Aspricks

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASPRIX ASPRIX

Composition:

Active substance: ketorolac;

1 vial contains 0.63 g of ketorolac tromethamine
(1 dose contains 15.75 mg of ketorolac tromethamine);

Excipients: dexpanthenol, potassium dihydrogen phosphate, sodium hydroxide, disodium edetate (trometamol), methylparaben (methyl p-hydroxybenzoate) (E 218), purified water.

Pharmaceutical form. Metered nasal spray.

Main physicochemical properties: clear yellow liquid with a characteristic odor.

Pharmacotherapeutic group.
Medicinal products affecting the musculoskeletal system. Anti-inflammatory and antirheumatic agents. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related compounds. Ketorolac. ATC code M01AB15.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

The medicinal product ASPRIX contains ketorolac – a non-steroidal anti-inflammatory drug (NSAID). Ketorolac is an analgesic that inhibits the enzyme cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in reduced synthesis of prostaglandins, thromboxanes, and prostacyclin.

Ketorolac is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations of ketorolac achieved during therapy produced effects in vivo. Prostaglandins increase the sensitivity of afferent nerves and enhance the action of bradykinin, promoting pain in animal models. Prostaglandins are mediators of inflammation. Since ketorolac is an inhibitor of prostaglandin synthesis, its mechanism of action may be attributed to reduced prostaglandin levels in peripheral tissues.

Pharmacokinetics.

The elimination half-lives of ketorolac after intranasal and intramuscular administration are similar. The bioavailability of ketorolac at a dose of 31.5 mg following intranasal administration is approximately 60% compared to intramuscular administration (see table).

Pharmacokinetic parameters of ketorolac after intramuscular and intranasal administration.

Cmax – maximum plasma concentration; Tmax – time to reach maximum plasma concentration; AUC0-∞ – area under the plasma concentration-time curve; T1/2 – half-life; CV – coefficient of variation.

Absorption.

In a study in which ketorolac (31.5 mg) was administered intranasally to healthy volunteers four times daily for 5 days, Cmax, Tmax, and AUC values after the last dose were comparable to those obtained in a single-dose study. Accumulation of ketorolac in special patient populations, such as elderly patients, children, patients with renal or hepatic impairment, has not been studied.

Distribution.

Scintigraphic evaluation of ketorolac distribution following intranasal administration showed that the majority of ketorolac localizes in the nasal cavity and pharynx, less than 20% localizes in the esophagus and stomach, and negligible or zero amount localizes in the lungs (< 0.5%).

The mean apparent volume of distribution (Vβ) of ketorolac after complete distribution was approximately 13 L. This parameter was determined from single-dose data. The racemate of ketorolac demonstrated high plasma protein binding (99.2%). However, plasma concentrations above 10 mcg/mL will occupy approximately 5% of albumin binding sites.

Thus, the unbound fraction for each enantiomer remains constant throughout the therapeutic range. However, decreased serum albumin levels will lead to increased free drug concentrations.

Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not affect ketorolac binding to plasma proteins. In vitro studies showed that at therapeutic salicylate concentrations (300 mcg/mL), ketorolac binding decreases from 99.2% to 97.5%, potentially doubling the unbound ketorolac concentration in plasma. In vitro studies also showed that at plasma ketorolac concentrations of 5–10 mcg/mL and in the presence of warfarin binding to plasma proteins, ketorolac binding slightly decreases (99.3% compared to 99.5%).

Ketorolac is excreted in breast milk.

Metabolism.

Ketorolac is extensively metabolized in the liver. Metabolites include hydroxylated and conjugated forms of the parent drug. Metabolites and some unchanged drug are excreted in urine. In animal and human studies, there is no evidence that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Excretion.

The primary route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is recovered in urine: 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of the dose is excreted in feces. In a single-dose study of 10 mg ketorolac (n = 9), the S-enantiomer was eliminated twice as fast as the R-enantiomer, and clearance was independent of the route of administration. This implies that the plasma concentration ratio of S-enantiomer to R-enantiomer decreases over time after each dose. Differences between S- and R-forms in humans are minimal or absent.

The elimination half-life of the S-enantiomer of ketorolac is approximately 2.5 hours (CV ± 0.4), and that of the R-enantiomer is 5 hours (CV ± 1.7). Other studies have reported a half-life of the racemate of 5–6 hours.

Pharmacokinetics in specific patient populations.

Elderly patients.

A comparative pharmacokinetic study of single intranasal doses of ketorolac (31.5 mg) was conducted in patients aged ≥ 65 years and those aged < 65 years. Exposure to ketorolac was 23% higher in patients aged ≥ 65 years compared to those aged < 65 years. Peak concentrations at 0.75 hours after dosing were 2028 ng/mL in elderly patients and 1840 ng/mL in younger adult patients, respectively. Elderly patients exhibited a longer terminal elimination half-life compared to younger adult patients (4.5 hours vs. 3.3 hours, respectively).

Race.

No pharmacokinetic differences were observed among patients of different racial groups.

Hepatic impairment.

Values for half-life, AUC∞, and Cmax in 7 patients with hepatic disease did not differ significantly from those in healthy volunteers.

Renal impairment.

Based solely on data obtained after single-dose administration, the mean elimination half-life of ketorolac in patients with impaired renal function ranges from 6 to 19 hours, depending on the severity of impairment. There is almost no correlation between creatinine clearance and total ketorolac clearance in elderly patients and patients with renal impairment (r = 0.5).

In patients with renal disease, AUC∞ values for each enantiomer increase by nearly 100% compared to healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by one-fifth for the R-enantiomer. The increased volume of distribution of ketorolac indicates an increased unbound fraction.

The ratio of AUC∞ of ketorolac enantiomers in healthy volunteers and patients remained similar, suggesting non-selective enantiomer excretion in patients compared to healthy volunteers.

Allergic rhinitis.

Comparison of ketorolac pharmacokinetics in patients with allergic rhinitis with data from previous studies in healthy volunteers showed no differences that would have a clinically significant impact on the safety and efficacy of ketorolac.

Drug interaction studies.

Acetylsalicylic acid.

Concomitant use of NSAIDs with acetylsalicylic acid reduces their plasma protein binding, although the clearance of the unbound form of the NSAID remains unchanged. The clinical significance of this interaction is unknown (see section "Interaction with other medicinal products and other forms of interaction").

Other nasal medicinal products.

A study was conducted in patients with symptomatic allergic rhinitis to evaluate the effect of nasal medications containing oxymetazoline hydrochloride and fluticasone propionate on the pharmacokinetics of ketorolac.

Probenecid.

Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance and volume of distribution of ketorolac and a significant increase in its plasma concentration (total AUC increased nearly threefold – from 5.4 mcg·hr/mL to 17.8 mcg·hr/mL); the terminal elimination half-life increased almost twofold – from 6.6 hours to 15.1 hours.

Clinical characteristics.

Indications.

Short-term treatment of moderate to moderately severe pain (up to 5 days) requiring opioid-level analgesia.

Contraindications.

• Hypersensitivity to ketorolac (anaphylactic reactions and serious skin reactions) or to any component of the drug;
• Active peptic ulcer, recent gastrointestinal bleeding or perforation;
• History of bronchial asthma, urticaria, or other allergic reactions after taking acetylsalicylic acid or other NSAIDs (due to the possibility of severe, sometimes fatal, anaphylactic reactions);
• Not to be used as an analgesic before and during surgery;
• Not to be used in the postoperative period following coronary artery bypass grafting (CABG);
• Severe renal impairment or risk of developing renal impairment due to reduced fluid volume;
• Not to be used during labor and delivery (due to the inhibitory effect of ketorolac on prostaglandin synthesis, which may adversely affect fetal circulation and inhibit uterine contractions, thereby increasing the risk of uterine bleeding);
• Patients with suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding;
• Concomitant use with probenecid;
• Concomitant use with pentoxifylline.

Interaction with other medicinal products and other forms of interaction.

Drugs affecting hemostasis.

Ketorolac and anticoagulants, such as warfarin, exhibit a synergistic effect on bleeding. Concomitant use of ketorolac and anticoagulants increases the risk of serious bleeding compared to using either drug alone.

Serotonin released by platelets plays an important role in hemostasis. Case-control studies and cohort epidemiological studies have shown that concomitant use of drugs that inhibit serotonin reuptake, together with NSAIDs, increases the risk of bleeding more than NSAID monotherapy.

There is an increased risk of bleeding when ketorolac is used concomitantly with pentoxifylline.

Patients receiving concomitant ketorolac and anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) should be monitored for bleeding (see sections "Contraindications" and "Special precautions").

Acetylsalicylic acid.

Controlled clinical studies have shown that concomitant use of NSAIDs and acetylsalicylic acid at analgesic doses does not provide greater therapeutic benefit than NSAID monotherapy. In clinical studies, concomitant use of NSAIDs and acetylsalicylic acid was associated with a significantly higher incidence of gastrointestinal adverse reactions compared to NSAID use alone (see section "Special precautions").

Concomitant use of ketorolac and acetylsalicylic acid at analgesic doses is generally not recommended due to increased risk of bleeding (see section "Special precautions"). Ketorolac must not be used as a substitute for low-dose acetylsalicylic acid in the prevention of cardiovascular diseases.

