INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOROLAC GRINDEKS (KETOROLAC GRINDEKS)

Composition:

Active substance: ketorolac;

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

Excipients: sodium chloride, ethanol (96%), disodium edetate, 5 M sodium hydroxide solution / 5 M hydrochloric acid solution to adjust pH to 6.9–7.9, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear yellowish liquid.

Pharmacotherapeutic group.

Non-steroidal anti-inflammatory and antirheumatic drugs; acetic acid derivatives and related substances.

ATC code M01AB15.

Pharmacological Properties

Pharmacodynamics

Ketorolac tromethamine is a potent analgesic agent belonging to the group of nonsteroidal anti-inflammatory drugs. 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. As a result, prostaglandins, which promote inflammation, fever, and pain, are not formed in the body's tissues. When used at doses providing analgesia, ketorolac exerts minimal anti-inflammatory effects. The biologically active form of ketorolac is the S-enantiomer.

It does not possess sedative or anxiolytic effects.

Pharmacokinetics

Absorption and Distribution

After intramuscular administration, ketorolac tromethamine is rapidly and completely absorbed. The mean maximum plasma concentration (Cmax) is 2.2 μg/mL, reached approximately 50 minutes after a single 30 mg dose. In healthy volunteers, the total clearance is 0.023 L/hr/kg, and the elimination half-life is 5.3 hours.

After intravenous administration of 10 mg, the mean maximum plasma concentration (Cmax) of ketorolac is 2.4 μg/mL, reached on average within 5.4 minutes after administration. The terminal elimination half-life (t½) from plasma 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 are linear. Steady-state plasma concentrations are achieved within one day when ketorolac tromethamine is administered every 6 hours. Following repeated dosing, clearance remains unchanged.

The extent of plasma protein binding of ketorolac averages 99.2% and is independent of concentration. Ketorolac poorly crosses the blood-brain barrier. It crosses the placental barrier and is excreted in small amounts into breast milk.

Metabolism and Excretion

Ketorolac and its metabolites are primarily eliminated via the kidneys: on average, 91.4% of the administered dose is excreted in urine and 6.1% in feces.

Special Patient Groups

In elderly patients and patients with renal impairment, the total clearance of the drug is reduced and the elimination half-life is prolonged.

Clinical characteristics.

Indications.

Used short-term for moderate to severe postoperative pain.

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

Contraindications.

Hypersensitivity to the active substance or to any component of the medicinal product, or to other NSAIDs (non-steroidal anti-inflammatory drugs);
allergic reactions to acetylsalicylic acid or other inhibitors of prostaglandin synthesis, which cause allergic reactions that may manifest as asthma, rhinitis, angioneurotic edema, or urticaria (severe, anaphylaxis-like reactions are observed);
history of bronchial asthma;
complete or partial syndrome of nasal polyps, angioneurotic edema, or bronchospasm;
active peptic ulcer or gastrointestinal bleeding, history of ulcer or perforation;
severe heart failure, severe renal failure, or hepatic failure;
moderate or severe renal function impairment (serum creatinine > 160 μmol/L);
hypovolemia or dehydration of any origin;
use of acetylsalicylic acid;
concomitant therapy with other NSAIDs, pentoxifylline, probenecid, or lithium salts;
use of anticoagulants (e.g., warfarin), even low-dose (2500–5000 IU every 12 hours) heparin;
cerebrovascular hemorrhage or suspicion of cerebrovascular hemorrhage;
recent surgical procedure with high risk of bleeding or hemostasis disorders;
hemorrhagic diathesis, including coagulation disorders;
during pregnancy, childbirth, and breastfeeding;
in children and adolescents under 16 years of age.

Ketorolac is contraindicated for prophylactic use before surgical procedures, as it inhibits platelet aggregation; it is also contraindicated during surgery due to increased risk of bleeding.

Ketorolac injection solution is contraindicated for epidural or intrathecal administration because it contains ethyl alcohol.

Interaction with other medicinal products and other types of interactions.

Medicinal products that must not be taken concurrently with Kеторолак Гріндекс

Other NSAIDs and aspirin

Ketorolac must not be taken with other NSAIDs or aspirin, as adverse reactions may be intensified (see section "Contraindications").

