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

Composition:

Active substances: ketorolac tromethamine, pitofenone hydrochloride, fenpipramid bromide;

1 ml of solution contains: ketorolac tromethamine 15 mg, pitofenone hydrochloride 5 mg, fenpipramid bromide 0.05 mg;

Excipients: sodium chloride, propylene glycol, disodium edetate, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, slightly yellowish or slightly greenish liquid.

Pharmacotherapeutic group. Spasmolytics in combination with analgesics.

ATC code A03D A02.

Pharmacological Properties

Pharmacodynamics

Neospazil® is a combination medicinal product belonging to the group of spasmolytics in combination with analgesics. It contains three active substances: the non-narcotic analgesic ketorolac tromethamine, the myotropic spasmolytic pitofenone hydrochloride, and the cholinolytic agent phenoperidine bromide.

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID), an inhibitor of cyclooxygenase (COX)-1 and COX-2, and a derivative of pyrrolizinecarboxylic acid, which exerts a pronounced analgesic effect. The mechanism of action of ketorolac (like other NSAIDs) is not fully understood but may involve inhibition of prostaglandin synthesis. The biological activity of ketorolac tromethamine is associated with its S-enantiomer. Ketorolac tromethamine has no sedative or anxiolytic properties. It is not an opioid and therefore does not affect opioid receptors.

The maximum analgesic effect of ketorolac is achieved within 2–3 hours. This effect shows no statistically significant differences across the recommended dosage range. The main difference between higher and lower doses of ketorolac lies in the duration of analgesia. The analgesic dose of ketorolac also exerts anti-inflammatory effects.

Phenoperidine bromide produces moderate ganglion-blocking and anticholinergic effects, reducing the tone and motor activity of smooth muscles in the stomach, intestines, and biliary and urinary tracts.

Pitofenone hydrochloride produces a papaverine-like effect with pronounced spasmolytic activity on smooth muscle.

The combination of the three components in the medicinal product results in mutual enhancement of their pharmacodynamic effects, manifested as pain relief, relaxation of smooth muscles, and reduction of body temperature.

Clinical Studies

A pivotal prospective, multicenter, randomized, comparative Phase II/III clinical study, KPF07-T, was conducted with Neospazil®. The objective of this study was to evaluate the efficacy and safety of Neospazil® compared to ketorolac tromethamine in patients with postoperative pain following abdominal and pelvic surgery. A total of 424 patients were randomized. Patients with a resting pain score of 4–8 inclusive on the 11-point Numerical Rating Scale (NRS) on the first day of treatment received the investigational medicinal products as an intramuscular injection solution (1 ampoule three times daily every 8 hours). From day 2, patients were switched to oral administration of the investigational medicinal products if, for example, their pain score during movement was 4–6 points on the NRS or 7 points provided that their resting pain score did not exceed 6 points on the 11-point NRS. The investigational medicinal products were administered orally as 1 tablet four times daily for 24 hours, followed by administration as needed. The total duration of investigational treatment in the KPF07-T trial did not exceed 5 days.

Superior efficacy of Neospazil® injection solution compared to ketorolac tromethamine injection solution was demonstrated in patients with postoperative pain following abdominal and pelvic surgery, both for the primary efficacy endpoint and secondary efficacy endpoints, including:

• The proportion of study subjects achieving treatment response within the first 24 hours of administration of the injection formulation was 68.9% in the main group (Neospazil®) versus 36.2% in the control group (ketorolac tromethamine) (p < 0.001).
• The median time to noticeable and significant reduction in resting pain intensity from the time of first dose of the injection formulation was 25 minutes and 55 minutes, respectively, in the main group, versus 34 minutes and 64 minutes, respectively, in the control group (p < 0.001).
• The median area under the curve (AUC) of resting pain intensity on the NRS during injection therapy was statistically significantly lower in the main group (Neospazil®) — 64.38 — compared to the control group (ketorolac tromethamine) — 72.5 (p < 0.001). During movement, this value was 77.25 and 90.13, respectively (p < 0.001).
• The median sum of differences in resting pain intensity compared to baseline over the first 6 hours after administration of the injection formulation was statistically significantly lower in the main group (Neospazil®) — (-17.5) — compared to the control group (ketorolac tromethamine) — (-13.0) (p < 0.001). During movement, this value was -20.5 and -16.5, respectively (p < 0.001).
• The proportion of study subjects achieving treatment response based on the patient's overall assessment of pain control over 24 hours of injection treatment, considering the use of other analgesics, was 84.0% in the main group (Neospazil®) and 16.7% in the control group (ketorolac tromethamine) (p < 0.001).