ACE inhibitors, angiotensin receptor blockers (ARBs), and β-blockers.

NSAIDs may reduce the antihypertensive effects of ACE inhibitors, ARBs, and β-blockers (including propranolol).

Concomitant use of NSAIDs with ACE inhibitors or ARBs in elderly patients, dehydrated patients (including those on diuretic therapy), and patients with impaired renal function may lead to deterioration in renal function, including acute renal failure. These effects are usually reversible.

When ketorolac is used concomitantly with ACE inhibitors, ARBs, or β-blockers, blood pressure should be monitored to ensure achievement of the desired blood pressure level.

When ketorolac is used concomitantly with ACE inhibitors or ARBs in elderly patients, dehydrated patients, or those with impaired renal function, patients should be monitored for signs of renal dysfunction (see section "Special precautions").

During concomitant use of these drugs, patients should maintain adequate fluid intake. Renal function should be assessed at the start of concomitant therapy and periodically thereafter.

Diuretics.

Clinical studies and post-marketing observations have shown that in some patients, NSAIDs may reduce the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics. This effect is attributed to NSAID-mediated inhibition of renal prostaglandin synthesis.

When the medicinal product ASPRIX is used concomitantly with diuretics, patients should be monitored for signs of renal impairment, and the efficacy of the diuretic, including its antihypertensive effect, should be verified (see section "Special precautions").

Digoxin.

Concomitant use of ketorolac with digoxin has been reported to increase serum digoxin concentrations and prolong its elimination half-life.

Serum digoxin levels should be monitored when ASPRIX is used concomitantly with digoxin.

Lithium.

NSAIDs have been associated with increased plasma lithium levels and reduced renal lithium clearance. The average minimum lithium concentration increased by 15%, and renal clearance decreased by approximately 20%. This effect is attributed to NSAID-mediated inhibition of renal prostaglandin synthesis.

Patients receiving concomitant ASPRIX and lithium preparations should be monitored for signs of lithium toxicity.

Metotrexate.

Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

Patients should be monitored for methotrexate toxicity during concomitant use of ASPRIX and methotrexate.

Cyclosporine.

Concomitant use of ketorolac with cyclosporine may increase the nephrotoxic potential of the latter.

Patients should be monitored for signs of renal dysfunction during concomitant use of ASPRIX and cyclosporine.

NSAIDs and salicylates.

Concomitant use of ketorolac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of gastrointestinal toxicity with little or no increase in efficacy (see section "Special precautions").

Concomitant use of ketorolac with other NSAIDs or salicylates is not recommended.

Pemetrexed.

Concomitant use of ketorolac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression and nephro- and gastrointestinal toxicity (see the pemetrexed prescribing information).

In patients receiving concomitant ketorolac and pemetrexed who have impaired renal function (creatinine clearance between 45 ml/min and 79 ml/min), signs of myelosuppression and nephro- and gastrointestinal toxicity should be monitored.

NSAIDs with a short elimination half-life (e.g., diclofenac, indomethacin) should be avoided for 2 days before and after, as well as on the day of pemetrexed administration.

In the absence of data on potential interactions between pemetrexed and NSAIDs with a longer half-life (e.g., meloxicam, nabumetone), patients taking these NSAIDs should discontinue their use at least 5 days before pemetrexed administration, on the day of pemetrexed administration, and for 2 days thereafter.

Probenecid.

Concomitant administration of ketorolac and probenecid leads to increased plasma levels and prolonged elimination half-life of ketorolac.

Concomitant use of ketorolac and probenecid is contraindicated.

Antiepileptic drugs.

Isolated sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).

Patients should be monitored for seizures during concomitant use of ASPRIX with antiepileptic drugs.

Psychotropic agents.

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

Patients should be monitored for hallucinations during concomitant use of ASPRIX with psychotropic agents.

Non-depolarizing muscle relaxants.

During the post-marketing period, cases of possible interaction between ketorolac and non-depolarizing muscle relaxants leading to apnea have been reported. No formal studies on the concomitant use of ketorolac and muscle relaxants have been conducted.

Patients should be monitored for apnea during concomitant use of ASPRIX with non-depolarizing muscle relaxants.

Special precautions for use.

Cardiovascular and thrombotic effects.

Clinical studies of several selective and non-selective COX-2 inhibitors from the NSAID group, with durations of up to 3 years, have demonstrated an increased risk of serious thrombotic adverse events, including myocardial infarction and stroke, which may be fatal. Based on available data, it is unclear whether the risk of developing thrombotic cardiovascular complications is similar for all NSAIDs. The relative increase in the incidence of serious thrombotic cardiovascular complications associated with NSAID use occurs both in patients with known cardiovascular diseases and risk factors for their development, and in patients without such diseases or risk factors. However, patients with known cardiovascular disease or cardiovascular risk factors had an even higher absolute incidence of serious thrombotic cardiovascular complications due to the increased baseline prevalence of these factors and conditions. In some observational studies, this increased risk of serious thrombotic cardiovascular complications appeared as early as the first weeks of treatment. The increased risk of thrombotic cardiovascular complications was most consistently observed with the use of higher drug doses.

To minimize the potential risk of cardiovascular adverse reactions in patients receiving NSAIDs, the lowest effective dose should be used for the shortest possible duration of treatment. Physicians and patients should remain vigilant for such reactions throughout the entire course of treatment, even in the absence of prior cardiovascular symptoms. Patients should be informed about the symptoms of serious cardiovascular adverse reactions and the measures to be taken if they occur.

There is no direct evidence that concomitant use of acetylsalicylic acid reduces the increased risk of serious thrombotic cardiovascular complications associated with NSAID use. Concomitant use of acetylsalicylic acid and NSAIDs, such as ketorolac, increases the risk of serious gastrointestinal adverse reactions (see section "Special precautions for use").

Post-aortocoronary bypass surgery state.

In two large controlled clinical trials, the use of selective COX-2 NSAIDs for pain control during the first 10–14 days after aortocoronary bypass surgery was associated with an increased incidence of myocardial infarction and stroke. The use of NSAIDs after aortocoronary bypass surgery is contraindicated (see section "Contraindications").

Patients after myocardial infarction.

Observational studies conducted by the Danish National Registry demonstrated that patients who used NSAIDs in the period following myocardial infarction were at increased risk of recurrent myocardial infarction, cardiovascular mortality, and all-cause mortality, starting from the first week of treatment. In the same group, among patients who used NSAIDs, the rate of mortality during the first year after myocardial infarction was 20 cases per 100 patient-years compared to 12 cases per 100 patient-years among patients who did not use NSAIDs. Although the absolute number of fatal outcomes decreases after the first year following myocardial infarction, analysis of results from at least four subsequent years of follow-up demonstrated that the elevated relative risk of fatal outcomes in patients using NSAIDs persists.

The use of the medicinal product ASPRIX should be avoided in patients with recent myocardial infarction, except when the expected benefit of treatment outweighs the risk of recurrence of thrombotic cardiovascular complications. If the medicinal product ASPRIX is used in patients with recent myocardial infarction, the patient should be monitored for signs of cardiac ischemia.

Gastrointestinal effects.

The drug is contraindicated in patients with active peptic ulcer and/or gastrointestinal bleeding and in patients with recent gastrointestinal bleeding or perforation (see section "Contraindications"). Ketorolac may cause severe adverse gastrointestinal reactions, including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, and intestine, which may be fatal. These adverse effects may occur in patients receiving the drug at any time (with or without warning symptoms). Only one in five patients receiving NSAIDs develops serious upper gastrointestinal symptoms. Upper gastrointestinal ulcers, severe bleeding, or perforation occurred in approximately 1% of patients receiving NSAID treatment for 3–6 months and in approximately 2–4% of patients receiving NSAID treatment for one year. However, adverse effects may occur even with short-term therapy.

Risk factors for gastrointestinal bleeding, ulceration, or perforation.

Patients with a history of peptic ulcer disease and/or gastrointestinal bleeding who received NSAID treatment had more than a 10-fold increased risk of gastrointestinal bleeding compared to patients without such risk factors. Other factors increasing the risk of gastrointestinal bleeding include longer duration of NSAID therapy, concomitant use of oral corticosteroids, acetylsalicylic acid, anticoagulants, or SSRIs, smoking, alcohol consumption, advanced age, and poor general health. Most spontaneous reports of fatal gastrointestinal events involved elderly or debilitated younger patients. Patients with progressive liver disease and/or coagulopathy have an increased risk of gastrointestinal bleeding.

Strategies to minimize gastrointestinal risks in patients receiving NSAIDs:

• Use the lowest effective dose of ketorolac for the shortest possible duration;
• Avoid concomitant use of more than one NSAID;
• For patients at risk, when the expected benefit does not outweigh the risk of bleeding, prescribe an alternative therapy not involving NSAIDs (the drug is contraindicated in patients with active gastrointestinal bleeding);
• Continuously monitor for signs and symptoms of gastrointestinal ulceration and/or bleeding during NSAID therapy;
• Discontinue the drug immediately if gastrointestinal disturbances occur;
• Patients receiving low-dose acetylsalicylic acid for cardiovascular disease prevention should be under continuous medical supervision due to the risk of gastrointestinal bleeding;
• Use the drug with caution in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) due to the risk of exacerbation.

