Neospastil

APPROVED
by the Order of the Ministry of Health of Ukraine 25.08.2020 No. 1957
Marketing Authorization No. UA/18292/01/01

VARIATONS APPLIED
by the Order of the Ministry of Health of Ukraine 09.12.2021 № 2740

PACKAGE LEAFLET
for medical use of a medicinal product
NEOSPASTIL®

 

Qualitative and quantitative composition:

active substance: ketorolac tromethamine, pitofenone hydrochloride, fenpiverinium bromide.

1 ml of solution contains: ketorolac tromethamine 15 mg, pitophenone hydrochloride 5 mg, fenpiverine bromide 0.05 mg.

list of excipients: sodium chloride, propylene glycol, disodium edetate, water for injections.

 

Pharmaceutical form. Solution for injection.

Main physical and chemical properties: clear slightly yellowish or slightly greenish liquid.

 

Pharmacotherapeutic group. Antispasmodics in combination with analgesics.

ATC Code А03D A02.

 

Pharmacological properties.

Pharmacodynamic properties.

Neospastil® is a combination medicinal product that belongs to the group of antispasmodics in combination with analgesics. It consists of three active substances: non-narcotic analgesic ketorolac tromethamine, myotropic antispasmodic pitofenone hydrochloride and choline-blocking agent fenpiverine bromide.

Ketorolac is a non-steroidal anti-inflammatory drug (NSAID), a cyclooxygenase inhibitor (COX) -1 and COX-2, a derivative of pyrrolizinecarboxylic acid, which has a pronounced analgesic effect. The mechanism of action of ketorolac (as well as other NSAIDs) is not fully understood, but may be inhibition of prostaglandin synthesis. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine has not sedative or anxiolytic properties. It is not an opioid, so it does not affect opiate receptors.

The maximum analgesic effect of ketorolac is achieved within 2-3 hours. This effect has no statistically significant differences within the recommended dosage range. The biggest difference between high and low doses of ketorolac is the duration of analgesia. The analgesic dose of ketorolac also has an anti-inflammatory effect.

Fenpiverine bromide has a moderate ganglioblocking and cholinolytic effect, inhibits the tone and motility of the smooth muscles of the stomach, intestines, bile and urinary tract.

Pitofenone hydrochloride has a papaverine-like effect with pronounced antispasmodic activity on smooth muscle.

The combination of the three components of the medicinal product leads to a mutual strengthening of their pharmacodynamic action, which is manifested by pain relief, relaxation of smooth muscles, and a decrease in body temperature.

Pharmacokinetic properties.

Neospastil®

In healthy volunteers, after intramuscular administration of Neospastil®, peak plasma concentrations of fenpiverine and pitophenone were reached after 0.75 hours and ketorolac after 1.33 hours.

AUC0–t and Cmax of ketorolac, fenpiverine and pitofenone after a single intramuscular injection of 2 ml of Neospastil® (mean ± SD)

​

Table 1

Active substance:	AUC0–t ng year/ml	Cmax, ng/ml
Ketorolac	9571 ± 2504	1726 ± 387,4
Fenpiverine	2,201 ± 0,354	0,734 ± 0,166
Pitophenone	40,38 ± 14,18	22,48 ± 11,72

​​

AUC0–t — area under the pharmacokinetic curve "concentration-time" (from zero to the last blood sample); Cmax - maximum concentration in blood plasma; SD - standard deviation.

In healthy volunteers after intramuscular administration of Neospastil®, the half-lives of ketorolac, fenpiverine and pitofenone were 5.71 ± 0.65 h, 4.44 ± 1.60 h and 2.25 ± 2.65 h, respectively. The pharmacokinetic profiles of ketorolac, fenpiverine and pitofenone decreased multiexponentially.

Ketorolac tromethamine

Ketorolac tromethamine is a racemic mixture of [-] S and [+] R-enantiomeric forms, with analgesic activity due to the S-form. Ketorolac is rapidly and completely absorbed after intramuscular administration. The average maximum plasma concentration of 2.2 μg/ml is reached on average 50 min after a single dose of 30 mg.

Linear pharmacokinetic properties.