Pharmacokinetics

Neospazil®

In healthy volunteers, after intramuscular administration of Neospazil® medicinal product, maximum plasma concentrations of phenoperidine and pitofenone were reached within 0.75 hours, and of ketorolac within 1.33 hours.

Table 1

AUC0–t and Cmax of ketorolac, phenoperidine, and pitofenone after single intramuscular administration of 2 ml of Neospazil® medicinal product (mean ± SD)

In healthy volunteers, after intramuscular administration of the medicinal product Neospazhil**®**, the elimination half-life of ketorolac, fenpiverinium, and pitofenone was 5.71 ± 0.65 h, 4.44 ± 1.60 h, and 2.25 ± 2.65 h, respectively. The pharmacokinetic profiles of ketorolac, fenpiverinium, and pitofenone declined in a multiexponential manner.

Ketorolac tromethamine

Ketorolac tromethamine is a racemic mixture of [-] S and [+] R-enantiomeric forms, with analgesic activity attributed to the S-form. After intramuscular administration, ketorolac is rapidly and completely absorbed. The mean peak plasma concentration of 2.2 µg/mL is reached on average within 50 minutes after a single 30 mg dose.

Linear pharmacokinetics

In adults, following intramuscular administration of ketorolac tromethamine within the recommended dosage range, the clearance of the racemate remains unchanged. This indicates that the pharmacokinetics of ketorolac tromethamine in adults after single or multiple intramuscular doses are linear. With higher recommended doses, a proportional increase in concentrations of both free and protein-bound racemate is observed.

Ketorolac poorly penetrates the blood-brain barrier. Ketorolac crosses the placenta and is excreted in small amounts into breast milk. In blood plasma, more than 99% of ketorolac is protein-bound across a wide range of concentrations.

Table 2

Approximate mean pharmacokinetic parameters of ketorolac after intramuscular administration (mean ± SD)

1 Time to reach maximum plasma concentration.

2 Maximum plasma concentration.

3 Minimum plasma concentration in blood plasma.

4 Average concentration in blood plasma.

5 Volume of distribution.

* Mean values were modeled using plasma concentration data, and standard deviation was modeled using the percentage coefficient of variation of Cmax and Tmax values.

Not applicable, as pharmacokinetic parameters were not studied with this administration regimen.

SD — standard deviation.

Metabolism

Ketorolac tromethamine is extensively metabolized in the liver. Metabolites include hydroxylated and conjugated derivatives of the drug. Metabolites and some unchanged drug are excreted in urine.

Excretion

The primary route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is recovered in urine: about 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of the dose is excreted in feces. In a study with single 10 mg dose of ketorolac, 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 subsequent dose. Differences between S- and R-forms in humans are negligible or absent.

The elimination half-life of the S-enantiomer of ketorolac tromethamine is approximately 2.5 hours, and that of the R-enantiomer is 5 hours. Other studies have reported a half-life of 5–6 hours for the racemate.

Accumulation

Intravenous bolus administration of ketorolac tromethamine every 6 hours for 5 days in healthy volunteers did not show a significant difference in Cmax values between day 1 and day 5. Minimum levels averaged 0.29 mcg/mL on day 1 and 0.55 mcg/mL on day 6. Steady state was achieved after the fourth dose. Accumulation of ketorolac tromethamine has not been studied in specific patient populations (elderly patients, children, patients with renal or hepatic impairment).

Pharmacokinetics in specific patient populations

Elderly patients

Based on data obtained after single-dose administration, the elimination half-life of ketorolac tromethamine racemate increased from 5 to 7 hours in elderly patients (65–78 years) compared to younger healthy volunteers (24–35 years).

