Blockpain

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BLOKPEIN (BLOCKPAIN)

Composition:

Active substance: ketorolac;

1 ml of solution contains ketorolac tromethamine equivalent to 30.0 mg of 100% substance;

Excipients: sodium chloride, ethanol (96%), disodium edetate, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear yellowish liquid.

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

ATC code M01AB15.

Pharmacological Properties.

Pharmacodynamics.

BLOKPEYN is a potent analgesic agent from the class of nonsteroidal anti-inflammatory drugs (NSAIDs). It is not an opioid and has no known effects on opioid receptors. Its mechanism of action involves inhibition of the cyclooxygenase enzyme system, thereby suppressing the synthesis of prostaglandins. When administered at analgesic doses, it exhibits minimal anti-inflammatory activity.

Pharmacokinetics.

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

Category of patients	Clearance (L/h/kg) mean value (range)	Terminal half-life (hours) mean value (range)
Typical patients (n=54)	0.023 (0.010–0.046)	5.3 (3.5–9.2)
Patients with hepatic impairment (n=7)	0.029 (0.013–0.066)	5.4 (2.2–6.9)
Patients with renal impairment (n=25) (serum creatinine 160–430 µmol/L)	0.016 (0.005–0.043)	10.3 (5.9–19.2)
Patients on dialysis (n=9)	0.016 (0.003–0.036)	13.6 (8.0–39.1)
Healthy elderly patients (n=13) (mean age 72 years)	0.019 (0.013–0.034)	7.0 (4.7–8.6)

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

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

More than 99% of ketorolac tromethamine is protein-bound in plasma over a wide concentration range.

Clinical characteristics.

Indications.

BLOCKPAIN is indicated for short-term management of moderate to severe postoperative acute pain.

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

Contraindications.

BLOCKPAIN is contraindicated:

• in patients with hypersensitivity to ketorolac tromethamine, to any of the excipients of the medicinal product, or to other NSAIDs in their medical history, as well as in patients with allergic reactions to acetylsalicylic acid or to other inhibitors of prostaglandin synthesis (in such patients, severe anaphylactoid reactions have been observed). Such reactions included asthma, rhinitis, angioedema, or urticaria;
• in patients with a history of asthma;
• in children under 16 years of age;
• in patients with active peptic ulcer or gastrointestinal bleeding, or with a history of ulcers or perforation;
• like other NSAIDs, BLOCKPAIN is contraindicated in patients with severe heart, liver, or kidney failure;
• in patients with moderate or severe renal function impairment (serum creatinine level >160 µmol/L) or in patients at risk of developing renal failure due to hypovolemia or dehydration;
• during pregnancy, during labor and delivery, or during breastfeeding;
• as a prophylactic analgesic before surgery due to inhibition of platelet aggregation, and during surgery due to increased risk of bleeding;
• BLOCKPAIN inhibits platelet function; therefore, it is contraindicated in patients with suspected or confirmed cerebrovascular hemorrhage, in patients who have undergone surgeries with a high risk of bleeding or incomplete hemostasis, and in patients at high risk of bleeding, e.g., patients with hemorrhagic diathesis, including coagulation disorders;
• in patients receiving anticoagulants, including warfarin and low-dose heparin (2500–5000 units every 12 hours);
• in patients receiving acetylsalicylic acid or other NSAIDs (including selective cyclooxygenase-2 inhibitors);
• for neuraxial (epidural or intrathecal) administration, as it contains alcohol;
• in combination with oxpentifylline;
• concomitant treatment with probenecid or lithium salts;
• in patients with complete or partial nasal polyposis, angioedema, or bronchospasm.

Interaction with other medicinal products and other forms of interaction.

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

Medicinal products that must not be used concomitantly with BLOCKPAIN:

BLOCKPAIN should not be used with other acetylsalicylic acid preparations or with other NSAIDs, including selective cyclooxygenase-2 inhibitors, as this may increase the risk of serious adverse reactions associated with NSAID use.

BLOCKPAIN inhibits platelet aggregation, reduces thromboxane levels, and prolongs bleeding time. Unlike the prolonged effect after acetylsalicylic acid intake, platelet function returns to normal within 24–48 hours after discontinuation of BLOCKPAIN.

Combination of BLOCKPAIN with other anticoagulants, such as warfarin, is contraindicated, as concomitant use of NSAIDs and anticoagulants may enhance the anticoagulant effect.

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

With the use of some prostaglandin synthesis inhibitors, reduced renal clearance of lithium has been reported, leading to elevated plasma lithium levels. Cases of increased plasma lithium levels during ketorolac tromethamine therapy have been documented.

Concomitant use of probenecid and ketorolac tromethamine is not recommended, as probenecid increases the plasma level of ketorolac tromethamine and prolongs its elimination half-life.

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

Concomitant use of ketorolac tromethamine with oxpentifylline increases the tendency to bleeding.

Medicinal products that should be used with caution in combination with BLOCKPAIN:

As with all NSAIDs, ketorolac tromethamine should be used with caution concomitantly with corticosteroids due to an increased risk of gastrointestinal ulcers or bleeding.

