Ambit

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMBIT® (AMBIT)

Composition:

Active substance: ketorolac;

1 ml of solution contains ketorolac tromethamine 30 mg;

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or pale yellow liquid.

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

ATC code M01A B15.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

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

Intravenous administration. After intravenous administration of a single 10 mg dose of ketorolac tromethamine, the mean peak plasma concentration reached 2.4 μg/mL on average at 5.4 minutes after dosing, with a terminal elimination half-life in plasma of 5.1 hours, a mean volume of distribution of 0.15 L/kg, and a total plasma clearance of 0.35 mL/min/kg.

The pharmacokinetics of ketorolac in humans after single or multiple doses are linear. Steady-state plasma concentrations are achieved after dosing every 6 hours over one day. With continuous administration, clearance remains unchanged. The primary route of elimination of ketorolac and its metabolites is renal: 91.4% (on average) of the administered dose is recovered in urine, and 6.1% (on average) is excreted in feces.

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

Clinical characteristics.

Indications.

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

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

Contraindications.

Ketorolac is contraindicated:

• in patients with a history of hypersensitivity reactions to ketorolac, any of the excipients, or to other 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 ulceration, recent gastrointestinal bleeding, peptic ulcer disease, or gastrointestinal perforation;
• as with other NSAIDs, in patients with severe heart failure, hepatic failure, or renal failure;
• 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, during labor and delivery, and during breastfeeding;
• as a prophylactic analgesic prior to 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, in patients with high risk of bleeding or incomplete hemostasis, and in patients with high risk of hemorrhage such as hemorrhagic diatheses, including coagulation disorders;
• in patients receiving anticoagulants, including warfarin and low-dose heparin (2500–5000 units every 12 hours);
• concomitantly 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;
• concomitant treatment with probenecid or lithium salts;
• in patients with complete or partial nasal polyp syndrome, angioedema, or bronchospasm.

Interaction with other medicinal products and other forms of interaction.

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

Medicinal products that must not be taken concurrently with ketorolac

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

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

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

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.

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

Concomitant administration of ketorolac and probenecid resulted in increased plasma levels and half-life (T½) of ketorolac. Therefore, concomitant use of ketorolac and probenecid is contraindicated.

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

When ketorolac and oxpentifylline are administered concomitantly, there is an increased tendency to bleeding.

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

As with all NSAIDs, concomitant use with corticosteroids should be done with caution due to increased risk of gastrointestinal bleeding.

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

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

Ketorolac tromethamine does not alter 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%, demonstrating a potential doubling of unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not affect the plasma protein binding of ketorolac.

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 nephrotoxicity.

As with all NSAIDs, concomitant use of cyclosporine should be done with caution due to increased risk of nephrotoxic effects.

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

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

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

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

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

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

Animal and human studies have provided no evidence that ketorolac tromethamine induces or inhibits liver enzymes involved in the metabolism of ketorolac itself or other drugs. Therefore, it is unlikely that ketorolac would alter the pharmacokinetics of other drugs 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 some other NSAIDs, particularly when used off-label and/or for prolonged periods.

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

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

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

Gastrointestinal ulcers, bleeding, and perforation

Gastrointestinal bleeding, ulcers, or perforation have been reported with all NSAIDs, sometimes fatal, both in patients with and without prior warning signs or history of serious gastrointestinal events.

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

Elderly patients are at increased risk of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal.

The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher doses of NSAIDs, including intravenous ketorolac. The risk is also increased in patients with a prior history of peptic ulcer, especially complicated with bleeding or perforation, and in elderly patients. The risk of clinically significant gastrointestinal bleeding is dose-dependent. Such patients should be initiated on the lowest possible dose. In such cases, and when taking low-dose aspirin or other drugs with increased gastrointestinal risk, concomitant use of gastroprotective agents (e.g., misoprostol or proton pump inhibitors) may be considered. The age-related risk of gastrointestinal bleeding and perforation is common to all NSAIDs. Compared to younger individuals, elderly patients have a prolonged plasma half-life and reduced plasma clearance of ketorolac. A longer dosing interval is recommended.

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. Patients with a history of gastrointestinal disorders, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially early in treatment. If gastrointestinal bleeding or ulceration occurs in a patient receiving intravenous ketorolac, treatment should be discontinued.

Particular caution is required in patients concomitantly taking medications that may increase the risk of ulceration or bleeding, such as corticosteroids, selective serotonin reuptake inhibitors (SSRIs), or antithrombotic agents (e.g., aspirin).

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

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

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.