Children

Pharmacokinetic data on intramuscular administration of ketorolac tromethamine in children are lacking.

Renal impairment

Based on data from single-dose administration, the elimination half-life of ketorolac tromethamine 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 clearance of ketorolac tromethamine in elderly patients or those with renal impairment. In patients with kidney disease, AUC0–∞ values for each enantiomer are nearly doubled 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 tromethamine suggests an increase in the unbound fraction.

Hepatic impairment

Half-life, AUC0–∞, and Cmax values in 7 patients with liver disease did not differ significantly from those in healthy volunteers.

Phenoperidine bromide

The pharmacokinetics of phenoperidine was not studied separately.

Pitofenone hydrochloride

The pharmacokinetics of pitofenone was not studied separately.

Clinical characteristics

Indications

For short-term symptomatic treatment of moderate to severe pain:

• due to spasms of smooth muscle of internal organs: renal colic, spasms of the urinary bladder and urinary tract, hepatic colic, spasms of the stomach and intestines, spastic dyskinesia of the biliary tract;
• following surgical interventions and diagnostic procedures on visceral organs of the abdominal cavity and small pelvis.

Contraindications

Warning: Do not use the medicinal product for mild or chronic pain.

• Hypersensitivity to ketorolac, fenpiverine, pitothenone, or to any other component of the medicinal product;
• active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer or gastrointestinal bleeding;
• bronchial asthma, rhinitis, angioedema or urticaria caused by acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (due to the possibility of severe anaphylactic reactions);
• history of bronchial asthma;
• complete or partial nasal polyp syndrome, angioedema or bronchospasm;
• use as an analgesic before and during surgery, during manipulations on coronary vessels;
• use in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis, and in patients receiving anticoagulants, including warfarin or low-dose heparin (2500–5000 units every 12 hours);
• severe heart failure;
• severe hepatic insufficiency;
• moderate/severe renal insufficiency (serum creatinine concentration >160 µmol/L);
• suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders, high risk of bleeding;
• concomitant treatment with acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 inhibitors), pentoxifylline, probenecid, or lithium salts;
• hypovolemia, dehydration with risk of renal failure due to reduced fluid volume;
• use in patients undergoing intensive diuretic therapy;
• labor and delivery;
• II and III degree prostatic hyperplasia;
• atony of the gallbladder and urinary bladder;
• tachyarrhythmia;
• collapse state;
• closed-angle glaucoma;
• gastrointestinal tract obstruction and megacolon;
• epidural or intrathecal administration of the medicinal product;
• the medicinal product is contraindicated in children under 18 years of age.

Interaction with other medicinal products and other types of interactions

The interaction of Neospastil® with other medicinal products is due to the presence of ketorolac tromethamine. Ketorolac is highly bound to plasma proteins (on average 99.2%). Ketorolac does not alter the pharmacokinetics of other agents through enzyme induction or inhibition.

Ketorolac tromethamine does not affect the protein binding of digoxin in plasma. In vitro studies show that at therapeutic concentrations of salicylates (300 µg/mL), ketorolac binding decreased from approximately 99.2% to 97.5%, indicating a potential twofold increase in unbound ketorolac levels in plasma. Digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide at therapeutic concentrations do not alter the protein binding of ketorolac tromethamine. Concomitant use of ketorolac and prophylactic low-dose heparin (2500–5000 IU every 12 hours) has not been widely studied but may be associated with an increased risk of bleeding. Ketorolac should not be administered to patients receiving anticoagulants or low-dose heparin.

Since ketorolac is a potent agent and its plasma concentration is low, it is unlikely that it will significantly displace other medicinal products from plasma protein binding.

Medicinal products contraindicated for concomitant use with Neospastil®

Acetylsalicylic acid and other NSAIDs. When used with acetylsalicylic acid, the protein binding of ketorolac decreases, although the clearance of free ketorolac remains unchanged. The clinical significance of this interaction is unknown; however, as with other NSAIDs, concomitant use of ketorolac tromethamine and acetylsalicylic acid is contraindicated due to the potential increased frequency of adverse effects.