In adults, the clearance of the racemate does not change after the intramuscular administration of ketorolac tromethamine within the recommended dosage ranges. This indicates that the pharmacokinetic properties of ketorolac tromethamine in adults after single or multiple intramuscular injections are linear. At higher recommended doses, proportional increases in free and bound racemate concentrations are observed.

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

Table 2

Pharmacokinetic parameters (units)	15 mg	30 mg	60 mg
Bioavailability (degree)	100 %
Тmax1 (min)	33 ± 21*	44 ± 29	33 ± 21*
Cmax2 (μg/ml) (single injection)	1,14 ± 0,32*	2,42 ± 0,69	4,55 ± 1,27*
Cmax (μg/ml) (at steady state when applied 4 times a day)	1,56 ± 0,44*	3,11 ± 0,87*	Not applicable#
Cmin3 (μg/ml) (at steady state when applied 4 times a day)	0,47 ± 0,13*	0,93 ± 0,26*	Not applicable
Cavg4 (μg/ml) (at steady state when applied 4 times a day)	0,94 ± 0,29*	1,88 ± 0,59*	Not applicable
Vβ5 (L/kg)	0,175 ± 0,039
3 Minimum plasma concentration. 4 Average plasma concentration. 5 Volume of distribution. * The mean was modeled using plasma concentrations, and the standard deviation was simulated using the percentage of variation of Cmax and Tmax. # Not applicable because pharmacokinetic parameters under such a regimen have not been studied. SD — standard deviation.

Metabolism.

Ketorolac tromethamine is extensively metabolized in the liver. The products of metabolism are hydroxylated and conjugated forms of the medicinal product derivatives. The metabolic products and some of the unchanged agent are excreted in the urine.

Excretion.

The main route of excretion of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is determined in the urine: approximately 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of the dose is excreted in the feces. In a study with a single administration of ketorolac at a dose of 10 mg, it was demonstrated that the S-enantiomer is excreted twice as fast as the R-enantiomer, and the clearance does not depend on the method of administration. This means that the ratio of plasma concentrations of S-enantiomer/R-enantiomer after administration of each subsequent dose decreases over time. Differences between S- and R-forms in the human body are insignificant or absent.

The 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 that the half-life of the racemate is 5-6 hours.

Accumulation.

Intravenous bolus administration of ketorolac tromethamine to healthy volunteers every 6 hours for 5 days did not show a significant difference between Cmax values on the 1st and 5th day. The minimum levels averaged 0.29 μg/ml on day 1 and 0.55 μg/ml on day 6. Steady state was reached after the fourth dose. The accumulation of ketorolac tromethamine in patients of certain groups (elderly patients, children, patients with renal failure or liver disease) has not been studied.

Pharmacokinetic properties in patients of certain groups.

Use in elderly patients

Based only on data obtained after a single injection, the half-life of ketorolac tromethamine racemate increased from 5 to 7 hours in elderly patients (65‑78 years) compared with young healthy volunteers (24-35 years).

Children. There are no pharmacokinetic data on intramuscular administration of ketorolac tromethamine to children.

Renal failure.

Based only on data obtained after a single administration of the medicinal product, the half-life of ketorolac tromethamine in patients with renal impairment is 6-19 hours and depends on the severity of the disorders. There is almost no correlation between creatinine clearance and total ketorolac tromethamine clearance in elderly and renal patients. In patients with kidney disease, the AUC0–∞ – value of each of the enantiomers is increased by almost 100% compared to healthy volunteers. The volume of distribution is doubled for the S-enantiomer and increased by 1/5 for the R-enantiomer. An increase in the volume of distribution of ketorolac tromethamine indicates an increase in the unbound fraction.

Hepatic failure.

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

Fenpiverine bromide.

The pharmacokinetic properties of fenpiverine have not been studied separately.

Pitophenone hydrochloride.

The pharmacokinetic properties of pitophenone have not been studied separately.

 

Clinical particulars.

Therapeutic indications.

For short-term symptomatic treatment of moderate and severe pain syndrome:

- with spasms of smooth muscles of internal organs: renal colic, spasms of the bladder and urinary tract, hepatic colic, spasms of the stomach and intestines, spastic dyskinesia of the biliary tract;
- as an aid to relieve visceral pain after diagnostic procedures.