Use in patients with hepatic impairment.

Significant elevations of ALT and AST (more than 3 times the upper limit of normal) in serum were observed in less than 1% of patients in controlled clinical trials. Additionally, there have been reports of isolated cases of severe hepatic reactions, including fatal fulminant hepatitis, hepatic necrosis, and hepatic failure.

Elevations of ALT and AST (less than 3 times the upper limit of normal) were observed in 15% of patients receiving NSAIDs, including ketorolac.

Patients should be informed about possible signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, malaise, diarrhea, pruritus, jaundice, right upper quadrant pain, and flu-like symptoms). Ketorolac should be discontinued if clinical symptoms of liver disease or systemic manifestations such as eosinophilia or rash develop.

Arterial hypertension.

The use of NSAIDs, including ketorolac, may lead to the development of arterial hypertension or worsening of pre-existing hypertension, and in each case may increase the frequency of cardiovascular adverse reactions. In patients taking ACE inhibitors, thiazide diuretics, or loop diuretics, a diminished response to these drugs may occur with NSAID use (see section "Interaction with other medicinal products and other forms of interaction").

Heart failure and edema.

Results from a combined meta-analysis by the "Trialists’ Collaboration" and randomized controlled trials of coxibs and traditional NSAIDs demonstrated approximately a twofold increase in hospitalizations due to heart failure in patients receiving selective and non-selective COX-2 inhibitors, and in patients receiving non-selective NSAIDs, compared to patients receiving placebo.

In the Danish National Registry study, NSAID use in patients with heart failure increased the risk of myocardial infarction, hospitalization due to heart failure, and mortality.

Furthermore, fluid retention and edema have been observed in some patients receiving NSAIDs. Ketorolac may attenuate the cardiovascular effects of several drugs used to treat these conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers) (see section "Interaction with other medicinal products and other forms of interaction").

The use of the medicinal product ASPRIX should be avoided in patients with severe heart failure, except when the expected benefit of treatment outweighs the risk of worsening heart failure. If the medicinal product ASPRIX is used in patients with severe heart failure, monitoring for signs of worsening heart failure should be performed.

Use in patients with renal impairment.

Ketorolac and its metabolites are primarily excreted by the kidneys. Patients with reduced creatinine clearance will have reduced drug clearance. The medicinal product ASPRIX is contraindicated in patients with severe renal impairment (see section "Contraindications").

Nephrotoxicity.

Prolonged use of NSAIDs has led to renal medullary necrosis and other kidney damage.

Nephrotoxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. In such patients, NSAID use may cause dose-dependent reduction in prostaglandin production and, consequently, decreased renal blood flow, potentially leading to significant renal decompensation. Patients at increased risk of these reactions include those with renal impairment, dehydration, hypovolemia, heart failure, hepatic dysfunction, patients taking diuretics, ACE inhibitors, ARBs, and elderly patients. Discontinuation of the drug usually results in return to the pre-treatment state.

Controlled clinical trials lack information on the use of ketorolac in patients with progressive kidney disease. The effect of ketorolac on the kidneys may accelerate the progression of pre-existing renal impairment.

Before initiating treatment with the medicinal product ASPRIX, dehydration or hypovolemia, if present, should be corrected. In patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia, renal function should be monitored during treatment with ASPRIX (see section "Interaction with other medicinal products and other forms of interaction"). If the medicinal product ASPRIX is used in patients with progressive kidney disease, patients should be monitored for signs of renal function impairment.

Hyperkalemia.

Cases of elevated serum potassium concentration, including hyperkalemia, have been reported with NSAID use, even in some patients without renal impairment. In patients with normal renal function, these effects were associated with a hyporeninemic-hypoaldosteronemic state.

Anaphylactic reactions.

The use of ketorolac has been associated with anaphylactic reactions in patients with known hypersensitivity to ketorolac or without it, as well as in patients with aspirin-induced asthma. Medical help should be sought immediately if anaphylactic reactions occur.

Exacerbation of bronchial asthma related to sensitivity to acetylsalicylic acid.

Some patients with bronchial asthma may have aspirin-induced asthma, which may include chronic rhinosinusitis complicated by nasal polyps, severe potentially fatal bronchospasm, and intolerance to acetylsalicylic acid and other NSAIDs. Since cross-reactivity between acetylsalicylic acid and other NSAIDs has been documented in such aspirin-sensitive patients, the use of the medicinal product ASPRIX is contraindicated in patients with this form of sensitivity to acetylsalicylic acid (see section "Contraindications"). When using the medicinal product ASPRIX in patients with pre-existing bronchial asthma (without known sensitivity to acetylsalicylic acid), patients should be monitored for changes in signs and symptoms of bronchial asthma.

Serious skin reactions.

Ketorolac may cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which may be fatal. These serious reactions may develop without warning symptoms.

Patients should be informed about the signs and symptoms of serious skin reactions and the necessity to discontinue the medicinal product ASPRIX at the first appearance of skin rash or any other signs of hypersensitivity. Ketorolac is contraindicated in patients with a history of serious skin reactions to NSAIDs (see section "Contraindications").

Premature closure of fetal ductus arteriosus.

Ketorolac may cause premature closure of the fetal ductus arteriosus; therefore, the use of the drug should be avoided in pregnant women starting from the 30th week of pregnancy (third trimester) (see section "Use during pregnancy or lactation").

Hematological toxicity.

Cases of anemia have been reported in patients receiving NSAIDs. This may be due to occult or significant blood loss, fluid retention, or an effect on erythropoiesis that is not fully characterized. If a patient develops any signs or symptoms of anemia during ketorolac use, hemoglobin or hematocrit levels should be monitored. The use of ketorolac is contraindicated in patients with an increased risk of bleeding (see section "Contraindications").

Ketorolac may increase the risk of bleeding. Concomitant factors such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., acetylsalicylic acid), SSRIs, or SNRIs may increase this risk. Such patients should be monitored for signs of bleeding (see section "Interaction with other medicinal products and other forms of interaction"). Studies on the concomitant use of ketorolac with prophylactic low-dose heparin (2500–5000 IU every 12 hours), warfarin, or dextran have not been conducted, so such regimens may also increase the risk of bleeding. Since data from such studies are lacking, the benefit-risk ratio should be carefully evaluated, and such concomitant therapy should be used with particular caution. Close monitoring is required for patients taking other medicinal products that adversely affect hemostasis during ketorolac use. Serious adverse reactions related to bleeding occurred more frequently in patients receiving ketorolac compared to those receiving placebo. Clinical trials and post-marketing experience with ketorolac (intramuscular and intravenous administration) indicate postoperative hematomas and wound bleeding with perioperative use. Therefore, the medicinal product ASPRIX should be used with caution in the postoperative period, especially in patients at increased risk of bleeding.

Masking of inflammation and fever.

The pharmacological activity of ketorolac, which includes reducing inflammation and possibly lowering elevated body temperature, may diminish the diagnostic value of clinical signs in detecting infections.

Monitoring of laboratory test results.

Since serious gastrointestinal bleeding, hepatotoxicity, and renal damage may occur without warning symptoms or signs, consideration should be given to monitoring patients receiving long-term treatment with periodic complete blood count and biochemical blood tests (see section "Special precautions for use").

Ocular effects.

Contact of the medicinal product ASPRIX with the eyes should be avoided. If the drug gets into the eyes, they should be rinsed with water or saline solution. If eye irritation persists for more than one hour, medical advice should be sought.

Use limitations.

The total duration of treatment with the medicinal product ASPRIX, either alone or sequentially with other forms of ketorolac, should not exceed 5 days. The medicinal product ASPRIX should not be used concomitantly with other forms of ketorolac or other NSAIDs.

Elderly patients.

Ketorolac should be used with caution in elderly patients. Elderly patients, compared to younger patients, have a higher risk of developing serious adverse reactions associated with NSAID use, including cardiovascular, gastrointestinal, and/or renal adverse reactions. If the expected benefit for elderly patients outweighs the potential risks, treatment should be initiated at the lowest dose, and the patient should be monitored for adverse reactions. After assessing the patient's response to initial therapy with ASPRIX, the dose and frequency of administration should be adjusted according to individual patient characteristics. Since ketorolac and its metabolites are substantially excreted by the kidneys, the risk of adverse reactions may be higher in patients with impaired renal function. Ketorolac should be used with caution in elderly patients, as they are more likely to have decreased renal function. Continuous monitoring of renal function is required.

Use during pregnancy or lactation.

The use of ketorolac during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus; therefore, the use of the drug should be avoided in pregnant women starting from the 30th week of pregnancy (third trimester).

Studies on the use of ketorolac in pregnant women have not been conducted. Data from observational studies on potential embryofetal risks of NSAID use in women during the first or second trimester of pregnancy are inconclusive.

In the general U.S. patient population, regardless of drug effects, all clinically recognized pregnancies have a background incidence of 2–4% major congenital defects and 15–20% pregnancy loss.

Reproductive animal studies in rabbits and rats, administered ketorolac at doses 0.6 and 1.5 times higher than the maximum recommended human intranasal dose of 31.5 mg four times daily, showed no evidence of teratogenicity or other adverse fetal developmental outcomes.