Anticoagulants. Concomitant use with anticoagulants may enhance bleeding. Concomitant use with anticoagulants (such as warfarin) is contraindicated.

Lithium. Concomitant use of NSAIDs and lithium preparations is contraindicated due to possible inhibition of renal lithium clearance, increased plasma lithium concentration, and lithium toxicity.

Probenecid. Concurrent administration of ketorolac tromethamine and probenecid leads to reduced clearance of ketorolac, significant increase in its plasma levels, and prolonged elimination half-life. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Oxpentifylline. Concomitant use is not recommended due to increased risk of hemorrhage.

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

Pentoxifylline. Concomitant use of ketorolac tromethamine and pentoxifylline increases the risk of bleeding.

Medicinal products that should be used with caution in combination with Neospastil®

Corticosteroids. As with all NSAIDs, corticosteroids should be used concomitantly with caution due to increased risk of gastrointestinal bleeding.

Selective serotonin reuptake inhibitors (SSRIs). There is an increased risk of gastrointestinal bleeding with concomitant use of SSRIs and NSAIDs. Caution should be exercised when using them together.

MTX (Methotrexate). Since NSAIDs may reduce methotrexate clearance, increased toxicity of the latter is possible.

Diuretics. In some patients, ketorolac may reduce the natriuretic effect of furosemide and thiazides. During concomitant therapy with NSAIDs, patients should be closely monitored for signs of renal impairment and to ensure diuretic efficacy (see section "Special precautions"). In healthy volunteers with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%; therefore, special attention is required when prescribing ketorolac to patients with cardiac decompensation.

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

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

Thrombolytic agents. Concomitant use with NSAIDs increases the risk of bleeding.

Although studies do not indicate significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac with agents affecting hemostasis, including anticoagulant doses (warfarin), low-dose prophylactic heparin (2500–5000 IU every 12 hours), and dextrans, may be associated with an increased risk of bleeding.

Cyclosporine. As with all NSAIDs, concomitant use with cyclosporine is contraindicated due to increased risk of nephrotoxic effects.

Tacrolimus. NSAIDs may increase the risk of nephrotoxicity.

Opioid analgesics. The effect of opioid analgesics is enhanced, allowing for dose reduction during analgesia.

Quinolones. Patients taking quinolones may have an increased risk of seizures.

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

Anticonvulsants. Isolated cases of seizures have been reported during concomitant use of ketorolac tromethamine and anticonvulsants (phenytoin, carbamazepine).

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

Non-depolarizing muscle relaxants

No official studies on the concomitant use of ketorolac tromethamine and muscle relaxants have been conducted. NSAIDs may reduce the excretion of baclofen (increasing the risk of toxicity). Animal and human studies have not shown evidence that ketorolac tromethamine induces or inhibits liver enzymes capable of metabolizing it or other drugs. Therefore, ketorolac is not expected to alter the pharmacokinetics of other drugs via enzyme induction or inhibition.

Antidiabetic agents. NSAIDs may potentiate the effect of sulfonylurea derivatives.

Preparations containing garlic, onion, or Ginkgo biloba may enhance the effect of ketorolac and increase the risk of hemorrhagic complications.

Concomitant use of Neospastil® with quinine-containing preparations may enhance the anticholinergic effect.

Oral administration of ketorolac tablets after a high-fat meal resulted in delayed and reduced peak concentration of ketorolac by approximately 1 hour. Antacids did not affect the extent of absorption.

Special precautions for use

It is recommended to use the drug under hospital conditions.

When using the injectable form, the drug should not be mixed in the same syringe with other medicinal products.

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

Concomitant use of the drug Neospastil® and NSAIDs, as well as selective cyclooxygenase-2 inhibitors, is contraindicated (see section "Contraindications").

The combined use of intramuscular and oral ketorolac tromethamine in adult patients should not exceed 2 days.

