to aspirin or other inhibitors of prostaglandin synthesis (in such patients, severe anaphylactic reactions have been observed). Such reactions include asthma, rhinitis, angioedema, or 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, history of peptic ulcer disease, or gastrointestinal perforation;
• like other NSAIDs, 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, and delivery; during breastfeeding;
• as a prophylactic analgesic before surgery due to inhibition of platelet aggregation, and during surgery due to increased risk of bleeding;
• due to inhibition of platelet function, in patients with suspected or confirmed cerebrovascular hemorrhage, patients at high risk of bleeding or with incomplete hemostasis, and in patients with a high risk of bleeding such as hemorrhagic diatheses, including coagulation disorders;
• in patients receiving anticoagulants, including warfarin and low-dose heparin (2500–5000 units every 12 hours);
• during concomitant therapy with acetylsalicylic acid or other NSAIDs (including selective cyclooxygenase-2 inhibitors);
• for neuraxial (epidural or intrathecal) administration due to alcohol content;
• in combination with oxpentifylline;
• during concomitant therapy with probenecid or lithium salts;
• in patients with complete or partial syndrome of nasal polyps, angioedema, or bronchospasm.

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

Other NSAIDs and aspirin. Ketorolac should not be used with acetylsalicylic acid or other NSAIDs, including selective cyclooxygenase-2 inhibitors, as this may increase the risk of inducing serious adverse effects associated with NSAID use.

Thromboxane. Ketorolac inhibits platelet aggregation, reduces thromboxane concentration, and increases bleeding time. Unlike the prolonged effects of aspirin, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac.

Anticoagulants. Ketorolac is not recommended in combination with anticoagulants such as warfarin, as concomitant use of NSAIDs and anticoagulants may enhance the anticoagulant effect (see section "Contraindications").

Although studies do not indicate a significant degree of interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac and 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.

Lithium. In patients receiving lithium concomitantly with NSAIDs, renal excretion of lithium may be inhibited, leading to increased plasma lithium concentrations. Reports exist of increased plasma lithium concentrations when used concomitantly with ketorolac.

Probenecid. Concomitant use of ketorolac and probenecid is contraindicated, as probenecid reduces plasma clearance and volume of distribution of ketorolac, thereby increasing its plasma concentration and half-life.

Mifepristone. NSAIDs should not be used within 8 to 12 days after the last administration of mifepristone, as NSAIDs reduce its efficacy.

Oxpentifylline. Ketorolac must not be used concomitantly with pentoxifylline, as this increases the risk of bleeding.

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

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

Antihypertensive and diuretic agents. The effects of these drugs may be weakened when used concomitantly with ketorolac. Ketorolac and other NSAIDs may reduce the antihypertensive effects of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-II receptor antagonists, and may increase the risk of renal dysfunction, particularly in patients with reduced blood volume or elderly patients. Therefore, this combination should be prescribed with caution, especially in elderly patients. Close monitoring is required, and renal function should be periodically assessed after initiation and discontinuation of concomitant therapy, particularly when diuretics and ACE inhibitors are used.

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

Methotrexate. Concomitant administration should be done with caution, as some NSAIDs inhibit prostaglandin synthesis, thereby reducing methotrexate clearance and potentially increasing its toxicity.

Cyclosporine. As with all NSAIDs, cyclosporine should be co-administered with caution due to an increased risk of nephrotoxic effects.

Corticosteroids. As with all NSAIDs, corticosteroids should be co-administered with caution due to an increased risk of gastrointestinal ulceration or bleeding (see section "Special precautions").

Quinolones. In patients receiving quinolone derivatives concomitantly, there is an increased risk of seizures.

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

Tacrolimus. NSAIDs may increase the risk of nephrotoxicity.

Zidovudine. Concomitant use of NSAIDs with zidovudine increases the risk of hematological toxicity. There is an increased risk of hematoma development in HIV-infected patients with hemophilia who are treated concomitantly with zidovudine and ibuprofen.

Warfarin, digoxin, salicylates, and heparin.

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

It has been shown that ketorolac use for relief of postoperative pain reduces the need for concomitant opioid analgesics.

Antacids. Do not affect the extent of absorption.

There is no evidence that ketorolac induces or inhibits liver enzymes involved in the metabolism of ketorolac itself or other drugs. Therefore, it is unlikely that ketorolac would alter 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 off-label and/or for prolonged periods (see sections "Indications", "Dosage and administration", and "Contraindications").