 

Contraindications.

- Hypersensitivity to ketorolac, fenpiverine, pitofenone or to any other component of the medicinal product;
- active peptic ulcer, recent gastrointestinal bleeding or perforation, peptic ulcer disease or history of gastrointestinal bleeding;
- bronchial asthma, rhinitis, angioneurotic edema or urticaria caused by acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (due to the possibility of severe anaphylactic reactions);
- history of bronchial asthma;
- complete or partial nasal polyp syndrome, angioneurotic edema or bronchospasm;
- use as an analgesic before and during surgery, when manipulating the coronary vessels;
- use in patients who have had surgery at high risk of hemorrhage or incomplete bleeding, and in patients receiving anticoagulants, including warfarin or low-dose heparin (2500‑5000 units every 12 hours);
- severe heart failure;
- severe hepatic impairment;
- moderate/severe renal insufficiency (serum creatinine concentration greater than 160 μmol/l);
- suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, including coagulation disorders, high risk of bleeding;
- concomitant treatment with acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase-2 inhibitors), pentoxifylline, probenecid or lithium salts;
- hypovolemia, dehydration with the risk of renal failure due to decreased fluid volume;
- contractions and childbirth;
- prostate adenoma ΙΙ and ΙΙΙ degree;
- atony of the gallbladder and bladder;
- tachyarrhythmia;
- colaptoid state;
- angle-closure glaucoma;
- gastrointestinal obstruction and megacolon;
- administration of the medicinal product epidurally or intrathecally.

 

Interaction with other medicinal products and other forms of interaction.

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

Ketorolac tromethamine does not affect the binding of digoxin to plasma proteins. In vitro studies indicate that at therapeutic salicylate concentrations (300 μg/ml), ketorolac binding decreased from approximately 99.2 % to 97.5 %, indicating a potential two-fold increase in plasma levels of unbound ketorolac. Digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide at therapeutic concentrations do not alter the binding of ketorolac tromethamine to plasma proteins.

Because ketorolac is a potent medicinal product and is low in plasma, it is unlikely that it can significantly displace other medicinal product from binding to plasma proteins.

Medicines that are contraindicated in combination with Neospastil®

Acetylsalicylic acid and other NSAIDs. When used with acetylsalicylic acid, the binding of ketorolac to plasma proteins decreases, although the clearance of free ketorolac does not change. The clinical significance of this interaction is unknown, although, as with other NSAIDs, co-administration of ketorolac tromethamine and acetylsalicylic acid is contraindicated due to the potential increase in the incidence of adverse events.

Anticoagulants. At simultaneous use with anticoagulants strengthening of bleedings is possible. Concomitant use with anticoagulants (such as warfarin) is contraindicated.

Lithium. Concomitant use of NSAIDs and lithium medicinal products is contraindicated.

Probenecid. Concomitant use of ketorolac tromethamine and probenecid led to a decrease in the clearance of ketorolac, a significant increase in its plasma levels and a prolongation of the half-life. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Mifepristone. After the use of mifepristone for 8-12 days, NSAIDs should not be used because they can weaken the effects 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 with caution due to the 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 concomitantly.

Methotrexate. Because NSAIDs may reduce the clearance of methotrexate, the toxicity of methotrexate may increase.

Diuretics. In some patients, ketorolac may reduce the natriuretic effect of furosemide and thiazides. During concomitant NSAID therapy, the patient's condition should be closely monitored for signs of renal insufficiency, as well as to ensure the effectiveness of diuretics.

Antihypertensive medicinal products. Concomitant use with ketorolac weakens the effect of these medicinal products. Ketorolac and other NSAIDs may reduce the antihypertensive effects of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor antagonists, as well as increase the risk of renal impairment; this is especially true for patients with low blood volume or elderly patients. Therefore, the combination should be used with caution, especially in elderly patients. Patients should be closely monitored and renal function should be monitored periodically after initiation and completion of concomitant therapy, in particular with the use of diuretics and ACE inhibitors.