Anticoagulants

Concomitant use with NSAIDs increases the risk of bleeding. NSAIDs may enhance the effect of anticoagulants, such as warfarin (see sections "Contraindications" and "Special precautions").

Concomitant use of ketorolac and prophylactic low-dose heparin (2500–5000 IU every 12 hours) has not been widely studied but may be associated with an increased risk of bleeding. Ketorolac must not be administered to patients receiving anticoagulants or low-dose heparin.

Probenecid

Ketorolac must not be used with probenecid, as it slows the elimination of ketorolac and increases its plasma concentration (see section "Contraindications").

Pentoxifylline

Ketorolac must not be taken concurrently with pentoxifylline, as it increases the risk of bleeding (see section "Contraindications").

Lithium

Concomitant use with ketorolac may inhibit renal clearance of lithium, increase plasma lithium concentration, and increase lithium toxicity (see section "Contraindications").

Mifepristone

NSAIDs are not recommended from eight to twelve days after discontinuation of mifepristone, as NSAIDs may reduce its effect.

Medicinal products that should be used with caution in combination with Kеторолак Гріндекс

Antithrombotic agents and selective serotonin reuptake inhibitors (SSRIs)

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

Thrombolytic agents

Concomitant use with NSAIDs increases the risk of bleeding.

Corticosteroids

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

Antihypertensive and diuretic agents

The effect of these medicinal products may be reduced when used concomitantly with ketorolac. Ketorolac and other NSAIDs may reduce the antihypertensive effect of beta-blockers, ACE inhibitors (angiotensin-converting enzyme inhibitors), and angiotensin-II receptor antagonists, and may increase the risk of renal dysfunction; this is particularly relevant in patients with reduced blood volume or elderly patients. Therefore, this combination should be prescribed with caution, especially in elderly patients. Patients should be closely monitored, and renal function should be periodically assessed after initiation and discontinuation of concomitant therapy, particularly when diuretics and ACE inhibitors are used.

Concomitant use with diuretic agents may reduce diuretic efficacy and increase the risk of NSAID nephrotoxicity (see section "Special precautions").

Furosemide

In healthy volunteers with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%; therefore, special attention is required when prescribing ketorolac to patients with cardiac decompensation.

Cardiac glycosides

NSAIDs, when taken concomitantly with cardiac glycosides, may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma concentrations of cardiac glycosides.

Methotrexate

Since NSAIDs may impair kidney function and thus reduce methotrexate clearance, methotrexate toxicity may increase.

Cyclosporine

As with other NSAIDs, concomitant use with cyclosporine requires caution due to increased risk of nephrotoxicity.

Tacrolimus

NSAIDs may increase the risk of nephrotoxicity.

Antibacterial agents

In patients receiving quinolone group agents, the risk of seizures is increased.

Antiviral agents

Concomitant use with zidovudine increases the risk of hematological toxicity; ritonavir may increase plasma concentrations of NSAIDs.

Antiepileptic agents

NSAIDs may potentiate the effect of phenytoin.

Antidiabetic agents

NSAIDs may potentiate the effect of sulfonylurea derivatives.

Muscle relaxants

NSAIDs may reduce the elimination of baclofen (increasing the risk of toxicity).

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

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

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 medications.

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

Special precautions.

The physician should be aware that in some patients, pain may not be reduced within 30 minutes or even longer after parenteral administration of the drug.

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

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

Use in elderly patients

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

The increased risk associated with age is characteristic of all NSAIDs. Compared to younger patients, these patients have a prolonged elimination half-life from plasma and reduced plasma clearance. Therefore, elderly patients should not be prescribed a total daily dose exceeding 60 mg (see section "Dosage and administration").

Gastrointestinal (GI) bleeding, ulceration, and perforation

Reports of gastrointestinal bleeding, ulceration, and perforation (including fatal cases) have been associated with all NSAIDs. Reports indicate that these adverse reactions may occur regardless of the duration of NSAID use. Warning signs may be present or absent, and adverse reactions may occur in patients without prior gastrointestinal disorders.