Based on animal data, prostaglandins have been shown to play an important role in regulating endometrial vascular permeability, blastocyst implantation, and decidualization. Animal studies have shown that administration of prostaglandin synthesis inhibitors, such as ketorolac, increases the frequency of pre- and post-implantation losses.

Labor and delivery.

Studies on the effect of ketorolac on labor or delivery have not been conducted. Animal studies showed that ketorolac inhibits prostaglandin synthesis, leading to delayed delivery and increased incidence of stillbirth.

Human data.

There are no adequate and well-controlled studies on the use of ketorolac in pregnant women.

Animal data.

Reproductive studies were conducted during organogenesis using daily oral doses of ketorolac at 3.6 mg/kg (0.6 times the systemic exposure in humans at the recommended maximum intranasal dose of 31.5 mg daily based on AUC) in rabbits and 10 mg/kg (1.5 times the AUC in humans) in rats. These studies showed no evidence of teratogenicity or other adverse developmental outcomes. Since the animal doses were limited by maternal toxicity, the potential for adverse developmental outcomes in humans with ketorolac use cannot be adequately assessed.

Lactation.

Ketorolac is excreted in breast milk. The benefit of breastfeeding for the infant's health and development should be weighed against the mother's clinical need for the medicinal product and any potential adverse effects of ketorolac or the impact of the mother's underlying condition on the infant.

The medicinal product ASPRIX should be used with caution in breastfeeding women. Available information has not demonstrated specific adverse effects in breastfed infants. If any adverse reactions occur, medical advice should be sought.

Limited data from one published study involving 10 breastfeeding mothers during 2–6 days postpartum indicate low levels of ketorolac in breast milk. Levels were undetectable (<5 ng/mL) in 4 patients. After a single 10 mg dose of ketorolac, the maximum concentration in milk was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037.

After multiple dosing of ketorolac (10 mg every 6 hours), the maximum concentration in milk was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming daily consumption of 400–1000 mL of maternal milk and a maternal body weight of 60 kg, the calculated maximum daily infant dose is 0.00263 mg/kg, which is 0.4% of the dose adjusted for maternal body weight.

Fertility.

Given that the mechanism of action of ketorolac is mediated through prostaglandins, its use may delay or prevent follicular rupture in the ovary, which may be associated with temporary infertility in some women. Published animal studies have shown that prostaglandin synthesis inhibitors may potentially disrupt prostaglandin-mediated follicular rupture necessary for ovulation. Small studies in women using ketorolac have also demonstrated reversible ovulation delay. Consideration should be given to discontinuing ketorolac in women experiencing difficulty conceiving or undergoing infertility evaluation.

Ability to affect reaction speed when driving vehicles or operating machinery.

The medicinal product does not affect the ability to drive vehicles or operate machinery. However, the possibility of nervous system adverse reactions should be considered.

Dosage and Administration

The medicinal product ASPRIX is recommended for short-term use only (up to 5 days). To minimize adverse effects, the drug should be used at the lowest effective dose for the shortest duration necessary to control symptoms. The product must not be used concomitantly with other forms of ketorolac tromethamine or with other NSAIDs (see section "Special Precautions").

Adult Patients

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 126 mg (4 recommended doses).

Adult Patients with Body Weight Less Than 50 kg

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 63 mg (2 recommended doses).

Elderly Patients

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 63 mg (2 recommended doses).

Patients with Renal Impairment

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 63 mg (2 recommended doses).

Instructions for Use

For optimal effectiveness of ASPRIX nasal spray, clear the nostrils before use (gently blow the nose).

Remove the protective cap before use.

Before first use, prime the pump by depressing it 5 times into the air until a fine, uniform mist is produced. The product is now ready for use.

If the product has not been used for more than 24 hours, re-prime the pump once into the air before use to ensure delivery of a full dose.

Hold the bottle upright with the spray nozzle pointing upwards during administration.

Tilt the head slightly forward, insert the spray nozzle into the left nostril, and slightly angle the tip away from the center of the nose. Administer one spray. Repeat the same procedure in the right nostril.

After use, replace the protective cap to prevent accidental activation.

Store the bottle in a cool, protected place away from light (see section "Storage Conditions").

Children

The safety and efficacy of the product in children have not been established; therefore, ASPRIX should not be used in pediatric practice.

Overdose

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric abdominal pain, and are generally reversible with supportive treatment. Cases of gastrointestinal bleeding have been reported. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma have been observed.

No cases of ketorolac overdose were reported during clinical trials. In controlled overdose studies using intramuscular ketorolac at a dose of 360 mg daily for 5 days (approximately 3 times the maximum recommended daily dose), cases of abdominal pain and gastric ulceration were observed, which resolved after discontinuation of the drug.

Individual cases of ketorolac overdose have been associated with stomach pain, nausea, vomiting, hyperventilation, peptic ulcers, and/or erosive gastritis, as well as impaired renal function.

Following overdose, patients should receive symptomatic and supportive treatment. There are no specific antidotes. Consider inducing emesis and/or administering activated charcoal (60–100 g) and/or an osmotic laxative in patients who develop symptoms within 4 hours after administration, as well as in patients with severe overdose (dose 5–10 times the recommended dose).

Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion are not recommended due to high protein binding.

Adverse Reactions.

Clinical Trial Experience.

Since clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a particular drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

According to data from clinical trials, the most commonly reported adverse reactions in patients receiving ketorolac were nasal discomfort or irritation. These adverse reactions were usually mild and transient. The most frequent adverse reactions leading to discontinuation of the drug were nasal discomfort or nasal pain (rhinalgia).

Adverse reactions reported in clinical trials with other doses and dosage forms of ketorolac or other NSAIDs.

The incidence of adverse reactions increases with higher doses of ketorolac. Serious complications associated with ketorolac use, such as gastrointestinal ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and hepatic failure, require careful monitoring. If ketorolac is used improperly, these complications may have serious consequences.

The following adverse reactions were reported in 1–10% of patients treated with ketorolac or other NSAIDs:

Gastrointestinal: gastrointestinal pain, flatulence, gastrointestinal bleeding or perforation, stomatitis, constipation, diarrhea, bloating, heartburn, vomiting, dyspepsia, peptic ulcer (gastric/duodenal), nausea.

Other: renal function impairment, somnolence, headache, injection site pain, rash, anemia, edema, arterial hypertension, pruritus, tinnitus, dizziness, elevated liver enzymes, prolonged bleeding time, purpura, increased sweating.

Rare adverse reactions reported in clinical trials in <1% of patients treated with ketorolac or other NSAIDs:

Infections and infestations: fever, infections, sepsis.

Cardiovascular system disorders: congestive heart failure, palpitations, pallor, tachycardia, syncope.

Gastrointestinal disorders: anorexia, dry mouth, eructation, esophagitis, increased thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding.

Blood and lymphatic system disorders: ecchymoses, eosinophilia, epistaxis, leukopenia, thrombocytopenia.

Metabolism and nutrition disorders: changes in body weight.

Nervous system disorders: abnormal dreams, thinking disturbances, anxiety, malaise, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesia, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremor, vertigo, malaise.

Respiratory, thoracic and mediastinal disorders: asthma, dyspnea, pulmonary edema, rhinitis.

Specific reactions: taste disturbances, visual disturbances, blurred vision, hearing loss.

Renal and urinary system disorders: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention.

Postmarketing Experience.

The following adverse reactions have been identified during postmarketing use of ketorolac or other NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders: angioneurotic edema, hypersensitivity reactions such as anaphylaxis (which may be fatal), anaphylactoid reactions, laryngeal edema, tongue swelling, myalgia.

Cardiovascular system disorders: arrhythmia, bradycardia, chest pain, hyperemia, hypotension, myocardial infarction, vasculitis.

Skin and subcutaneous tissue disorders: exfoliative dermatitis, erythema multiforme, Lyell’s syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Gastrointestinal disorders: acute pancreatitis, hepatic failure, ulcerative stomatitis, exacerbation of ulcerative colitis and Crohn’s disease.

Blood and lymphatic system disorders: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative bleeding (rarely requiring blood transfusion).

Metabolism and nutrition disorders: hyperglycemia, hypokalemia, hyponatremia.

Central nervous system disorders: aseptic meningitis, seizures, coma, psychosis.

Respiratory, thoracic and mediastinal disorders: bronchospasm, respiratory depression, pneumonia.

Specific reactions: conjunctivitis.

Renal and urinary system disorders: flank pain (with or without hematuria and/or azotemia), hemolytic uremic syndrome.

Shelf life.

2 years.

Storage conditions.

Store at 2 to 8 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 ml (40 doses) in amber glass bottles, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC "MIKROKHEM".

Manufacturer's address and location of business activity.

Ukraine, 93000, Luhansk region, Rubizhne, Lenin St., 33.

To report an adverse event associated with the use of this medicinal product, please call +38 (050) 309-83-54 (24/7).

INSTRUCTION

for medical use of the medicinal product

ASPRIX

ASPRIX

Composition:

Active substance: ketorolac;

1 vial contains ketorolac tromethamine 0.63 g

(1 dose contains 15.75 mg ketorolac tromethamine);

Excipients: dexpanthenol, potassium dihydrogen phosphate, sodium hydroxide, disodium edetate (trometamol), methylparaben (methyl hydroxybenzoate) (E 218), purified water.