The physician should be aware that in some patients, analgesia may occur only 30 minutes or even longer after intravenous or intramuscular administration of the drug.

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

Adverse reactions (ARs) can be minimized by using the lowest effective dose for the shortest possible duration required to control symptoms (see section "Dosage and administration").

Gastrointestinal bleeding, ulceration, and perforation

Gastrointestinal bleeding, ulceration, or perforation have been reported with all NSAIDs, sometimes fatal, both in the presence and absence of warning symptoms or prior serious gastrointestinal events in history.

In an uncontrolled post-marketing observational inpatient study, higher rates of clinically significant gastrointestinal bleeding were observed in patients aged <65 years receiving an average daily dose >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 age-related risk of gastrointestinal bleeding and perforation is common to all NSAIDs. Compared to younger patients, elderly patients have prolonged plasma elimination half-life and reduced plasma clearance of ketorolac. A longer dosing interval is recommended.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including ketorolac, in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), 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 of NSAID. In such cases, and when using low-dose aspirin or other drugs that may increase the risk of gastrointestinal adverse reactions, additional use of gastroprotective agents such as misoprostol or proton pump inhibitors may be considered (see section "Interaction with other medicinal products and other forms of interaction").

Patients with a history of gastrointestinal disorders, particularly elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), especially in the early stages of treatment. If gastrointestinal bleeding or ulceration is diagnosed in a patient taking ketorolac, the drug should be discontinued.

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.

Particular caution is required in patients who are concurrently using drugs that may increase the risk of ulceration and bleeding, such as oral corticosteroids, SSRIs, or antithrombotic agents (e.g., aspirin) (see section "Interaction with other medicinal products and other forms of interaction").

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

As with all NSAIDs, the frequency and severity of gastrointestinal disorders may increase with higher doses and longer duration of ketorolac treatment. 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. The likelihood of serious gastrointestinal complications during ketorolac therapy increases with a history of peptic ulcer disease.

Hematological effects

Ketorolac must not be administered to patients with coagulation disorders. Patients receiving anticoagulants have an increased risk of bleeding when ketorolac is used concomitantly. Detailed studies on the concomitant use of ketorolac with prophylactic low-dose heparin (2500–5000 units every 12 hours), warfarin, and dextrans have 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. Careful monitoring is required in patients receiving any other drugs affecting hemostasis during ketorolac treatment. In controlled clinical trials, the incidence of clinically significant postoperative bleeding was less than 1%.

Ketorolac delays platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding time increases but remains within normal limits (2 to 11 minutes). Unlike the prolonged effect of aspirin, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac.

Postoperative wound bleeding has been reported following immediate parenteral administration of ketorolac during surgery. Therefore, ketorolac must not be administered to patients who have undergone surgery with a high risk of bleeding or in whom hemostasis is incomplete. Caution should be exercised when stable hemostasis is critical, such as in cosmetic or outpatient procedures, prostatectomy, or tonsillectomy. Hematomas, other signs of wound bleeding, and epistaxis may occur with ketorolac use. When prescribing ketorolac, its similarity to other cyclooxygenase-inhibiting NSAIDs 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 (see section "Adverse reactions"). The highest risk of these reactions occurs early in treatment, with most cases appearing within the first month of therapy. Ketorolac use should be discontinued if a rash, mucosal lesions, or any other signs of hypersensitivity appear.

Systemic lupus erythematosus (SLE) and mixed connective tissue disease

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

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 cardiac decompensation, hypertension, or similar conditions.

Effects on the cardiovascular system and cerebral vessels

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

Clinical and epidemiological studies indicate that the use of coxibs and certain NSAIDs (particularly at high doses and long-term) 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 with ketorolac treatment, data are insufficient to exclude such a risk with ketorolac use.

In cases of uncontrolled arterial hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease, ketorolac may be prescribed only after careful assessment of the benefits and risks of its use. A similar assessment is required when long-term treatment with ketorolac is planned in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes, smoking).

Effects on renal function

As with other NSAIDs, ketorolac should be used with caution in patients with impaired renal function or a history of kidney disease, as it inhibits prostaglandin synthesis. Caution is advised, 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 ketorolac or other NSAIDs may dose-dependently reduce prostaglandin production and trigger overt renal failure. At-risk patients include those with impaired renal function, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Usually, after discontinuation of ketorolac or other NSAIDs, the patient's condition returns to the pre-treatment baseline.