Epidemiological data suggest that, compared to some other NSAIDs, the use of ketorolac (especially off-label and/or prolonged use) may be associated with an increased risk of gastrointestinal disorders (see sections "Indications", "Dosage and administration", and "Contraindications").

The risk of gastrointestinal bleeding, ulceration, and perforation increases with higher doses of NSAIDs. The risk of these adverse reactions is higher in patients with a history of peptic ulcer, especially if complications such as bleeding or perforation have occurred (see section "Contraindications"), as well as in elderly patients. The risk of severe gastrointestinal bleeding depends on the dosage of the drug. Treatment in such patients should begin with the lowest possible NSAID dose. In these cases, as well as when using low-dose aspirin or other drugs that may increase the risk of gastrointestinal adverse reactions, careful consideration should be given to combining NSAIDs with gastroprotective agents such as misoprostol or a proton pump inhibitor (see section "Interaction with other medicinal products and other forms of interaction").

Patients (especially elderly) with diagnosed gastrointestinal disorders in their history should report any abdominal symptoms (particularly gastrointestinal bleeding). These symptoms should be closely monitored at the beginning of treatment.

Caution should be exercised in patients who are concurrently using drugs that may increase the risk of ulceration and bleeding, such as oral corticosteroids, selective serotonin reuptake inhibitors, or antithrombotic agents (e.g., aspirin) (see section "Interaction with other medicinal products and other forms of interaction").

The use of ketorolac in patients taking anticoagulants (e.g., warfarin) is contraindicated.

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

Patients with diagnosed gastrointestinal diseases in their history (ulcerative colitis, Crohn's disease) should use NSAIDs cautiously, as disease exacerbation is possible (see section "Adverse reactions").

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

Anaphylactic (anaphylactoid) reactions

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

Effects on renal function

Drugs that inhibit prostaglandin biosynthesis (including NSAIDs) have been reported to enhance nephrotoxicity and cause glomerulonephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, and acute renal failure.

Caution should be exercised in patients with impaired renal, cardiac, or hepatic function, as NSAID use may worsen renal function. Like other prostaglandin synthesis inhibitors, ketorolac may increase serum urea, creatinine, and potassium ion levels; deviations from normal may occur even after a single dose.

Since ketorolac and its metabolites are primarily excreted by the kidneys, it should not be administered to patients with moderate to severe renal impairment (serum creatinine >160 µmol/L) (see section "Contraindications"). Patients with mild renal impairment should receive lower doses (no more than 60 mg daily intramuscularly or intravenously) and have their renal function monitored periodically.

Caution should be exercised in patients in whom disease may lead to reduced blood volume and/or renal blood flow, where prostaglandins play an important role in maintaining perfusion. In such patients, NSAID use may cause dose-dependent inhibition of prostaglandin synthesis and renal failure. Patients at increased risk include those 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. After discontinuation of NSAID therapy, patients' condition usually normalizes. Inadequate fluid/blood transfusion during surgery followed by hypovolemia may cause renal dysfunction exacerbated by ketorolac administration. Correction of reduced extracellular fluid volume is required; careful monitoring of serum urea and creatinine levels and observation of urine output are necessary until blood volume is normalized. In patients undergoing renal dialysis, ketorolac clearance is approximately half the normal value, and the terminal elimination half-life is prolonged by about three times.

Effects on hepatic function

In patients with hepatic impairment due to cirrhosis, ketorolac clearance and terminal elimination 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 elevated ALT and AST levels (more than three times above normal). If clinical symptoms indicating hepatic dysfunction or systemic manifestations appear, ketorolac use should be discontinued.

Cardiovascular and cerebrovascular effects

Reports indicate an association between NSAID use and fluid retention and edema. Therefore, appropriate monitoring and consultation are required for patients with diagnosed arterial hypertension and/or mild to moderate congestive heart failure.

Clinical trials and epidemiological data suggest that the use of some NSAIDs (especially at high doses and for prolonged periods) may be associated with a slightly increased risk of arterial thrombosis (e.g., myocardial infarction or stroke). There are insufficient data 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 necessity of use. Such an assessment is also required when initiating long-term treatment in patients with cardiovascular risk factors (such as arterial hypertension, hyperlipidemia, diabetes, smoking).