Pharmaceutical form. Metered nasal spray.

Main physicochemical characteristics: clear yellow liquid with a specific odor.

Pharmacotherapeutic group.

Drugs affecting the musculoskeletal system. Anti-inflammatory and antirheumatic agents. Nonsteroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances. Ketorolac. ATC code M01A B15.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

The medicinal product ASPRIX contains ketorolac – a non-steroidal anti-inflammatory drug (NSAID). Ketorolac is an analgesic that inhibits the enzyme cyclooxygenase (COX), an early component of the arachidonic acid cascade, resulting in reduced synthesis of prostaglandins, thromboxanes, and prostacyclin.

Ketorolac is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations of ketorolac achieved during therapy produced effects in vivo. Prostaglandins increase the sensitivity of afferent nerves and enhance the action of bradykinin, thereby promoting pain in animal models. Prostaglandins are mediators of inflammation. Since ketorolac inhibits prostaglandin synthesis, its mechanism of action may be attributed to reduced prostaglandin levels in peripheral tissues.

Pharmacokinetics.

The half-life periods of ketorolac following intranasal and intramuscular administration are similar. The bioavailability of ketorolac at a dose of 31.5 mg following intranasal administration is approximately 60% compared to intramuscular administration (see table).

Pharmacokinetic parameters of ketorolac after intramuscular and intranasal administration.

Cmax – maximum plasma concentration; tmax – time to reach maximum plasma concentration; AUC0-∞ – area under the “concentration-time” curve; T1/2 – half-life; CV – coefficient of variation.

Absorption.

In a study where ketorolac (31.5 mg) was administered intranasally to healthy volunteers four times daily for 5 days, Cmax, Tmax, and AUC values after the last dose were comparable to those obtained in a single-dose study. Accumulation of ketorolac in special patient populations, such as elderly patients, children, patients with renal or hepatic impairment, has not been studied.

Distribution.

Scintigraphic assessment of ketorolac distribution after intranasal dosing showed that the majority of ketorolac localizes in the nasal cavity and pharynx, less than 20% localizes in the esophagus and stomach, and negligible or zero amounts are found in the lungs (< 0.5%).

The mean apparent volume of distribution (Vβ) of ketorolac after complete distribution was approximately 13 L. This parameter was determined from single-dose administration data. The racemate of ketorolac demonstrated high plasma protein binding capacity (99.2%). However, plasma concentrations above 10 µg/mL occupy approximately 5% of albumin binding sites.

Thus, the unbound fraction for each enantiomer remains constant throughout the therapeutic range. However, reduced serum albumin levels will lead to an increase in free drug concentration.

Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not affect ketorolac binding to plasma proteins. In vitro studies showed that at therapeutic salicylate concentrations (300 mg/mL), ketorolac binding decreases from 99.2% to 97.5%, potentially doubling the level of unbound ketorolac in plasma. In vitro studies also showed that at plasma ketorolac concentrations of 5–10 µg/mL and in the presence of warfarin bound to plasma proteins, ketorolac concentration slightly decreases (99.3% compared to 99.5%).

Ketorolac is excreted into breast milk.

Metabolism.

Ketorolac is extensively metabolized in the liver. Metabolites include hydroxylated and conjugated forms of the parent drug. Metabolites and some unchanged drug are excreted in urine. Studies in animals and humans provide no evidence that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs.

Excretion.

The primary route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is recovered in urine: 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of the dose is excreted in feces. In a single-dose study of ketorolac 10 mg (n = 9), it was demonstrated that the S-enantiomer is eliminated twice as fast as the R-enantiomer, and clearance is independent of the route of administration. This indicates that the plasma concentration ratio of S-enantiomer to R-enantiomer decreases over time after each dose. Differences between S- and R-forms in humans are minimal or absent.

The elimination half-life of the S-enantiomer of ketorolac is approximately 2.5 hours (CV ± 0.4), and that of the R-enantiomer is 5 hours (CV ± 1.7). Other studies have reported a half-life of the racemate of 5–6 hours.

Pharmacokinetics in specific patient populations.

Elderly patients.

A comparative pharmacokinetic study of ketorolac (31.5 mg) after single intranasal administration was conducted in patients aged ≥ 65 years and those aged < 65 years. The effect of ketorolac was increased by 23% in patients aged ≥ 65 years compared to those aged < 65 years. Peak concentrations at 0.75 hours were 2028 ng/mL in elderly patients and 1840 ng/mL in younger adults, respectively. Elderly patients showed a longer terminal elimination half-life compared to younger adults (4.5 hours vs. 3.3 hours, respectively).

Race.

No pharmacokinetic differences were observed among patients of different racial groups.

Hepatic impairment.

Values for half-life, AUC∞, and Cmax in 7 patients with liver disease did not significantly differ from those in healthy volunteers.

Renal impairment.

Based solely on data obtained after single-dose administration, the mean elimination half-life of ketorolac in patients with renal impairment ranges from 6 to 19 hours, depending on the severity of impairment. There is almost no correlation between creatinine clearance and total ketorolac clearance in elderly patients and patients with renal impairment (r = 0.5).

In patients with renal disease, AUC∞ values for each enantiomer increase by nearly 100% compared to healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by one-fifth for the R-enantiomer. The increased volume of distribution of ketorolac indicates an increased unbound fraction.

The ratio of AUC∞ of ketorolac enantiomers in healthy volunteers and patients remained similar, indicating non-selective enantiomer excretion in patients compared to healthy volunteers.

Allergic rhinitis.

Comparison of ketorolac pharmacokinetics in patients with allergic rhinitis with data from a previous study in healthy volunteers showed no differences that would have a clinically significant impact on the safety and efficacy of ketorolac.

Drug interaction studies.

Acetylsalicylic acid.

Concomitant use of NSAIDs with acetylsalicylic acid reduces their plasma protein binding, although the clearance of the unbound form of the NSAID remains unchanged. The clinical significance of this interaction is unknown (see section “Interaction with other medicinal products and other forms of interaction”).

Other nasal medicinal products.

A study was conducted in patients with symptomatic allergic rhinitis to evaluate the effect of nasal medications containing oxymetazoline hydrochloride and fluticasone propionate on the pharmacokinetics of ketorolac.

Probenecid.

Concomitant administration of oral ketorolac and probenecid resulted in reduced clearance and volume of distribution of ketorolac and a significant increase in its plasma concentration (total AUC increased nearly threefold – from 5.4 µg·h/mL to 17.8 µg·h/mL); the terminal elimination half-life increased almost twofold – from 6.6 hours to 15.1 hours.

Clinical characteristics.

Indications.

Short-term treatment of moderate to moderately severe pain (up to 5 days) requiring opioid-level analgesia.

Contraindications.

• Hypersensitivity to ketorolac (anaphylactic reactions and serious skin reactions) or to any component of the drug;
• active peptic ulcer, recent gastrointestinal bleeding or perforation;
• bronchial asthma, urticaria, or other allergic reactions in history induced by acetylsalicylic acid or other NSAIDs (due to the possibility of severe, sometimes fatal, anaphylactic reactions);
• not to be used as an analgesic before and during surgery;
• not to be used in the postoperative period following coronary artery bypass grafting (CABG);
• severe renal impairment or risk of developing renal impairment due to reduced fluid volume;
• not to be used during labor and delivery (due to the inhibitory effect of ketorolac on prostaglandin synthesis, which may adversely affect fetal circulation and inhibit uterine contractions, thereby increasing the risk of uterine bleeding);
• patients with suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding;
• concomitant use with probenecid;
• concomitant use with pentoxifylline.

Interaction with other medicinal products and other forms of interaction.

Drugs affecting hemostasis.

Ketorolac and anticoagulants, such as warfarin, exhibit a synergistic effect on bleeding. Concomitant use of ketorolac and anticoagulants increases the risk of serious bleeding compared to the use of each of these drugs separately.

Serotonin released by platelets plays an important role in hemostasis. Case-control studies and cohort epidemiological studies have shown that concomitant use of drugs that inhibit serotonin reuptake and NSAIDs increases the risk of bleeding more than NSAID monotherapy.

There is an increased risk of bleeding when ketorolac is used concomitantly with pentoxifylline.

Patients receiving concomitant ketorolac and anticoagulants (e.g., warfarin), antiplatelet agents (e.g., acetylsalicylic acid), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) should be monitored for signs of bleeding (see sections "Contraindications" and "Special precautions for use").

Acetylsalicylic acid.

Controlled clinical studies have shown that concomitant use of NSAIDs and acetylsalicylic acid at analgesic doses does not provide any additional therapeutic benefit compared to NSAID monotherapy. In a clinical study, concomitant use of NSAIDs and acetylsalicylic acid was associated with a significantly increased incidence of gastrointestinal adverse reactions compared to NSAID monotherapy (see section "Special precautions for use").

Concomitant use of ketorolac and acetylsalicylic acid at analgesic doses is generally not recommended due to the increased risk of bleeding (see section "Special precautions for use"). Ketorolac must not be used as a substitute for low-dose acetylsalicylic acid for the prevention of cardiovascular diseases.