Like other prostaglandin synthesis inhibitors, ketorolac may increase serum urea, creatinine, and potassium levels; deviations from normal may occur even after a single dose.

Use in patients with impaired renal function

Since ketorolac and its metabolites are primarily excreted by the kidneys, it must not be administered to patients with moderate to severe renal impairment (serum creatinine >160 µmol/L). Lower doses (no more than 60 mg daily intramuscularly or intravenously) should be used in patients with mild renal impairment, and renal function should be monitored periodically.

Use in patients with impaired hepatic function

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

Elevation of one or more liver function test parameters may occur. These abnormalities may be transient, remain unchanged, or progress if treatment continues. In controlled clinical trials, less than 1% of patients had elevated ALT and AST levels (more than 3 times above normal). If clinical symptoms indicating hepatic dysfunction or visible systemic manifestations occur, ketorolac use should be discontinued.

Anaphylactic (anaphylactoid) reactions

Anaphylactic (anaphylactoid) reactions (such as anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) may occur both in patients with previously identified hypersensitivity to aspirin, other NSAIDs, or intravenous ketorolac, and in those without prior hypersensitivity reactions. Such reactions may occur in individuals with a history of angioedema, bronchospastic reactions (e.g., asthma), or nasal polyps. Anaphylactoid reactions such as anaphylaxis may be fatal. Therefore, ketorolac must not be used in patients with a history of asthma, complete or partial nasal polyp syndrome, angioedema, or bronchospasm (see section "Contraindications").

Fertility-related safety measures

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

Fluid retention and edema

Fluid retention, hypertension, 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.

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

Abuse and drug dependence

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

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

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

Use during pregnancy or breastfeeding

Pregnancy

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

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

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate 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%. This risk is believed to increase with higher doses and longer duration of therapy. Animal studies show that prostaglandin synthesis inhibitors lead to pre- and post-implantation losses and embryonic and fetal death. Additionally, increased incidence of congenital developmental abnormalities, including cardiovascular diseases, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Oligohydramnios/renal dysfunction in the fetus

From the 20th week of pregnancy, the use of ketorolac may cause oligohydramnios due to fetal renal dysfunction.

During pregnancy, all prostaglandin synthesis inhibitors may contribute to the following fetal disorders:

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

• renal dysfunction, which may progress to renal failure with oligohydramnios;

towards the end of pregnancy in the mother and newborn:

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

Approximately 10% of ketorolac crosses the placenta.

Labor and delivery

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

There is an increased likelihood of bleeding in both mother and child (see section "Contraindications").

Breastfeeding

It has been demonstrated that ketorolac and its metabolites cross the placenta and are present in animal milk. Ketorolac has been detected in human breast milk at low concentrations; therefore, it is contraindicated in breastfeeding mothers.

Ability to affect reaction speed when driving or operating machinery

Dizziness, drowsiness, fatigue, visual disturbances, headache, vertigo, insomnia, or depression may occur in some patients after ketorolac administration. If such disorders occur, patients should not drive or operate machinery.

Administration and Dosage

Ketorolac is intended for intramuscular (IM) or bolus intravenous (IV) injection.

Intravenous bolus injections should last no less than 15 seconds. The drug must not be used for epidural or spinal administration.

The onset of analgesic effect is similar following both intramuscular (IM) and intravenous (IV) administration, occurring within approximately 30 minutes. Maximum analgesic intensity is achieved within 1–2 hours. The average duration of analgesia is 4–6 hours.

Dosage selection and adjustments should be based on the intensity of pain and the patient's response to treatment. Adverse reactions may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

The maximum duration of continuous treatment with multiple daily doses of ketorolac administered IM or IV should not exceed 2 days, as prolonged use increases the risk of adverse reactions. There is insufficient experience with long-term use, since most patients are either switched to oral therapy or no longer require analgesic treatment.

Adults

The recommended initial dose of ketorolac tromethamine injection solution is 10 mg, followed by 10–30 mg every 4–6 hours as needed. During the early postoperative period, the drug 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, or patients weighing less than 50 kg. The maximum treatment duration should not exceed 2 days.

The dose should be reduced in patients weighing less than 50 kg.

Concomitant use of opioid analgesics (e.g., morphine, pethidine) may be considered to achieve optimal analgesia during the early postoperative period when pain is most intense. Ketorolac does not interfere with opioid receptor binding and does not potentiate respiratory depression or sedative effects of opioids. When used in combination with parenteral ketorolac, a lower daily dose of opioids is typically required compared to their use alone. However, opioid-related adverse effects should still be considered, especially during minor outpatient surgical procedures.