Hematological effects

Ketorolac should not be prescribed to patients with coagulation disorders. The risk of bleeding is increased in patients taking anticoagulants when ketorolac is used concomitantly. Concomitant use of ketorolac and prophylactic low-dose heparin (2500–5000 IU every 12 hours) has not been widely studied but may be associated with an increased risk of bleeding. Ketorolac should not be administered to patients taking anticoagulants or receiving low-dose heparin (see section "Contraindications"). Careful monitoring is required for patients taking any other drugs affecting hemostasis during ketorolac treatment. Clinical trials have shown that the frequency of postoperative bleeding is less than 1%.

Ketorolac delays platelet aggregation and prolongs bleeding time. In patients with normal hemostasis, bleeding time increases but does not exceed normal limits—between 2 and 11 minutes. Unlike the prolonged effect of aspirin, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac.

Reports have been received of postoperative wound bleeding associated with immediate parenteral administration of ketorolac during surgery. Therefore, ketorolac should not be prescribed to patients who have undergone surgery with a high risk of bleeding or in whom hemostasis is incomplete (see section "Contraindications"). Caution should be exercised when stable hemostasis is critical, for example, in cosmetic or ambulatory surgeries, 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.

Ketorolac has no sedative or anxiolytic properties and therefore is not prescribed for preoperative treatment when such effects are required to enhance anesthesia.

Skin reactions

Rarely, severe skin reactions (some with fatal outcomes), including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with NSAID use (see section "Adverse reactions"). The risk of adverse reactions is highest at the beginning of treatment. Ketorolac use should be discontinued if skin rash, mucosal lesions, or any other signs of hypersensitivity appear.

Systemic lupus erythematosus (SLE) and mixed connective tissue disease

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

Excipients

This medicinal product contains 11.89% v/v ethanol (alcohol), equivalent to up to 100 mg, corresponding to 2.47 ml of beer or 1.03 ml of wine.

Caution should be exercised when administering the medicinal product to children aged 16 years, as well as to high-risk groups: patients with liver disease or epilepsy. The product is harmful to individuals suffering from alcoholism.

1 ml of ketorolac tromethamine injection solution contains 1.72 mg of sodium, meaning the product contains less than 1 mmol (23 mg) of sodium per dose—essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy.

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

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

From the 20th week of pregnancy, the use of ketorolac may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after initiation of treatment and is usually reversible upon discontinuation. Additionally, reports of ductus arteriosus constriction after second-trimester treatment, most of which resolved after treatment cessation, have been documented.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may pose risks to the fetus:

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

In turn, at the end of pregnancy, these drugs may affect both the mother and the newborn by:

potentially prolonging bleeding time due to antiplatelet effects, which may occur even with very low doses;
inhibiting uterine contractions, leading to delayed or prolonged labor.

Therefore, the use of ketorolac is contraindicated throughout pregnancy.

Breastfeeding.

Ketorolac has been detected in breast milk in low concentrations. Ketorolac should not be used during lactation.

Fertility.

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

Ability to influence reaction speed when driving or operating machinery.

Some patients may experience dizziness, fatigue, somnolence, vertigo, visual disturbances, insomnia, or depression during ketorolac treatment. If any of these symptoms occur, driving vehicles or operating machinery should be avoided.

Dosage and Administration

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

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see below "Duration of treatment" and section "Special precautions").

Adults

The recommended initial dose is 10 mg. If necessary, treatment may be continued with doses of 10–30 mg every 4–6 hours. During the initial postoperative period, ketorolac tromethamine may be administered every 2 hours if needed. In cases of severe pain, the initial dose may be 30 mg. The lowest effective dose should always be used whenever possible.

The maximum daily dose should not exceed 90 mg in adults and 60 mg in elderly patients, patients with renal impairment, and patients with body weight less than 50 kg (see below). The maximum duration of treatment should not exceed 2 days (see "Duration of treatment" below).