When NSAIDs are used concomitantly with antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs), the risk of gastrointestinal bleeding increases.

It has been reported that some prostaglandin synthesis inhibitors reduce methotrexate clearance and thus may increase its toxicity.

Ketorolac tromethamine does not alter digoxin protein binding in plasma. In vitro studies show that at therapeutic salicylate concentrations (300 µg/mL), ketorolac tromethamine binding decreased from approximately 99.2% to 97.5%, indicating a potential doubling of unbound ketorolac tromethamine plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not alter the protein binding of ketorolac tromethamine in plasma.

BLOCKPAIN, injection solution, reduced the diuretic response to furosemide by approximately 20% in healthy normovolemic volunteers; therefore, special attention should be paid to patients with cardiac decompensation.

Concomitant use of the drug with diuretics may lead to reduced diuretic effect and increased risk of NSAID nephrotoxicity.

As with all NSAIDs, it is recommended to use cyclosporine concomitantly with BLOCKPAIN with caution due to an increased risk of nephrotoxicity.

When NSAIDs are used with tacrolimus, there may be an increased risk of nephrotoxicity.

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

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

It has been demonstrated that the use of ketorolac tromethamine reduces the need for concomitant opioid analgesics for relief of postoperative pain.

Animal studies have shown that NSAIDs may increase the risk of seizures associated with quinolone use. In patients receiving NSAIDs and quinolones, the risk of developing seizures may be increased.

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

Animal and human studies do not indicate that ketorolac tromethamine induces or inhibits liver enzymes capable of metabolizing BLOCKPAIN itself or other drugs. Therefore, BLOCKPAIN is not expected to alter the pharmacokinetics of other drugs via enzyme induction or inhibition mechanisms.

Special precautions for use.

Epidemiological data indicate that the use of ketorolac tromethamine may be associated with a high risk of serious gastrointestinal toxicity, similar to other NSAIDs, particularly when the drug is used off-label and/or for prolonged periods.

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

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

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

Gastrointestinal ulcers, bleeding, and perforation

Gastrointestinal ulcers, bleeding, and perforation (in some cases fatal) have been reported with the use of all NSAIDs, including ketorolac tromethamine, at any time during treatment, with or without preceding symptoms or history of serious gastrointestinal events.

In a non-randomized, post-marketing observational hospital study, a higher incidence of clinically significant gastrointestinal bleeding was observed in patients under 65 years of age receiving a mean daily dose of ketorolac tromethamine >90 mg intramuscularly compared to patients receiving parenteral opioid analgesics.

The frequency of adverse reactions with NSAIDs, particularly gastrointestinal bleeding and perforation (in some cases fatal), is higher in elderly patients.

In patients with a history of peptic ulcer, especially complicated by bleeding or perforation, and in elderly patients, the risk of gastrointestinal bleeding or perforation increases with higher doses of NSAIDs, including intravenous ketorolac tromethamine. The risk of clinically significant gastrointestinal bleeding is dose-dependent. These patients should start treatment with the lowest possible dose. In such cases, and in cases of concomitant use of low-dose acetylsalicylic acid or other drugs with increased gastrointestinal risk, additional use of gastroprotective agents, such as misoprostol or proton pump inhibitors, may be considered. The age-related risk of gastrointestinal bleeding and perforation is characteristic of all NSAIDs. Compared to younger patients, elderly patients have a prolonged plasma half-life and reduced plasma clearance of ketorolac tromethamine. A longer dosing interval is recommended.

NSAIDs should be used with caution in patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) due to the possibility of exacerbation of these conditions. Patients with gastrointestinal disorders in history, especially elderly patients, should report any unusual abdominal symptoms (particularly gastrointestinal bleeding), especially in the early stages of treatment. If gastrointestinal bleeding or ulcers occur in patients receiving intravenous ketorolac tromethamine, treatment should be discontinued.

Particular attention should be paid to patients receiving concomitant medications that may increase the risk of ulcers and bleeding, such as oral corticosteroids, SSRIs, or antiplatelet agents like acetylsalicylic acid.

Use of the drug in patients taking anticoagulants, such as warfarin, is contraindicated.

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

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

Effects on hemostasis

Patients with coagulation disorders should not use ketorolac tromethamine. Concomitant use of BLOCKANE in patients receiving anticoagulant therapy may increase the risk of bleeding. Detailed studies on the concomitant use of ketorolac tromethamine with prophylactic low-dose heparin (2500–5000 units every 12 hours) and dextrans have not been conducted; therefore, such regimens may also increase the risk of bleeding. Patients already taking anticoagulants or requiring low-dose heparin should not use ketorolac tromethamine. Patients receiving other drugs that negatively affect hemostasis should be closely monitored when receiving BLOCKANE. In controlled clinical trials, the incidence of clinically significant postoperative bleeding was less than 1%.

Ketorolac tromethamine inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding time increased but remained within the normal range of 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 tromethamine.