In patients with cardiac, renal, or hepatic insufficiency who are taking diuretics, or in patients with hypovolemia after surgery, careful monitoring of diuresis and renal function is required.

Use in elderly patients

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

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

Gastrointestinal disorders. The active ingredient of Neospastil®, ketorolac tromethamine, may cause severe adverse reactions in the gastrointestinal tract. These adverse effects may occur in patients taking ketorolac tromethamine at any time, with or without preceding symptoms, and may be fatal. The risk of clinically significant gastrointestinal bleeding is dose-dependent. However, adverse effects may occur even during short-term therapy. Predisposing factors include a history of peptic ulcer, concomitant use of oral corticosteroids, anticoagulants, long-term NSAID therapy, smoking, alcohol consumption, advanced age, and poor general health. In such cases, careful consideration should be given to combining NSAIDs with gastroprotective agents, such as misoprostol or a proton pump inhibitor. Most spontaneous reports of gastrointestinal adverse effects involved elderly or debilitated patients; therefore, special attention is required when treating such patients, and the drug should be discontinued if adverse reactions are suspected. Alternative therapies not involving NSAIDs should be considered for high-risk patients. Patients (especially elderly) with diagnosed gastrointestinal disorders in their medical history should report any abdominal symptoms (especially gastrointestinal bleeding). These symptoms should be closely monitored at the beginning of treatment.

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

NSAIDs should be used with caution in patients with a history of Crohn's disease or ulcerative colitis due to the possibility of worsening the disease course.

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

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

Hematological effects. Concomitant use of ketorolac tromethamine in patients receiving anticoagulant therapy may increase the risk of bleeding. Although detailed studies on the concomitant use of ketorolac and low-dose prophylactic heparin (2,500–5,000 IU every 12 hours) have not been conducted, an increased risk of bleeding with this regimen cannot be excluded. Patients already taking anticoagulants or requiring low-dose heparin should not receive ketorolac tromethamine. Close monitoring is required in patients receiving other agents that negatively affect hemostasis when administering ketorolac tromethamine. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal hemostasis, bleeding duration increases but remains within normal limits (2 to 11 minutes). Unlike the prolonged effect after acetylsalicylic acid intake, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac. Ketorolac tromethamine preparations are contraindicated in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis. Caution is advised when stable hemostasis is critical, such as in cosmetic or outpatient procedures, prostatectomy, or tonsillectomy. Hematomas, other signs of wound bleeding, and epistaxis may occur during ketorolac use.

When prescribing ketorolac, its similarity to other cyclooxygenase-inhibiting NSAIDs and the potential risk of bleeding, especially in elderly patients, should be considered. Ketorolac tromethamine is not an anesthetic and does not possess sedative or anxiolytic properties.

Use in patients with impaired renal function (see "Contraindications"). Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have toxic effects on the kidneys (e.g., glomerulonephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, acute renal failure); therefore, it should be used with caution in patients with impaired renal function or a history of kidney disease. High-risk groups include patients with impaired renal function, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Caution is required in patients whose disease may reduce blood volume and/or renal blood flow, where prostaglandins play a crucial role in maintaining perfusion. In such patients, NSAID use may cause dose-dependent inhibition of prostaglandin synthesis and renal failure.

Ketorolac may increase serum levels of urea, creatinine, and potassium ions; deviations from normal may occur even after a single dose. After discontinuation of NSAID therapy, patients' condition usually normalizes.

Patients with mild renal impairment should receive lower doses of ketorolac (not exceeding 60 mg/day intramuscularly). Renal function in these patients should be closely monitored. Patients should be adequately hydrated before starting treatment. In patients undergoing hemodialysis, ketorolac clearance is reduced by approximately half compared to normal, and the terminal elimination half-life is nearly tripled.

Due to the fact that both advanced age (>65 years) and impaired renal function require dose reduction, and considering the lack of clinical pharmacokinetic data in this population, the drug should be used in elderly patients with impaired renal function only after careful assessment of the benefits and risks associated with such therapy.