ACE inhibitors, angiotensin receptor blockers (ARBs), and β-blockers.

NSAIDs may reduce the antihypertensive effect of ACE inhibitors, ARBs, and β-blockers (including propranolol).

Concomitant use of NSAIDs with ACE inhibitors or ARBs in elderly patients, dehydrated patients (including those on diuretic therapy), and patients with impaired renal function may lead to deterioration of renal function, including acute renal failure. These effects are usually reversible.

When ketorolac is used concomitantly with ACE inhibitors, ARBs, or β-blockers, blood pressure should be monitored to ensure the achievement of the desired blood pressure level.

When ketorolac is used concomitantly with ACE inhibitors or ARBs in elderly patients, dehydrated patients, or those with impaired renal function, monitoring for signs of renal dysfunction should be performed (see section "Special precautions for use").

During concomitant use of these drugs, patients should receive adequate fluid intake. Renal function should be assessed at the start of concomitant therapy and periodically thereafter.

Diuretics.

Clinical studies and post-marketing observations have shown that in some patients, NSAIDs may reduce the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics. This effect is explained by NSAID inhibition of prostaglandin synthesis in the kidneys.

When the medicinal product ASPRIX is used concomitantly with diuretics, patients should be monitored for signs of renal impairment, and the effectiveness of the diuretic, including its antihypertensive effect, should be additionally confirmed (see section "Special precautions for use").

Digoxin.

Concomitant use of ketorolac with digoxin has been reported to increase serum digoxin concentrations and prolong its elimination half-life.

When ASPRIX is used concomitantly with digoxin, serum digoxin levels should be monitored.

Lithium.

NSAIDs have been associated with increased plasma lithium levels and decreased renal lithium clearance. The average minimum lithium concentration increased by 15%, and renal clearance decreased by approximately 20%. This effect is explained by NSAID inhibition of prostaglandin synthesis in the kidneys.

When ASPRIX is used concomitantly with lithium-containing preparations, patients should be monitored for signs of lithium toxicity.

Methotrexate.

Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

During concomitant use of ASPRIX with methotrexate, patients should be monitored for methotrexate toxicity.

Cyclosporine.

Concomitant use of ketorolac with cyclosporine may increase the nephrotoxicity of the latter.

During concomitant use of ASPRIX with cyclosporine, patients should be monitored for signs of renal dysfunction.

NSAIDs and salicylates.

Concomitant use of ketorolac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of gastrointestinal toxicity with little or no increase in efficacy (see section "Special precautions for use").

Concomitant use of ketorolac with other NSAIDs or salicylates is not recommended.

Pemetrexed.

Concomitant use of ketorolac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression and renal and gastrointestinal toxicity (see the pemetrexed prescribing information).

When ketorolac and pemetrexed are used concomitantly in patients with renal impairment (creatinine clearance between 45 ml/min and 79 ml/min), signs of myelosuppression and renal and gastrointestinal toxicity should be monitored.

Avoid using NSAIDs with a short elimination half-life (e.g., diclofenac and indomethacin) for 2 days before and after, as well as on the day of pemetrexed administration.

In the absence of data on the potential interaction between pemetrexed and NSAIDs with a longer half-life (e.g., meloxicam and nabumetone), patients taking these NSAIDs should discontinue their use at least 5 days before pemetrexed administration, on the day of pemetrexed administration, and for the following 2 days after administration.

Probenecid.

Concomitant administration of ketorolac and probenecid results in increased plasma levels and prolonged elimination half-life of ketorolac.

Concomitant use of ketorolac and probenecid is contraindicated.

Antiepileptic drugs.

Isolated sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).

During concomitant use of ASPRIX with antiepileptic drugs, patients should be monitored for the occurrence of seizures.

Psychotropic agents.

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

During concomitant use of ASPRIX with psychotropic agents, patients should be monitored for the occurrence of hallucinations.

Non-depolarizing muscle relaxants.

In the post-marketing period, cases of possible interaction between ketorolac and non-depolarizing muscle relaxants leading to apnea have been reported. No formal studies on the concomitant use of ketorolac and muscle relaxants have been conducted.

During concomitant use of ASPRIX with non-depolarizing muscle relaxants, patients should be monitored for the occurrence of apnea.

Special precautions for use.

Cardiovascular and thrombotic effects.

Clinical trials of several selective and non-selective COX-2 inhibitors from the NSAID group, with durations of up to 3 years, have demonstrated an increased risk of serious thrombotic events, including myocardial infarction and stroke, which may be fatal. Based on available data, it is unclear whether the risk of developing thrombotic cardiovascular complications is similar for all NSAIDs. The relative increase in the frequency of serious thrombotic cardiovascular complications associated with NSAID use, compared to baseline levels, occurs both in patients with known cardiovascular diseases and risk factors for their development, and in patients without such conditions or risk factors. However, patients with known cardiovascular disease or cardiovascular risk factors had an even higher absolute frequency of serious thrombotic cardiovascular complications due to their elevated baseline prevalence of these factors and diseases. In some observational studies, this increased risk of serious thrombotic cardiovascular complications appeared as early as the first weeks of treatment. The increased risk of thrombotic cardiovascular complications was most consistently observed with higher doses of the drug.

To minimize the potential risk of adverse cardiovascular reactions in patients using NSAIDs, the lowest effective dose should be used for the shortest possible duration of treatment. Physicians and patients should carefully monitor for such reactions throughout the entire course of treatment, even in the absence of prior cardiovascular symptoms. Patients should be informed about symptoms of serious cardiovascular adverse reactions and the necessary actions to take if they occur.

There is no direct evidence that concomitant use of acetylsalicylic acid reduces the increased risk of serious thrombotic cardiovascular complications associated with NSAID use. Concomitant use of acetylsalicylic acid and NSAIDs, such as ketorolac, increases the risk of serious gastrointestinal adverse reactions (see section "Special precautions for use").

Post-aortocoronary bypass surgery state.

In two large controlled clinical trials, the use of a COX-2 selective NSAID for pain control during the first 10–14 days after aortocoronary bypass surgery was associated with an increased incidence of myocardial infarction and stroke. The use of NSAIDs after aortocoronary bypass surgery is contraindicated (see section "Contraindications").

Patients after myocardial infarction.

Observational studies conducted by the Danish National Registry demonstrated that patients who used NSAIDs after myocardial infarction were at increased risk of recurrent myocardial infarction, cardiovascular death, and all-cause mortality, starting from the first week of treatment. In the same group, among patients using NSAIDs, the rate of fatal outcomes in the first year after myocardial infarction was 20 cases per 100 patient-years, compared to 12 cases per 100 patient-years among patients not using NSAIDs. Although the absolute number of fatal outcomes decreases after the first year following myocardial infarction, analysis of results from at least four subsequent years of follow-up demonstrated that the elevated relative risk of fatal outcomes in patients using NSAIDs persists.

The use of the medicinal product ASPRIX should be avoided in patients with recent myocardial infarction, except when the expected benefit of treatment outweighs the risk of recurrence of thrombotic cardiovascular complications. If ASPRIX is administered to patients with recent myocardial infarction, monitoring for signs of cardiac ischemia should be performed.

Gastrointestinal effects.

The drug is contraindicated in patients with active peptic ulcer and/or gastrointestinal bleeding, and in patients with recent gastrointestinal bleeding or perforation (see section "Contraindications"). Ketorolac may cause severe gastrointestinal adverse reactions, including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, and intestine, which may be fatal. These adverse effects may occur in patients receiving the drug at any time (with or without preceding symptoms). Only one in five patients receiving NSAIDs develops serious upper gastrointestinal symptoms. Upper gastrointestinal ulcers, severe bleeding, or perforation occur in approximately 1% of patients treated with NSAIDs for 3–6 months and in approximately 2–4% of patients treated for one year. However, adverse effects may occur even during short-term therapy.

Risk factors for gastrointestinal bleeding, ulceration, or perforation.

Patients with a history of peptic ulcer disease and/or gastrointestinal bleeding receiving NSAID treatment had more than a 10-fold increased risk of gastrointestinal bleeding compared to patients without such risk factors. Other factors increasing the risk of gastrointestinal bleeding include longer duration of NSAID therapy, concomitant use of oral corticosteroids, acetylsalicylic acid, anticoagulants, or SSRIs, smoking, alcohol consumption, advanced age, and poor general health. Most spontaneous reports of fatal gastrointestinal disease occurred in elderly or debilitated younger patients. Patients with progressive liver disease and/or coagulopathy have an increased risk of gastrointestinal bleeding.

Strategies to minimize gastrointestinal risks in patients using NSAIDs:

• Use the lowest effective dose of ketorolac for the shortest possible duration;
• Avoid using more than one NSAID simultaneously;
• For patients at risk, when the expected benefit does not outweigh the risk of bleeding, consider alternative non-NSAID therapies (the drug is contraindicated in patients with active gastrointestinal bleeding);
• Continuously monitor for signs and symptoms of gastrointestinal ulceration and/or bleeding during NSAID therapy;
• Discontinue the drug immediately if gastrointestinal disturbances occur;
• Patients using low-dose acetylsalicylic acid for cardiovascular disease prevention should be under continuous medical supervision due to the risk of gastrointestinal bleeding;
• Use the drug cautiously in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) due to the risk of exacerbation.