Cardiac glycosides. NSAIDs may worsen heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when co-administered with the latter.

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

Ciclosporin. As with all NSAIDs, cyclosporine should be used with caution due to the increased risk of nephrotoxic effects.

Tacrolimus. NSAIDs may increase the risk of nephrotoxicity.

Opioid analgesics. The effect of opioid analgesics is enhanced, which makes it possible to reduce the dose of the latter during analgesia.

Quinolones. Patients taking quinolines may be at increased risk of seizures.

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

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

Psychotropic medicinal products. Hallucinations have been reported with the concomitant use of ketorolac and psychotropic medicinal products (fluoxetine, thiotexen, alprazolam).

Non-depolarizing muscle relaxants. Studies of concomitant use of ketorolac tromethamine and muscle relaxants have not been performed. Cases of possible interaction of ketorolac and non-depolarizing muscle relaxants, which led to apnea, have been reported.

Antidiabetic medicinal products. NSAIDs may increase the effect of sulfonylureas.

Preparations containing garlic, onion, gingival lobe may increase the effect of ketorolac and increase the risk of hemorrhagic complications.

Concomitant use of the medicinal product Neospastil® with quinine medicinal products may increase the anticholinergic effect.

 

Special warnings and precautions for use.

It is recommended to apply in the conditions of a hospital.

Do not mix the medicine in the same syringe with other medicines when using the injection form.

The likelihood of adverse reactions can be minimized by using the lowest effective dose for the shortest amount of time required to control symptoms.

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

Careful monitoring of diuresis and renal function should be performed when treating patients with heart, kidney or liver failure who are taking diuretics or patients with hypovolaemia after surgery.

Use in elderly patients

In elderly patients (over 65 years of age), the use of NSAIDs is more likely to cause adverse reactions, especially bleeding and perforation of the gastrointestinal tract, including fatalities (see section "Posology and method of administration").

An increase in this type of age-related risk is common with all NSAIDs. Compared with younger patients, these patients have an increased plasma half-life and decreased plasma clearance. Therefore, Neospastil® is not recommended for elderly patients in a daily dose exceeding 60 mg in terms of ketorolac tromethamine (see section "Posology and method of administration").

Effects on the digestive tract. The active substance in Neospastil® ketorolac, tromethamine, can cause severe gastrointestinal side effects. These side effects can occur in patients taking ketorolac tromethamine at any time after or without precursor symptoms and can be fatal. The risk of clinically serious gastrointestinal bleeding is dose-dependent. But adverse reactions can occur even with short-term therapy. In addition to a history of peptic ulcer disease, concomitant use is the concomitant use of oral corticosteroids, anticoagulants, long-term NSAID therapy, smoking, alcohol use, old age, and poor health in general. Most spontaneous reports of gastrointestinal adverse reactions have been reported in the elderly or debilitated, so special care should be taken when treating this category of patients, and the medicinal product should be discontinued if adverse reactions are suspected. Patients at risk should be prescribed alternative therapies that do not include NSAIDs.

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

The medicinal product should be used with caution in patients with obstructive diseases of the gastrointestinal tract (achalasia, pyloroduodenal stenosis). Repeated use of Neospastil® in these cases may delay the excretion of gastrointestinal contents. The use of Neospastil® in patients with gastroesophageal reflux disease, intestinal atony, inflammatory bowel disease, including nonspecific ulcerative colitis and Crohn's disease, requires special care and medical supervision.