Effects on the cardiovascular system and cerebral vessels. Close monitoring is required in patients with arterial hypertension and/or a history of mild to moderate heart failure. Use of Neospastil® in patients with cardiac diseases (arrhythmias, ischemic heart disease, congestive heart failure) requires special caution and physician supervision.

To minimize the potential risk of cardiovascular complications in patients taking NSAIDs, the lowest effective dose should be prescribed for the shortest possible duration.

Ketorolac tromethamine preparations may be prescribed to patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful consideration of the benefits and risks of such treatment. Similarly, the appropriateness of prescribing ketorolac preparations should be evaluated before initiating long-term treatment in patients at risk of cardiovascular diseases (e.g., patients with arterial hypertension, hyperlipidemia, diabetes mellitus, and smokers).

Clinical studies and epidemiological data suggest that the use of certain NSAIDs, particularly at high doses and for prolonged periods, may be associated with a slight increase in the risk of arterial thromboembolic events, such as myocardial infarction or stroke. Such a risk cannot be excluded for ketorolac.

In patients who have experienced myocardial infarction, there is a risk of recurrent myocardial infarction during the first week of NSAID use. Injectable formulations containing ketorolac tromethamine should be avoided in patients who have recently had a myocardial infarction, except when the expected benefit outweighs the risk of recurrent cardiovascular thrombosis. If a drug containing ketorolac tromethamine is used in patients with recent myocardial infarction, the patient should be under close surveillance for signs of cardiac ischemia.

Use in patients with impaired hepatic function. Ketorolac tromethamine preparations should be prescribed with caution in patients with impaired liver function or a history of liver disease. Significant increases (more than three times the normal value) in serum alanine aminotransferase and aspartate aminotransferase activities have been observed in less than 1% of patients. Additionally, there have been reports of rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, hepatic necrosis, and liver failure, some of which were fatal. Ketorolac preparations should be discontinued if clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash) appear.

Respiratory system. The patient's condition should be monitored for the possible development of bronchospasm.

Systemic lupus erythematosus and mixed connective tissue diseases. Patients with systemic lupus erythematosus and various mixed connective tissue diseases have an increased risk of developing aseptic meningitis.

Skin disorders. Serious skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and Lyell's syndrome, have been reported. The highest risk of these reactions occurs at the beginning of treatment. Patients should discontinue the drug at the first sign of rash, mucosal lesions, or other signs of hypersensitivity.

Fluid retention and edema. Fluid retention and edema have been reported during ketorolac use; therefore, its preparations should be prescribed with caution to patients with cardiac decompensation, arterial hypertension, or similar conditions.

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

Prostatic hyperplasia. Use with caution in patients with grade I prostatic hyperplasia, as the anticholinergic effect of the drug may cause urinary retention in susceptible patients. If symptoms of difficult urination occur, treatment should be discontinued.

Nervous system and visual organs. Use of Neospastil® in patients with glaucoma or myasthenia gravis requires special caution and physician supervision. Prolonged use of the drug may lead to dizziness or accommodation disorders due to its cholinolytic effect.

Effects on fertility. In women undergoing infertility evaluation, the use of ketorolac tromethamine preparations should be discontinued. Women with reduced fertility should avoid using the drug.

Excipients. When using the drug at the maximum daily dose, the highest dose of propylene glycol that a patient may receive does not exceed 50 mg/kg/day.

Use during pregnancy or breastfeeding

Due to the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system, drugs containing ketorolac are contraindicated during pregnancy (especially in the third trimester).

Pregnancy.

The safety of use during pregnancy has not been established. It has been proven that ketorolac crosses the placental barrier and enters the fetal organism. Therefore, ketorolac tromethamine is contraindicated during pregnancy and childbirth.

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

From the 20th week of pregnancy, the use of ketorolac tromethamine may cause oligohydramnios due to fetal renal dysfunction. This condition may occur shortly after starting treatment and is usually reversible after discontinuation of therapy. Additionally, reports of arterial duct constriction after treatment in the second trimester, most of which were reversible after discontinuation, have been documented.

Also, during pregnancy, all prostaglandin synthesis inhibitors may cause the following in the fetus:

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

At the end of pregnancy, these drugs may affect both the mother and the newborn by:

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

Therefore, the use of ketorolac is contraindicated throughout pregnancy.