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

Elderly Patients

In patients aged 65 years and older, the lowest possible dose is recommended. The total daily dose should not exceed 60 mg. Elderly patients are at increased risk of adverse reactions; therefore, the lowest effective dose for the shortest possible duration should be used whenever feasible. During NSAID therapy, gastrointestinal function should be monitored regularly due to the risk of bleeding.

Renal Impairment

The drug is contraindicated in patients with moderate to severe renal impairment. In patients with mild renal impairment, dosage reduction is required (not exceeding 60 mg/day IV or IM).

Children

The safety and efficacy of the drug in pediatric patients have not been established; therefore, ketorolac is not recommended for use in children under 16 years of age.

Overdose

Symptoms and Signs

Acute overdose of ketorolac has led at various times to abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction, which resolved after discontinuation of the drug.

Gastrointestinal bleeding may occur. Arterial hypertension, acute renal failure, respiratory depression, and coma have been reported after NSAID overdose, although such symptoms are rare.

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

Rare cases of diarrhea and isolated seizures have been reported.

Anaphylactoid reactions have also been reported, which may occur even in overdose situations.

Treatment

Patients should receive symptomatic and supportive treatment to maintain vital functions after NSAID overdose. There is no specific antidote. Dialysis does not significantly remove ketorolac from the blood due to its high protein binding. Activated charcoal or gastric lavage may be administered within 1 hour after ingestion of potentially toxic doses as emergency treatment in adult patients with life-threatening overdose.

Additionally, adequate diuresis should be maintained. Patients should be closely monitored for at least 4 hours after ingestion, with regular monitoring of liver and kidney function. In cases of recurrent or prolonged seizures, intravenous diazepam is recommended. Other therapeutic measures may also be applied depending on the patient's clinical condition.

Side effects.

The following adverse reactions may occur in patients receiving ketorolac, injection solution. The frequency is unknown, as these are voluntary reports from a population of uncertain size.

Gastrointestinal disorders.

The most commonly observed adverse reactions are gastrointestinal disturbances. Peptic ulcer, ulcers, gastrointestinal perforation, or gastrointestinal bleeding, sometimes fatal, especially in elderly patients, may occur. Reported events include: nausea, dyspepsia, abdominal pain/discomfort, melena, vomiting of blood, stomatitis, ulcerative stomatitis, eructation, flatulence, esophagitis, gastrointestinal ulcer, rectal bleeding, pancreatitis, dry mouth sensation, feeling of stomach fullness, exacerbation of colitis or Crohn's disease. Gastritis has been observed less frequently.

Infections.

Aseptic meningitis (particularly in patients with existing 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.

Such reactions are possible 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.

Disturbance in thinking, depression, insomnia, anxiety, nervousness, psychotic reactions, unusual dreams, hallucinations, euphoria, difficulty concentrating, somnolence.

Confusion and agitation have been observed.

Nervous system disorders.

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

Eye disorders.

Visual disturbances, blurred vision, neuritis, optic nerve disorders.

Ear and labyrinth disorders.

Tinnitus, hearing loss, dizziness.

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 blood in urine, with or without azotemia). As with other inhibitors of prostaglandin synthesis, signs of renal impairment, including (but not limited to) elevated creatinine and potassium levels, have been reported during ketorolac use, which 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 suggest that the use of coxibs and certain NSAIDs (especially at high doses) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke).

Although an increased frequency of thrombotic events such as myocardial infarction has not been observed during treatment with ketorolac, data are insufficient to exclude such a risk with the use of this drug.

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, angioneurotic edema, sweating, bullous skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare). In addition, erythema multiforme and photosensitivity have been observed.

Musculoskeletal and connective tissue disorders.

Myalgia, functional impairment.

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, increased serum urea and creatinine levels, elevated liver transaminase activity.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

The drug should not be mixed in a small volume (e.g., in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride, or hydroxyzine hydrochloride, as precipitation of ketorolac may occur.

Ketorolac tromethamine is compatible with normal saline, 5% dextrose solution, Ringer's solution, Ringer's lactate solution, or plasma substitutes.

Compatibility of ketorolac with other medicinal products is unknown.

Packaging.

1 ml in a vial; 5 or 10 vials in a box.

Prescription category. Prescription only.

Manufacturer. Aspiro Pharma Limited.

Manufacturer's address and place of business.

Sy.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.