Anaphylactic (similar to anaphylactic) reactions. Anaphylactic (similar to anaphylactic) reactions (such as anaphylaxis, bronchospasm, redness, rash, hypotension, laryngeal edema, and angioneurotic edema) may occur in patients with pre-existing sensitivity to aspirin, other NSAIDs, or intravenous ketorol and in those who previously had no hypersensitivity reactions. Such reactions are possible in people with angioneurotic edema, a history of bronchospastic reactions (e.g. asthma) or nasal polyps. These anaphylactic reactions can be fatal. Therefore, ketorolac should not be used in patients with a history of asthma and in patients with complete or partial nasal polyp syndrome, angioneurotic edema 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 of concomitant use of ketorolac and heparin in prophylactic low doses (2500–5000 IU every 12 hours) have not been performed, an increased risk of bleeding with this regimen cannot be ruled out. Patients who are already taking anticoagulants or who require low doses of heparin should not receive ketorolac tromethamine. When administering ketorolac tromethamine medicinal products, the condition of patients who use other medicinal products that adversely affect hemostasis should be closely monitored. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal hemostasis, the duration of bleeding increases, but does not exceed normal limits - from 2 to 11 minutes. In contrast to the prolonged action due to acetylsalicylic acid, after the abolition of ketorolac, platelet function returns to normal within 24-48 hours. Ketorolac tromethamine is contraindicated in patients undergoing surgery with a high risk of bleeding or incomplete hemostasis. Ketorolac tromethamine is not an anesthetic and has no sedative or anxiolytic properties.

Use in patients with hepatic impairment (see section "Contraindications"). Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may be toxic to the kidneys, so it should be used with caution in patients with renal impairment or a history of kidney disease. The risk group includes patients with impaired renal function, hypovolemia, heart failure, hepatic impairment, patients taking diuretics, and elderly patients.

Patients with less severe renal impairment should receive lower doses of ketorolac (not more than 60 mg daily intramuscularly). The condition of the kidneys of such patients should be carefully monitored. Patients should be well hydrated before starting treatment with the medicinal product. In hemodialysis patients, the clearance of ketorolac was reduced by approximately half of normal and the terminal half-life was almost tripled.

Due to the fact that both old age (> 65 years) and renal impairment require a reduction in the daily dose of the medicinal product, as well as due to the lack of clinical data on the pharmacokinetic properties of the medicinal product in this population to use the drug in elderly patients with impaired function kidneys should only be performed after careful evaluation of the benefits and risks associated with such therapy.

Effects on the cardiovascular system and cerebral vessels. Patients with a history of hypertension and/or a history of mild to moderate heart failure should be closely monitored. The use of Neospastil® in patients with heart disease (arrhythmias, coronary heart disease, congestive heart failure) requires special care and monitoring by a physician.

To minimize the potential risk of cardiovascular adverse reactions in patients taking NSAIDs, the lowest effective dose should be given for the shortest possible period of time. Ketorolac tromethamine can be prescribed to patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease only after careful consideration of all the advantages and disadvantages of such treatment. It is also necessary to weigh the feasibility of prescribing ketorolac medicinal products before starting long-term treatment of patients at risk for cardiovascular disease (e.g., patients with hypertension, hyperlipidemia, diabetes, and smokers).

Clinical studies and epidemiological data suggest that the use of some NSAIDs, especially at high doses and over a long period of time, may be associated with a slight increased risk of arterial thromboembolic complications such as myocardial infarction or stroke. This risk for ketorolac cannot be ruled out.

Patients who have suffered a myocardial infarction are at risk of recurrent myocardial infarction with NSAIDs during the first week of treatment. Injections containing ketorolac tromethamine should be avoided in patients who have recently had a myocardial infarction unless the expected benefit outweighs the risk of recurrence of cardiovascular thrombosis. If the medicinal product contains ketorolac tromethamine is used in patients with a recent myocardial infarction, the patient should be closely monitored for cardiac ischemia.

Use in patients with hepatic impairment. Ketorolac tromethamine should be used with caution in patients with hepatic impairment or a history of liver disease. Significant increases (more than three times normal) in serum alanine aminotransferase and aspartate aminotransferase activity were observed in less than 1 % of patients. In addition, there have been isolated reports of severe hepatic reactions, including jaundice and lethal fulminant hepatitis, liver necrosis and liver failure, and in some cases fatal. Ketorolac medicinal products should be discontinued in case of clinical symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash).

Respiratory system. The patient's condition should be monitored for the likelihood of developing 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.

Dermatological 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 treatment at the first appearance of rash, mucosal lesions or other manifestations of hypersensitivity.

Fluid retention and edema. Fluid retention and edema have been reported with ketorolac and should be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

Prostate hyperplasia. Use with caution in prostate hyperplasia.