If a pregnant woman has taken the drug, antenatal monitoring for oligohydramnios after ketorolac exposure should be considered for several days starting from the 20th week of pregnancy. Ketorolac use should be discontinued.

Breastfeeding.

Ketorolac passes into breast milk in small amounts; therefore, Neospastil is contraindicated during breastfeeding.

Fertility.

The use of other cyclooxygenase/prostaglandin synthesis inhibitors suggests that ketorolac may negatively affect fertility; it is not recommended for women planning pregnancy. Women with fertility problems or undergoing infertility evaluation should discontinue ketorolac use.

Ability to affect reaction speed when driving or operating machinery

The drug may reduce patients' psychophysical abilities and negatively affect activities requiring increased attention, motor coordination, and rapid response (e.g., driving vehicles, operating machinery, working at heights). In some patients, dizziness, drowsiness, visual disturbances, headache, vertigo, insomnia, or depression may occur when using medicinal products containing ketorolac tromethamine. If a patient experiences these or similar adverse effects, they should not drive vehicles or operate other machinery.

Administration and Dosage

It is recommended to use the drug under hospital conditions.

After intramuscular administration, analgesic effect occurs approximately within 30 minutes, and maximum pain relief is achieved within 1–2 hours. Overall, the average duration of analgesia is 8–12 hours. The dose should be adjusted according to the severity of pain and the patient's response to treatment. The risk of adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. The drug is contraindicated for epidural or intraspinal administration.

Before injection, it is recommended to warm the ampoule with the drug to body temperature.

Adults

For smooth muscle spasms of internal organs

The recommended dose of Neospastil**®** is 1–2 mL (15–30 mg calculated as ketorolac tromethamine) every 8 hours. The lowest effective dose should be prescribed. The maximum duration of treatment should not exceed 2 days.

For relief of visceral pain after surgical interventions and diagnostic procedures on visceral organs of the abdominal cavity and pelvic region

The recommended initial dose of Neospastil**®** is 1 mL (15 mg calculated as ketorolac tromethamine), followed by 1–2 mL (15–30 mg calculated as ketorolac tromethamine) every 8–12 hours as needed. The lowest effective dose should be prescribed. The maximum duration of treatment should not exceed 2 days.

Additional recommendations for use in adults

The total daily dose, calculated as ketorolac tromethamine, should not exceed 90 mg in younger patients, and 60 mg in elderly patients, patients with renal impairment, and patients with body weight less than 50 kg. The dose should be reduced in patients with body weight less than 50 kg. Concomitant use of opioid analgesics (morphine, pethidine, etc.) is possible. Ketorolac does not negatively affect opioid receptor binding and does not enhance respiratory depression or sedative effects of opioid drugs. For patients receiving Neospastil**®** parenterally and being switched to oral Neospastil**®** tablets, the total combined daily dose should not exceed 90 mg of ketorolac tromethamine (60 mg for elderly patients, patients with renal impairment, and patients with body weight less than 50 kg). On the day of switching formulations, the dose of the oral component should not exceed 40 mg of ketorolac tromethamine. The maximum duration of treatment involving transition from injectable to oral form should not exceed 5 days (with the maximum duration of injectable treatment not exceeding 2 days). Patients should be switched to oral therapy as soon as possible.

Elderly patients. Elderly patients (over 65 years of age) should be prescribed the lowest dose within the recommended range. The total daily dose should not exceed 60 mg (calculated as ketorolac tromethamine).

Patients with renal impairment. Ketorolac is contraindicated in moderate to severe renal impairment. In milder forms of renal dysfunction, dosage reduction is required (not more than 60 mg calculated as ketorolac tromethamine per day by intramuscular route).

Children

The drug is contraindicated in children (under 18 years of age).

Overdose

Symptoms: depressed state, drowsiness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, arterial hypertension, acute renal failure, respiratory depression, and coma. Anticholinergic effects may also occur. Cases of anaphylactoid reactions have been reported.