Use in patients with hepatic impairment.

Significant elevations in serum ALT and AST (more than 3 times the upper normal limit) were observed in less than 1% of patients in controlled clinical trials. Additionally, there have been reports of isolated cases of severe hepatic reactions, including fatal fulminant hepatitis, hepatic necrosis, and hepatic failure.

Elevations in ALT and AST (less than 3 times the upper normal limit) were observed in 15% of patients receiving NSAIDs, including ketorolac.

Patients should be informed about possible signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant pain, and flu-like symptoms). Ketorolac should be discontinued if clinical signs of liver disease or systemic manifestations such as eosinophilia or rash develop.

Arterial hypertension.

The use of NSAIDs, including ketorolac, may lead to the development of arterial hypertension or worsening of existing hypertension, and in each case may increase the frequency of cardiovascular adverse reactions. In patients taking ACE inhibitors, thiazide diuretics, or loop diuretics, a reduced response to these drugs may occur with NSAID use (see section "Interaction with other medicinal products and other forms of interaction").

Heart failure and edema.

Results from a meta-analysis by the "Trialists’ Collaboration" and randomized controlled trials of coxibs and traditional NSAIDs demonstrated approximately a twofold increase in hospitalizations due to heart failure in patients receiving selective and non-selective COX-2 inhibitors, and in patients receiving non-selective NSAIDs, compared to patients receiving placebo.

In the Danish National Registry study, NSAID use in patients with heart failure increased the risk of myocardial infarction, hospitalization due to heart failure, and death.

Furthermore, fluid retention and edema have been observed in some patients using NSAIDs. Ketorolac may attenuate the cardiovascular effects of several drugs used to treat these conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers) (see section "Interaction with other medicinal products and other forms of interaction").

The use of the medicinal product ASPRIX should be avoided in patients with severe heart failure, except when the expected benefit of treatment outweighs the risk of worsening heart failure. If ASPRIX is administered to patients with severe heart failure, monitoring for signs of worsening heart failure should be performed.

Use in patients with renal impairment.

Ketorolac and its metabolites are primarily excreted by the kidneys. Patients with reduced creatinine clearance will have reduced drug clearance. The medicinal product ASPRIX is contraindicated in patients with severe renal impairment (see section "Contraindications").

Nephrotoxicity.

Prolonged use of NSAIDs has led to renal papillary necrosis and other kidney damage.

Nephrotoxicity has also been observed in patients in whom renal prostaglandins play a compensatory role in maintaining renal perfusion. In such patients, NSAID use may cause dose-dependent reduction in prostaglandin production and, consequently, decreased renal blood flow, potentially leading to marked deterioration in renal function. Patients at increased risk of these reactions include those with renal impairment, dehydration, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, ACE inhibitors, ARBs, and elderly patients. Discontinuation of the drug is usually followed by return to the pre-treatment state.

Controlled clinical trials lack information on the use of ketorolac in patients with progressive kidney disease. The effect of ketorolac on the kidneys may accelerate the progression of existing renal impairment.

Before initiating treatment with ASPRIX, dehydration or hypovolemia, if present, should be corrected. In patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia, renal function should be monitored during ASPRIX treatment (see section "Interaction with other medicinal products and other forms of interaction"). If ASPRIX is administered to patients with progressive kidney disease, monitoring for signs of renal dysfunction should be performed.

Hyperkalemia.

Cases of elevated serum potassium concentration, including hyperkalemia, have been reported with NSAID use, even in some patients without renal impairment. In patients with normal renal function, these effects were associated with a hyporeninemic-hypoaldosteronemic state.

Anaphylactic reactions.

Ketorolac use has been associated with anaphylactic reactions in patients with known hypersensitivity to ketorolac or without such history, as well as in patients with aspirin-induced asthma. Medical help should be sought immediately if anaphylactic reactions occur.

Exacerbation of bronchial asthma related to aspirin sensitivity.

Some patients with bronchial asthma may have aspirin-induced asthma, which may include chronic rhinosinusitis complicated by nasal polyps, severe, potentially fatal bronchospasm, and intolerance to acetylsalicylic acid and other NSAIDs. Since cross-reactivity between acetylsalicylic acid and other NSAIDs has been documented in such aspirin-sensitive patients, the use of the medicinal product ASPRIX is contraindicated in patients with this form of aspirin sensitivity (see section "Contraindications"). When ASPRIX is used in patients with pre-existing bronchial asthma (without known aspirin sensitivity), monitoring for changes in signs and symptoms of bronchial asthma should be performed.

Serious skin reactions.

Ketorolac may cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which may be fatal. These serious reactions may develop without warning symptoms.

Patients should be informed about the signs and symptoms of serious skin reactions and the necessity to discontinue ASPRIX at the first appearance of skin rash or any other signs of hypersensitivity. Ketorolac is contraindicated in patients with a history of serious skin reactions to NSAIDs (see section "Contraindications").

Premature closure of the fetal ductus arteriosus.

Ketorolac may cause premature closure of the fetal ductus arteriosus; therefore, the use of the drug should be avoided in pregnant women starting from the 30th week of pregnancy (third trimester) (see section "Use during pregnancy or breastfeeding").

Hematological toxicity.

Cases of anemia have been reported in patients using NSAIDs. This may be due to occult or significant blood loss, fluid retention, or an effect on erythropoiesis not fully characterized. If a patient exhibits any signs or symptoms of anemia during ketorolac use, hemoglobin or hematocrit levels should be monitored. Ketorolac is contraindicated in patients with an increased risk of bleeding (see section "Contraindications").

Ketorolac may increase the risk of bleeding. Concomitant factors such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., acetylsalicylic acid), SSRIs, or SNRIs may increase this risk. Such patients should be monitored for signs of bleeding (see section "Interaction with other medicinal products and other forms of interaction"). Studies on the concomitant use of ketorolac with prophylactic low-dose heparin (2500–5000 IU every 12 hours), warfarin, or dextran have not been conducted; therefore, such regimens may also increase bleeding risk. Due to the lack of data from such studies, the benefit-risk ratio must be evaluated, and such concomitant therapy should be used with particular caution. Close monitoring is required for patients taking other medicinal products that adversely affect hemostasis when ketorolac is administered. Serious adverse reactions related to bleeding occur more frequently in patients receiving ketorolac compared to those receiving placebo. Clinical trials and post-marketing experience with ketorolac (intramuscular and intravenous administration) indicate postoperative hematomas and wound bleeding with perioperative use. Therefore, ASPRIX should be used with caution in the postoperative period, especially in patients at increased risk of bleeding.

Masking of inflammation and fever.

The pharmacological activity of ketorolac in reducing inflammation and possibly lowering elevated temperature may diminish the diagnostic value of clinical signs in detecting infections.

Monitoring of laboratory test results.

Since serious gastrointestinal bleeding, hepatotoxicity, and renal damage may occur without warning symptoms or signs, consideration should be given to monitoring patients receiving long-term treatment with periodic complete blood count and biochemical blood tests (see section "Special precautions for use").

Ocular effects.

Contact of the medicinal product ASPRIX with the eyes should be avoided. If the drug enters the eyes, they should be rinsed with water or saline solution. If eye irritation persists for more than one hour, medical advice should be sought.

Use limitations.

The total duration of treatment with ASPRIX, either alone or sequentially with other ketorolac formulations, should not exceed 5 days. ASPRIX should not be used simultaneously with other ketorolac formulations or other NSAIDs.

Elderly patients.

Ketorolac should be used with caution in elderly patients. Elderly patients, compared to younger patients, have a higher risk of developing serious adverse reactions associated with NSAID use, including cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for elderly patients outweighs the potential risks, treatment should be initiated with the lowest dose, and the patient should be monitored for adverse reactions. After assessing the patient's response to initial ASPRIX therapy, the dose and frequency of administration should be adjusted according to individual patient characteristics. Since ketorolac and its metabolites are substantially excreted by the kidneys, the risk of adverse reactions may be greater in patients with impaired renal function. Ketorolac should be used with caution in elderly patients, who are at higher risk of decreased renal function. Renal function should be monitored continuously.

Use during pregnancy or breastfeeding.

The use of ketorolac during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus; therefore, the use of the drug should be avoided in pregnant women starting from the 30th week of pregnancy (third trimester).

Studies on the use of ketorolac in pregnant women have not been conducted. Observational data on potential embryofetal risks of NSAID use in women during the first or second trimester of pregnancy are inconclusive.

In the general U.S. patient population, regardless of drug effects, all clinically recognized pregnancies have a background incidence of 2–4% major congenital defects and 15–20% pregnancy loss.

Reproductive studies in rabbits and rats, where ketorolac was administered at doses 0.6 and 1.5 times higher than the maximum recommended human intranasal dose of 31.5 mg four times daily, showed no evidence of teratogenicity or other adverse developmental outcomes.

Based on animal data, prostaglandins have been shown to play an important role in regulating endometrial vascular permeability, blastocyst implantation, and decidualization. Animal studies administering prostaglandin synthesis inhibitors, such as ketorolac, resulted in increased pre- and post-implantation losses.

Labor and delivery.