Nervous system and organs of vision. The use of Neospastil® in patients with glaucoma or myasthenia gravis requires special care and supervision by a physician. With prolonged use of the medicinal product, its cholinolytic effect may lead to dizziness or accommodation disorders.

Effects on fertility. Ketorolac tromethamine should be discontinued in women who are unable to become pregnant and are therefore being screened. Women with reduced fertility should avoid the use of the medicinal product.

Excipients. When using the medicinal product in the maximum daily dose, the maximum dose of propylene glycol that a patient can receive does not exceed 50 mg/kg/day.

 

Fertility, pregnancy and lactation.

Due to the known effect of nonsteroidal anti-inflammatory drugs on the cardiovascular system of the fetus, medicinal products containing ketorolac are contraindicated during pregnancy (especially in the third trimester). The use of ketorolac tromethamine is contraindicated during pregnancy, contractions and childbirth.

Do not use during lactation due to the possible adverse reactions of prostaglandin synthesis inhibitors in infants.

 

Effects on ability to drive and use machines.

The medicinal product can reduce the psychophysical capabilities of patients and adversely affect activities that require increased attention, coordination and rapid response (e.g., driving, operating machinery, working at height). Some patients may experience dizziness, drowsiness, blurred vision, headache, vertigo, insomnia or depression when taking ketorolac-containing tromethamine. If the patient has these or other similar adverse reactions, he should not drive or operate machinery.

 

Posology and method of administration.

It is recommended to apply in the conditions of a hospital.

After intramuscular administration, the analgesic effect is observed in about 30 minutes, and the maximum analgesia occurs in 1-2 hours. In general, the average duration of analgesia is 8-12 hours. The dose should be adjusted according to the severity of the pain and the patient's response to treatment. The likelihood of adverse reactions can be minimized by using the lowest effective dose for the shortest amount of time required to control symptoms. The medicinal product is contraindicated epidurally or intraspinally.

It is recommended that the ampoule of the medicine be warmed to body temperature before injection.

With spasms of smooth muscles of internal organs.

Adults. The recommended dose of Neospastil® is 1-2 ml (15-30 mg in terms of ketorolac tromethamine) every 8 hours. The minimum effective dose should be prescribed. The maximum duration of treatment was 2-day.

As an aid to relieve visceral pain after diagnostic procedures.

Adults. The recommended initial dose of Neospastil® is 1 ml (15 mg in terms of ketorolac tromethamine) followed by 1-2 ml (15‑30 mg in terms of ketorolac tromethamine) every 8-12 hours if necessary. The minimum effective dose should be prescribed. The maximum duration of treatment should not exceed 2 days.

The total daily dose in terms of ketorolac tromethamine should not exceed 90 mg for young patients, 60 mg - for elderly patients, patients with renal insufficiency and body weight less than 50 kg. For patients weighing less than 50 kg, the dose should be reduced. The maximum duration of treatment should not exceed 2 days. Concomitant use of opioid analgesics (morphine, pethidine and others) is possible. Ketorolac has no adverse reactions on opioid receptor binding and does not potentiate respiratory depression or the sedative effects of opioid medicinal products. For patients receiving parenteral Neospastil® and who are switched to oral tablets containing ketorolac, the total combined daily dose should not exceed 90 mg of ketorolac tromethamine (60 mg - in the elderly, patients with impaired renal function and weighing less 50 kg), and on the day when changing the dosage form, the dose of the oral component should not exceed 40 mg of ketorolac tromethamine. Patients should be switched to oral administration as soon as possible.

Use in elderly patients It is recommended that patients over 65 years of age be given the lowest dose range. The total daily dose should not exceed 60 mg (in terms of ketorolac tromethamine).

Patients with renal impairment. Ketorolac is contraindicated in moderate and severe renal impairment. For less severe disorders, the dosage should be reduced (not more than 60 mg in terms of ketorolac tromethamine/day intramuscularly).

 

Children.

The medicinal product is contraindicated in children (under the age of 18 years).

 

Overdose.

Symptoms: inhibited condition, drowsiness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression and coma. Cholinolytic manifestations may also be observed. Anaphylactoid reactions have been reported.