Ketorolac tromethamine injections may be administered concomitantly with opioids (e.g., morphine, pethidine) to achieve optimal analgesia during the initial postoperative period when pain is most intense. Ketorolac does not compete with opioids for receptor binding and does not potentiate opioid-induced respiratory depression or sedation typical of narcotic agents. When used in combination with parenteral ketorolac, lower daily doses of opioids are usually required compared to their use alone. However, when performing minor outpatient surgical procedures, potential opioid-related adverse effects should be considered.

For patients receiving ketorolac tromethamine injections and being switched to oral formulation, the total daily dose of the combined drug should not exceed 90 mg (60 mg for elderly patients, patients with renal impairment, and patients with body weight less than 50 kg). When switching formulations, the oral dose should not exceed 40 mg per day. Transition to oral therapy should be made as soon as possible.

Special patient groups

Elderly patients

Dosage reduction is recommended for patients aged over 65 years. The total daily dose should not exceed 60 mg (see section "Special precautions").

Elderly patients are at increased risk of adverse reactions; therefore, the lowest effective dose for the shortest possible duration should be used. During NSAID therapy, gastrointestinal function should be monitored regularly due to the risk of bleeding.

Patients with renal impairment

Dosage reduction of ketorolac tromethamine is required in patients with mild renal impairment. The maximum daily dose should not exceed 60 mg. Ketorolac tromethamine is contraindicated in patients with moderate to severe renal impairment (see section "Contraindications").

Patients with hepatic impairment

Dosage adjustment is not required. However, caution should be exercised when administering the drug to patients with hepatic impairment (see section "Special precautions").

Patients with body weight less than 50 kg

Dosage of ketorolac tromethamine should be reduced in patients with body weight less than 50 kg.

The maximum daily dose should not exceed 60 mg when administered intramuscularly or intravenously.

Duration of treatment

The maximum duration of continuous treatment with intramuscular or intravenous ketorolac tromethamine administered several times daily should not exceed 2 days, as the risk of adverse reactions increases with prolonged use. There is insufficient experience with long-term use of ketorolac tromethamine, as most patients are either switched to oral therapy or treatment is discontinued.

Administration

Ketorolac tromethamine is administered intramuscularly or intravenously. When administered intravenously, the injection should last at least 15 seconds; intramuscular injection should be given slowly and deeply into the muscle.

The onset of analgesic effect is similar for both intramuscular and intravenous administration—approximately 30 minutes. Maximum analgesic effect is achieved within 1–2 hours. The average duration of analgesia is 4–6 hours.

Children

There is insufficient data on the safety and efficacy of ketorolac in children; therefore, this drug should not be used in children and adolescents under 16 years of age.

Adolescents aged 16 to 18 years should be treated the same as adults.

Overdose

Symptoms of acute NSAID overdose include lethargy, drowsiness, nausea, vomiting, epigastric pain. Gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression, and coma (rare) may occur.

Symptoms of overdose after a single dose of ketorolac: abdominal pain, nausea, vomiting, hyperventilation, peptic ulcer and/or erosive gastritis, and renal dysfunction, which resolve after discontinuation of the drug.

After administration of 360 mg of ketorolac intramuscularly over five days, abdominal pain and peptic ulcers were observed, which resolved after discontinuation of the drug. Overdose may also cause nausea, headache, dizziness, disorientation, tinnitus, and hyperventilation. Suicide attempts have been reported. In cases of intentional overdose, metabolic acidosis may occur.

Treatment: symptomatic. There is no specific antidote. Activated charcoal may be administered within one hour after oral (ingested) administration of potentially toxic doses; gastric lavage may be considered after ingestion of potentially life-threatening doses. Close monitoring of the patient is required, including liver and kidney function tests. In case of prolonged seizures, intravenous diazepam is recommended. Dialysis is poorly effective.

Side effects

Adverse reactions occurring more frequently than isolated cases are classified by system organ classes and frequency using the following conventional terms: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Common: swelling of fingers, ankles and/or feet.

Uncommon: postoperative wound bleeding, haematomas, epistaxis.

Infections and infestations

Frequency not known: aseptic meningitis (particularly in patients with autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as nuchal rigidity, headache, nausea, vomiting, fever or disorientation.

Immune system disorders

Hypersensitivity reactions, uncommon: anaphylaxis (potentially fatal outcome), bronchospasm, laryngeal oedema, hypotension, skin flushing and rash.