Effect on hemostasis

Patients with coagulation disorders should not receive ketorolac therapy. Concomitant use of ketorolac in patients receiving anticoagulant therapy may increase the risk of bleeding. There are no detailed studies on the concomitant use of ketorolac with prophylactic low-dose heparin (2500–5000 units every 12 hours) or dextrans; therefore, such regimens may also increase the risk of bleeding. Patients already receiving anticoagulants or requiring low-dose heparin should not receive ketorolac. Close monitoring is required in patients receiving other agents that negatively affect hemostasis when ketorolac is administered. In controlled clinical trials, the incidence of clinically significant postoperative bleeding was less than 1%.

Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding time increased but remained within the normal range of 2–11 minutes. Unlike the prolonged effect after aspirin use, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac.

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

Skin reactions

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

Systemic lupus erythematosus (SLE) and mixed connective tissue disease

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

Fluid/sodium 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 cautiously in patients with cardiac decompensation, hypertension, or similar conditions.

Effect on cardiovascular system and cerebral circulation

Close monitoring is required in patients with arterial hypertension and/or a history of mild to moderate congestive heart failure, as fluid retention and edema have been reported during NSAID therapy.

Clinical and epidemiological studies suggest that the use of COX-2 inhibitors and certain NSAIDs (particularly at high doses) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Although no increase in thrombotic events such as myocardial infarction has been observed with ketorolac therapy, data are insufficient to exclude such risk with ketorolac use.

Ketorolac should be prescribed to patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful assessment of benefits versus risks. Similarly, the appropriateness of ketorolac use in patients at risk for cardiovascular disease (e.g., with hypertension, hyperlipidemia, diabetes, or smokers) should be considered.

Patients with cardiovascular, renal, or hepatic impairment

NSAIDs should be used cautiously in patients with conditions that may lead to reduced blood volume and/or renal blood flow, where renal prostaglandins play a compensatory role in maintaining renal perfusion. In such cases, NSAID use may dose-dependently reduce prostaglandin production and precipitate overt renal failure. The risk is greatest in patients with fluid imbalance due to blood loss or severe dehydration, renal or hepatic impairment, heart failure, elderly patients, and those taking diuretics. Renal function should be monitored in these patients. Usually, the patient's condition returns to pre-treatment levels after discontinuation of NSAIDs. Inadequate correction of fluid/blood loss during surgery, leading to hypovolemia, may cause renal dysfunction, which may be exacerbated by ketorolac. Correction of interstitial fluid volume deficit is necessary; careful monitoring of serum urea and creatinine levels and urine output is required until blood volume is normalized. In patients undergoing renal dialysis, ketorolac clearance is approximately half the normal value, and the terminal half-life is increased approximately threefold.

Effect on kidneys

As with other NSAIDs, ketorolac should be used cautiously in patients with impaired renal function or a history of kidney disease, as it is a potent inhibitor of 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, use of ketorolac or other NSAIDs may dose-dependently reduce prostaglandin production and precipitate overt renal failure. High-risk groups include patients with impaired renal function, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Usually, the patient's condition returns to pre-treatment levels after discontinuation of ketorolac or other NSAIDs.

Additionally, as with other prostaglandin synthesis inhibitors, increases in serum urea, creatinine, and potassium have been reported with ketorolac tromethamine, which may occur after a single dose.

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

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

Elevation of one or more liver function tests may occur. These abnormalities may be transient, remain unchanged, or progress if treatment continues. In controlled clinical trials, less than 1% of patients experienced ALT or AST elevations (more than three times the upper limit of normal). If clinical symptoms indicating hepatic dysfunction or systemic manifestations appear, ketorolac use should be discontinued.

Anaphylactic (anaphylactoid) reactions

Anaphylactic (anaphylactoid) reactions (e.g., anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, angioedema) may occur in patients with known hypersensitivity to aspirin, other NSAIDs, or intravenous ketorolac, as well as in those without prior hypersensitivity reactions. Such reactions may occur in individuals with angioedema, bronchospastic reactions (e.g., asthma), or nasal polyps. Anaphylactoid reactions such as anaphylaxis may be fatal. Therefore, ketorolac is contraindicated in patients with a history of asthma, nasal polyps (complete or partial), angioedema, or bronchospasm.

Safety measures related to fertility

As with other cyclooxygenase/prostaglandin synthesis inhibitors, ketorolac may adversely affect fertility; it is not recommended for women planning pregnancy. Women with fertility issues or undergoing infertility evaluation should discontinue ketorolac.

Fluid retention and edema

Fluid retention, hypertension, and edema have been observed in some patients taking ketorolac; therefore, ketorolac should be used cautiously in patients with cardiac decompensation, hypertension, or similar conditions.

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

Abuse and dependence

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

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

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

Use during pregnancy or breastfeeding.

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

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

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

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

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

Fetal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after several days of ketorolac exposure from the 20th gestational week. Ambit® should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

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

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

• Renal dysfunction (see above);

• In the mother and newborn near term:*

• Prolonged bleeding time due to antiplatelet effects, even at low doses;

• Inhibition of uterine contractility, potentially leading to delayed or prolonged labor.