Treatment. Discontinue use of the medicinal product. Symptomatic and supportive therapy. There is no specific antidote. The use of forced diuresis, alkalization of urine, hemodialysis or blood transfusion may be ineffective due to the high binding of ketorolac to plasma proteins.

 

Undesirable effects.

Gastrointestinal disorders: dry mouth, abdominal discomfort, bloating, nausea, dyspepsia, change in taste, anorexia, gastrointestinal pain, epigastric pain, diarrhea, rarely - flatulence, belching, vomiting, constipation, erosive-ulcerative changes including bleeding and perforation of the gastrointestinal tract, sometimes fatal (especially in elderly patients), vomiting blood, gastritis, peptic ulcer, pancreatitis, melena, rectal bleeding, ulcerative stomatitis, esophagitis, exacerbation of Crohn's disease and colitis.

Hepatobiliary disorders: very rarely - liver dysfunction, liver failure, jaundice, hepatitis, increased activity of hepatic transaminases.

Nervous system disorders: headache, dizziness, fatigue, weakness, irritability, dry mouth, thirst, nervousness, restlessness, confusion, paresthesia, functional disorders, unusual dreams, depression, drowsiness, sleep disturbances, insomnia, impaired concentration, euphoria, hyperactivity, hallucinations, delusions, hyperkinesia, excitability, convulsions, psychotic reactions, pathological thoughts, aseptic meningitis (with appropriate symptoms), stiff neck muscles, anxiety, vertigo, disorientation, thinking disorders.

Organ of senses disorders: taste disturbances, visual disturbances, accommodation disorders, conjunctivitis, retrobulbar neuritis, tinnitus, hearing loss.

Musculoskeletal disorders: myalgia, functional disorders.

Renal and urinary disorders: severe pain at the projection of the kidneys, frequent urination, oliguria, polyuria, anuria, hyponatremia, hyperkalemia, hematuria, proteinuria, elevated serum urea and creatinine, urinary retention, acute renal failure, renal failure, interstitial nephritis, renal papillary necrosis, uremic syndrome, nephrotic syndrome (rare).

Cardiac disorders: pallor, hot flashes, chest pain, palpitations, bradycardia, heart failure, hypertension or hypotension, edema. Clinical and epidemiological data suggest that the use of some NSAIDs, especially in high doses and over a long period of time, may be associated with an increased risk of arterial thromboembolic complications (myocardial infarction or stroke) (see section “Special warnings and precautions for use”).

Blood system disorders: purpura, thrombocytopenia, neutropenia, agranulocytosis, granulocytopenia, anemia (aplastic, hemolytic), possible subcutaneous hemorrhage, hematoma, nosebleeds, decreased blood clotting rate, prolonged bleeding time and increased postoperative bleeding, bleeding or postoperative bleeding stop.

Respiratory, thoracic and mediastinal disorders: bronchospasm, shortness of breath, asthma, pulmonary edema.

Reproductive system: infertility (in women).

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

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

General disorders and administration site conditions: asthenia, edema, pain and infiltration at the injection site, fever, sweating, weight gain.

 

Reported suspected adverse reactions.

Reporting suspected adverse reactions after registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk ratio for the respective drug. Healthcare providers should be informed of any suspected adverse reactions through the national alert system.

 

Shelf life 4 years.

 

Special precautions for storage.

Store in the original package at a temperature of 2 ºC to 8 ºC.

It is allowed to store in the original packaging at a temperature not higher than 25 °C for no more than 6 months, after which the drug should not be used.

Keep out of the reach of children.

 

Incompatibilities.

The medicinal product should not be mixed in small containers (e.g. in a single syringe) with morphine sulphate, pethidine hydrochloride, promethazine or hydroxyzine, as one of its components, ketorolac, may precipitate.

 

Nature and contents of container.

1 ml per ampoule; 5 ampoules in a blister container; 2 blister containers in a pack.

 

Category of release. Prescription only medicine.

 

Manufacturer . PrJSC “Pharmaceutical firm “Darnitsa”.

 

The manufacturer's location and address of the place of business

13, Boryspilska Street, Kyiv, 02093, Ukraine.

 

Date of last revision .09.12.2021