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

Metabolism and nutrition disorders

Common: weight gain, anorexia.

Psychiatric disorders

Uncommon: somnolence, thinking disturbance, inability to concentrate, hallucinations.

Frequency not known: insomnia, restlessness, nervousness, excitability, confusion, depression, euphoria, delirium, psychotic reactions.

Nervous system disorders

Uncommon: headache, convulsions.

Frequency not known: dizziness, taste alteration, paraesthesia, hyperkinesia.

Eye disorders

Uncommon: visual disturbances.

Frequency not known: optic neuritis.

Ear and labyrinth disorders

Uncommon: tinnitus, hearing loss, vertigo.

Cardiac disorders

Uncommon: palpitations, chest pain.

Frequency not known: bradycardia.

Edema, hypertension, and heart failure have been reported with the use of NSAIDs.

Vascular disorders

Common: hypertension, hypotension, facial flushing, pallor.

Clinical trials and epidemiological data suggest that the use of certain NSAIDs (particularly at high doses and long-term) may be associated with a slightly increased risk of arterial thrombosis (e.g. myocardial infarction or stroke) (see section "Special precautions for use").

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea, asthma, pulmonary oedema.

Gastrointestinal disorders

The most commonly observed adverse reactions are gastrointestinal disorders. Peptic ulceration, gastrointestinal perforation or gastrointestinal bleeding (melena, haematemesis), sometimes fatal, especially in elderly patients, may occur (see section "Special precautions for use"). Reported adverse effects include: nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, ulcerative stomatitis, pancreatitis, dry mouth sensation, oesophagitis, belching, bloating, rectal bleeding, exacerbation of colitis or Crohn's disease (see section "Special precautions for use").

Uncommon: gastritis.

Hepatobiliary disorders

Uncommon: cholestatic jaundice, hepatitis.

Frequency not known: hepatic failure.

Skin and subcutaneous tissue disorders

Common: pruritus, purpura.

Uncommon: urticaria, exfoliative dermatitis.

Very rare: bullous skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome).

Frequency not known: photosensitivity, maculopapular rash, erythema multiforme.

Musculoskeletal and connective tissue disorders

Frequency not known: functional disorders, myalgia.

Renal and urinary disorders

Uncommon: haemolytic uraemic syndrome, acute renal failure.

Frequency not known: nephrotoxicity, including more frequent urination, oliguria, flank pain (with or without haematuria), interstitial nephritis, urinary retention, nephrotic syndrome.

The use of ketorolac (even after a single intravenous dose), like other agents that inhibit renal prostaglandin synthesis, may result in signs of renal impairment, not limited to increased serum creatinine and potassium levels.

Reproductive system disorders

Frequency not known: infertility (in women).

General disorders and administration site conditions

Uncommon: weakness, fatigue, asthenia, fever.

Rare: injection site pain.

Frequency not known: excessive thirst, increased sweating.

Laboratory test changes

Frequency not known: hyponatraemia, hyperkalaemia, increased serum urea and creatinine levels, prolonged bleeding time, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, abnormal liver function tests.

Shelf life. 4 years.

Do not use after the expiry date.

Storage conditions.

Store at a temperature not exceeding 25 °C. Do not freeze.

Keep in original packaging to protect from light.

Keep out of reach of children.

Incompatibilities.

In small volumes (e.g. in a syringe), ketorolac trometamol must not be mixed (used in combination) with morphine sulphate, pethidine hydrochloride, promethazine hydrochloride, or hydroxyzine hydrochloride, as precipitation of ketorolac may occur.

Ketorolac trometamol is compatible with physiological saline, 5% glucose solution, Ringer's solution, Ringer's lactate solution, or plasma substitutes.

Packaging.

1 ml in a vial made of colourless hydrolytic type I glass with a break line or score mark and two purple-coloured marking rings.

5 vials in a blister pack (cavity) made of polyvinyl chloride film.

2 or 20 blister packs (cavities) in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Manufacturer responsible for batch release, including batch control/testing:

JSC "Grindeks".

Manufacturer's name and address.

53 Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorisation Holder.

JSC "Grindeks".

Address of Marketing Authorisation Holder.