Treatment. Discontinue the drug. Treatment is symptomatic and supportive. There is no specific antidote. Forced diuresis, urine alkalinization, hemodialysis, or blood transfusion may be ineffective due to the high plasma protein binding of ketorolac.

Adverse Reactions

Gastrointestinal disorders: dry mouth, abdominal discomfort, bloating, nausea, dyspepsia, altered taste sensation, anorexia, gastrointestinal pain, epigastric pain, diarrhea; less frequently – flatulence, belching, vomiting, constipation, erosive and ulcerative changes including gastrointestinal bleeding and perforation, sometimes fatal (especially in elderly patients), hematemesis, gastritis, peptic ulcer, pancreatitis, melena, rectal bleeding, ulcerative stomatitis, esophagitis, exacerbation of Crohn’s disease and colitis.

Hepatobiliary and biliary tract disorders: very rarely – liver function abnormalities, hepatic failure, jaundice, hepatitis, increased liver transaminase activity.

Psychiatric disorders: cognitive disturbances, depression, insomnia, anxiety, irritability, nervousness, psychotic reactions, abnormal dreams, hallucinations, euphoria, decreased ability to concentrate, stupor, confusion.

Nervous system disorders: headache, dizziness, convulsions, paresthesia, hyperkinesia, taste disturbances.

Sensory organ disorders: visual disturbances, accommodation disorders, conjunctivitis, retrobulbar neuritis, tinnitus, hearing loss.

Musculoskeletal system disorders: myalgia, functional impairments.

Urinary system disorders: severe pain in the renal area, frequent urination, oliguria, polyuria, anuria, hyponatremia, hyperkalemia, hematuria, proteinuria, elevated serum urea and creatinine levels, urinary retention, acute renal failure, chronic renal failure, interstitial nephritis, papillary necrosis, hemolytic uremic syndrome, nephrotic syndrome (rare).

Cardiovascular system disorders: pallor, flushing, chest pain, palpitations, bradycardia, heart failure, arterial hypertension or hypotension, edema. Clinical and epidemiological data suggest that the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with an increased risk of arterial thromboembolic complications (myocardial infarction or stroke) (see section "Special Warnings and Precautions for Use").

Blood and lymphatic system disorders: purpura, thrombocytopenia, neutropenia, agranulocytosis, granulocytopenia, anemia (aplastic, hemolytic), possible occurrence of subcutaneous hemorrhages, hematomas, epistaxis.

Respiratory system disorders: bronchospasm, dyspnea, asthma, pulmonary edema.

Reproductive system disorders: infertility (in women).

Skin and subcutaneous tissue disorders: pruritus, urticaria, photosensitivity reactions, Lyell’s syndrome, bullous reactions, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, maculopapular and exudative rashes.

Allergic reactions: anaphylactic reactions, urticaria, bronchospasm, laryngeal edema, angioneurotic edema, dyspnea, arterial hypotension, flushing, exfoliative dermatitis, bullous dermatitis. Such reactions may occur in patients with or without known hypersensitivity to ketorolac or other NSAIDs. They may also occur in individuals with a history of angioneurotic edema or bronchospastic reactivity (e.g., asthma and nasal polyps). Anaphylactoid reactions such as anaphylaxis can be fatal.

General disorders: asthenia, edema, pain and infiltration at the injection site, increased body temperature, increased sweating, weight gain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 4 years.

Storage conditions

Store in the original packaging at a temperature between 2 °C and 8 °C.

Storage in the original packaging at temperatures not exceeding 25 °C is permitted for up to 6 months. After this period, the medicinal product must not be used.

Keep out of reach of children.

Incompatibilities

The medicinal product should not be mixed in small-volume containers (e.g., in the same syringe) with morphine sulfate, meperidine hydrochloride, promethazine, or hydroxyzine, as one of its components – ketorolac – may precipitate.

Packaging

2 ml in a vial; 5 vials in a blister pack; 2 blisters per carton.

Prescription status: Prescription only.

Manufacturer: JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and location of business activity

13, Borispilska Street, Kyiv, 02093, Ukraine.