Studies on the effect of ketorolac on labor or delivery have not been conducted. In animal studies, ketorolac inhibited prostaglandin synthesis, resulting in delayed delivery and increased stillbirth rates.

Human data.

There are no adequate and well-controlled studies on the use of ketorolac in pregnant women.

Animal data.

Reproductive studies were conducted during organogenesis using daily oral doses of ketorolac at 3.6 mg/kg (0.6 times higher systemic exposure in humans at the recommended maximum intranasal dose of 31.5 mg daily based on AUC) in rabbits and 10 mg/kg (1.5 times higher AUC in humans) in rats. These studies showed no evidence of teratogenicity or other adverse developmental outcomes. Since animal doses were limited by maternal toxicity, the potential for adverse developmental outcomes in humans with ketorolac use cannot be adequately assessed.

Breastfeeding.

Ketorolac is excreted in breast milk. The benefit of breastfeeding for the infant's health and development should be weighed against the mother's clinical need for the medicinal product and any potential adverse effects of ketorolac or the impact of the mother's underlying condition on the infant.

ASPRIX should be used with caution in breastfeeding women. Available information has not demonstrated specific adverse effects in breastfed infants. If any adverse reactions occur, medical advice should be sought.

Limited data from one published study involving 10 breastfeeding mothers 2–6 days postpartum indicate low levels of ketorolac in breast milk. Levels were undetectable (<5 mg/mL) in 4 patients. After a single 10 mg dose of ketorolac, the maximum concentration in milk was 7.3 ng/mL, with a maximum milk-to-plasma ratio of 0.037.

With daily dosing of ketorolac (10 mg every 6 hours), the maximum concentration in milk was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming daily consumption of 400–1000 mL of breast milk and a maternal body weight of 60 kg, the calculated maximum daily infant dose was 0.00263 mg/kg, or 0.4% of the maternal dose adjusted for body weight.

Fertility.

Given that the mechanism of action of ketorolac is mediated through prostaglandins, its use may delay or prevent follicular rupture in the ovary, potentially leading to temporary infertility in some women. Published animal studies have shown that prostaglandin synthesis inhibitors may potentially disrupt prostaglandin-mediated follicular rupture necessary for ovulation. Small studies in women using ketorolac have also demonstrated reversible ovulation delay. Consideration should be given to discontinuing ketorolac in women experiencing difficulties conceiving or undergoing infertility evaluation.

Ability to influence reaction speed when driving vehicles or operating machinery.

The medicinal product does not affect the ability to drive vehicles or operate machinery. However, the possibility of nervous system adverse reactions should be considered.

Method of Administration and Dosage

The medicinal product ASPRIX is recommended for short-term use only (up to 5 days). To minimize adverse effects, the drug should be used at the lowest effective dose for the shortest duration necessary to control symptoms. The drug must not be used concomitantly with other forms of ketorolac tromethamine or with other NSAIDs (see section "Special Warnings and Precautions for Use").

Adult Patients.

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 126 mg (4 recommended doses).

Adult patients with body weight less than 50 kg.

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 63 mg (2 recommended doses).

Elderly Patients.

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 63 mg (2 recommended doses).

Patients with Renal Impairment.

The recommended dose is 31.5 mg of ketorolac tromethamine (15.75 mg of ketorolac tromethamine in each nostril, i.e., one spray per nostril) every 6–8 hours. The maximum daily dose is 63 mg (2 recommended doses).

Instructions for Use.

For optimal effectiveness of ASPRIX nasal spray, the nostrils should be cleared (gently blown) before administration.

Remove the protective cap before use.

Before first use, press the pump 5 times to prime the device, directing the spray into the air until a fine, uniform mist is produced. The product is now ready for use.

If more than one day has passed since the last use, prime the pump once by spraying into the air before administration to prevent delivery of an incomplete dose.

Hold the bottle upright with the spray nozzle pointing upwards during administration.

Tilt the head slightly forward, insert the spray into the left nostril, slightly angling the tip away from the center of the nose, and administer one spray. Repeat the same procedure in the right nostril.

To prevent accidental spraying, replace the protective cap after use.

Store the bottle in a cool, dark place (see section "Storage Conditions").

Children.

Safety and efficacy of the drug in children have not been established; therefore, ASPRIX should not be used in pediatric practice.

Overdose.

Symptoms of acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric abdominal pain, and are generally reversible with supportive care. Cases of gastrointestinal bleeding have been reported. Rarely, arterial hypertension, acute renal failure, respiratory depression, and coma have been observed.

No cases of ketorolac overdose were reported during clinical trials. In controlled overdose studies using intramuscular ketorolac at a daily dose of 360 mg administered for 5 days (approximately 3 times the maximum recommended daily dose), cases of abdominal pain and gastric ulceration were observed, which resolved after discontinuation of the drug.

Individual cases of ketorolac overdose have been associated with gastric pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and impaired renal function.

Following overdose, patients require symptomatic and supportive treatment. There are no specific antidotes. Induction of emesis and/or administration of activated charcoal (60–100 g) and/or an osmotic laxative should be considered in patients who develop symptoms within 4 hours after administration, as well as in patients with severe overdose (dose 5–10 times higher than the recommended dose).

Forced diuresis, urine alkalinization, hemodialysis, or hemoperfusion are not recommended due to high protein binding.

Adverse Reactions.

Clinical trial experience.

Since clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of one drug cannot be directly compared to the frequency in the clinical trials of another drug, and may not reflect the frequencies observed in clinical practice.

Based on clinical trial data, the most commonly reported adverse reactions in patients receiving ketorolac were nasal discomfort or irritation. These adverse reactions were generally mild and transient. The most frequent adverse reactions leading to discontinuation of the drug were nasal discomfort or nasal pain (rhinalgia).

Adverse reactions reported in clinical trials with other doses and formulations of ketorolac or other NSAIDs.

The incidence of adverse reactions increases with higher doses of ketorolac. Serious complications associated with ketorolac use, including gastrointestinal ulcers, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and hepatic failure, require careful monitoring. Improper use of ketorolac may result in serious consequences.

The following adverse reactions were reported in 1–10% of patients treated with ketorolac or other NSAIDs:

Gastrointestinal: abdominal pain, flatulence, gastrointestinal bleeding or perforation, stomatitis, constipation, diarrhea, bloating, heartburn, vomiting, dyspepsia, peptic ulcer (gastric/duodenal), nausea.

Other: renal dysfunction, drowsiness, headache, injection site pain, rash, anemia, edema, hypertension, pruritus, tinnitus, dizziness, elevated liver enzymes, prolonged bleeding time, purpura, increased sweating.

Rare adverse reactions reported in clinical trials in <1% of patients treated with ketorolac or other NSAIDs:

Infections and infestations: fever, infections, sepsis.

Cardiovascular system disorders: congestive heart failure, palpitations, pallor, tachycardia, syncope.

Gastrointestinal disorders: anorexia, dry mouth, belching, esophagitis, increased thirst, gastritis, glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding.

Blood and lymphatic system disorders: ecchymoses, eosinophilia, epistaxis, leukopenia, thrombocytopenia.

Metabolism and nutrition disorders: weight changes.

Nervous system disorders: unusual dreams, cognitive disturbances, anxiety, malaise, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesia, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremor, vertigo, malaise.

Respiratory, thoracic and mediastinal disorders: asthma, dyspnea, pulmonary edema, rhinitis.

Specific reactions: taste disturbances, visual disturbances, blurred vision, hearing loss.

Renal and urinary system disorders: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention.

Post-marketing experience.

The following adverse reactions have been identified during post-approval use of ketorolac or other NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders: angioneurotic edema, hypersensitivity reactions such as anaphylaxis (which may be fatal), anaphylactoid reactions, laryngeal edema, tongue edema, myalgia.

Cardiovascular system disorders: arrhythmia, bradycardia, chest pain, hyperemia, hypotension, myocardial infarction, vasculitis.

Skin and subcutaneous tissue disorders: exfoliative dermatitis, erythema multiforme, Lyell's syndrome (toxic epidermal necrolysis), bullous reactions including Stevens–Johnson syndrome and toxic epidermal necrolysis.

Gastrointestinal disorders: acute pancreatitis, hepatic failure, ulcerative stomatitis, exacerbation of ulcerative colitis and Crohn's disease.

Blood and lymphatic system disorders: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative bleeding (rarely requiring blood transfusion).

Metabolism and nutrition disorders: hyperglycemia, hypokalemia, hyponatremia.

Central nervous system disorders: aseptic meningitis, seizures, coma, psychosis.

Respiratory, thoracic and mediastinal disorders: bronchospasm, respiratory depression, pneumonia.

Specific reactions: conjunctivitis.

Renal and urinary system disorders: flank pain (with/without hematuria and/or azotemia), hemolytic uremic syndrome.

Shelf life.

2 years.

Storage conditions.

Store at 2 to 8 °C in the original packaging.

Keep out of reach of children.

Packaging.

4 ml (40 doses) in amber glass bottles, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

MICROCHEM LLC (responsible for batch release, excluding batch control/testing).

Manufacturer's address and location of operations.

5 Budyndustrії Street, Kyiv, 01013, Ukraine.

To report an adverse event associated with the use of this medicinal product, please call +38 (050) 309-83-54 (24/7).