Therefore, ketorolac is contraindicated in the third trimester of pregnancy.

Breastfeeding

Ketorolac and its metabolites have been shown to cross the placenta and appear in milk in animals. 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, somnolence, 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 or intravenous bolus injection. Intravenous bolus doses should be administered over no less than 15 seconds. Ketorolac must not be used for epidural or spinal administration.

The onset of analgesic effect after injection is similar for both routes and occurs within approximately 30 minutes, with maximum intensity reached within 1–2 hours. The average duration of analgesia is 4–6 hours.

Dosage selection and adjustment should be based on the severity of pain and the individual patient's response to treatment.

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

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

Adults

The recommended initial dose of ketorolac is 10 mg, followed by 10–30 mg every 4–6 hours as needed. In the immediate postoperative period, ketorolac may be administered every 2 hours if necessary. The lowest effective dose should be prescribed. The total daily dose must not exceed 90 mg in younger patients, and 60 mg in elderly patients, patients with renal impairment, and patients weighing less than 50 kg. The maximum duration of treatment must not exceed 2 days.

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

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 sedation caused by opioids. When used in combination with intramuscular/intravenous ketorolac, the daily opioid dose is generally lower than usual. However, opioid-related adverse effects should still be considered, especially in surgical patients.

Elderly Patients

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

Renal Function Impairment

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

Children

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

Overdose

Symptoms

Acute overdose of ketorolac has been associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and transient renal dysfunction, which resolve after discontinuation of the drug.

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

Additional symptoms may include headache, epigastric pain, confusion, agitation, drowsiness, dizziness, tinnitus, and loss of consciousness. Diarrhea and isolated convulsions have also been reported rarely.

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

Treatment

Patients should receive symptomatic and supportive treatment to maintain vital functions following NSAID overdose. There is no specific antidote. Dialysis is not effective in significantly removing ketorolac from blood due to its high plasma protein binding.

If potentially toxic overdose is recognized within the first hour, activated charcoal or gastric lavage may be considered as treatment in adult patients at risk of life-threatening complications.

Adequate diuresis should be maintained. Liver and kidney function should be monitored, and the patient should be observed for at least 4 hours after ingestion of a potentially toxic dose. In cases of recurrent or prolonged seizures, diazepam should be administered. Other therapeutic measures may be applied as appropriate, depending on the patient's clinical condition.

Adverse Reactions

Post-marketing period

The following adverse effects may occur in patients receiving intravenous ketorolac. Frequency is unknown because these are voluntary reports from a population of uncertain size.

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

Infections. Aseptic meningitis (particularly in patients with pre-existing autoimmune disorders such as SLE or mixed connective tissue disease), with symptoms including 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, and anaphylactoid-like reactions, which may be fatal; hypersensitivity reactions such as bronchospasm, flushing, rash, hypotension, and 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. Pathological thinking, depression, insomnia, restlessness, nervousness, psychotic reactions, unusual dreams, hallucinations, euphoria, difficulty concentrating, somnolence.

Confusion and agitation have also been observed.

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

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

Ear and labyrinth disorders. Tinnitus, hearing loss, vertigo.

Renal and urinary system disorders. Acute renal failure, increased frequency of urination, interstitial nephritis, nephrotic syndrome, urinary retention, oliguria, hemolytic-uremic syndrome, flank pain (with or without hematuria, with or without azotemia). As with other inhibitors of prostaglandin synthesis, signs of renal failure, including elevated serum creatinine and potassium levels, have been reported during ketorolac therapy. These may occur after intravenous administration of a single dose of the drug.

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 COX-2 inhibitors and certain NSAIDs (especially at high doses) may be associated with a small increased risk of arterial thrombotic complications (e.g., myocardial infarction or stroke). Although treatment with ketorolac has not shown an increased incidence of thrombotic events such as myocardial infarction, data are insufficient to exclude such risk with ketorolac use.

Reproductive system and breast disorders. Female infertility.

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

Hepatobiliary disorders. Hepatitis, cholestatic jaundice, hepatic failure.

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

In addition, polymorphic erythema and increased photosensitivity have been reported.

Musculoskeletal and connective tissue disorders. Myalgia, functional disorders.

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

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

Investigations. Prolonged bleeding time, elevated blood urea nitrogen (BUN), elevated creatinine, abnormal liver function tests.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

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

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

Incompatibilities.

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

Ambyt® is compatible with normal saline, 5% dextrose solution, Ringer’s solution, lactated Ringer’s solution, and Plasmalyte solution.

Compatibility of ketorolac with other medicinal products is unknown.

Packaging. 1 ml in a vial. 10 vials in a blister; 1 blister in a carton.

5 vials in a blister; 1 or 2 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer’s address and place of business.

74 Kyrylivska St., Kyiv, 04080, Ukraine.