Post-marketing experience with perioperative intramuscular and intravenous use of ketorolac tromethamine indicates the occurrence of bleeding from postoperative wounds. Therefore, ketorolac tromethamine should not be administered to patients who have undergone surgery with a high risk of bleeding or with incomplete hemostasis. Particular caution is required when stable hemostasis is critical, such as in cosmetic or ambulatory surgeries, prostatectomy, or tonsillectomy. Hematomas and other signs of wound bleeding, as well as epistaxis, have been reported with the use of ketorolac tromethamine. Physicians should be aware of the pharmacological similarity of ketorolac tromethamine to other NSAIDs that inhibit cyclooxygenase and the associated risk of bleeding, especially in elderly patients.

Skin reactions

Serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported with NSAIDs, sometimes with fatal outcomes. The highest risk of such reactions occurs early in treatment, with most initial manifestations appearing within the first month of therapy. If skin rashes, mucosal lesions, or other signs of hypersensitivity occur, BLOCKANE should be discontinued immediately.

Systemic lupus erythematosus (SLE) and mixed connective tissue disease

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

Sodium/fluid retention in cardiovascular disease and peripheral edema

The drug should be used cautiously in patients with a history of hypertension and/or heart failure, as fluid retention and edema associated with NSAID use have been observed in such patients.

Fluid retention, hypertension, and edema have been reported in some patients receiving NSAIDs, including ketorolac tromethamine; therefore, the drug should be used cautiously in patients with cardiac decompensation, hypertension, or similar conditions.

Effects on the cardiovascular system and cerebral circulation

Patients with arterial hypertension and/or mild to moderate congestive heart failure should be closely monitored due to reports of fluid retention and edema associated with NSAID therapy.

Clinical and epidemiological studies suggest that the use of coxibs and certain NSAIDs (especially at high doses) may be associated with a small increase in the risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Although an increased risk of thrombotic events, such as myocardial infarction, has not been demonstrated with ketorolac tromethamine, there are insufficient data to exclude such a risk with ketorolac use.

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

Patients with cardiovascular, renal, and hepatic impairment

The drug should be used cautiously in patients with conditions leading to reduced blood volume and/or renal blood flow, where renal prostaglandins play a supportive role in maintaining renal perfusion. In such patients, NSAID use may lead to dose-dependent reduction in prostaglandin synthesis and may cause significant renal impairment. The highest risk of such reactions occurs in patients with hypovolemia due to blood loss or severe dehydration, patients with renal impairment, heart failure, hepatic dysfunction, elderly patients, and those taking diuretics. Renal function should be monitored in these patients. Typically, after discontinuation of NSAID therapy, the patient's condition returns to the pre-treatment state.

Impaired restoration of lost fluid/blood during surgery, leading to hypovolemia, may result in renal dysfunction, which may be worsened by the use of BLOCKANE. Therefore, correction of reduced extracellular fluid volume is necessary; careful monitoring of serum urea and creatinine levels and urine output is required until blood volume is normalized. In patients undergoing renal dialysis, ketorolac clearance is approximately half the normal value, and the terminal half-life is increased by about threefold.

Renal effects

As with other NSAIDs, ketorolac tromethamine should be used cautiously in patients with renal impairment or a history of kidney disease, as it is a potent inhibitor of prostaglandin synthesis. The drug should be used with caution, as nephrotoxicity has been observed with ketorolac tromethamine and other NSAIDs in patients with conditions leading to reduced blood volume and/or renal blood flow, where renal prostaglandins play a compensatory role in maintaining renal perfusion.

In such patients, use of ketorolac tromethamine or other NSAIDs may lead to dose-dependent reduction in prostaglandin production and may trigger significant renal impairment. The highest risk of such reactions occurs in patients with renal impairment, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Typically, after discontinuation of NSAID therapy, the patient's condition returns to the pre-treatment state.

As with other inhibitors of prostaglandin synthesis, use of ketorolac tromethamine may increase serum levels of urea, creatinine, and potassium, which may be observed after a single dose.

Patients with renal impairment. Since ketorolac tromethamine and its metabolites are primarily excreted by the kidneys, BLOCKANE should not be used in patients with moderate to severe renal impairment (serum creatinine >160 µmol/L). Patients with mild renal impairment should receive lower doses of ketorolac tromethamine (not more than 60 mg/day intramuscularly or intravenously), and renal function should be closely monitored.

Patients with hepatic impairment. Patients with hepatic dysfunction due to cirrhosis do not show clinically significant differences in ketorolac tromethamine clearance or elimination half-life.

Mild elevations in one or more liver function tests may occur. These abnormalities may be transient, remain stable, or progress with continued therapy. In controlled clinical trials, significant elevations (more than three times the upper limit of normal) in serum glutamate-pyruvate transaminase (SGPT/ALT) or serum glutamate-oxaloacetate transaminase (SGOT/AST) were observed in less than 1% of patients. If clinical signs or symptoms suggestive of liver disease occur, or if systemic manifestations appear, BLOCKANE should be discontinued.

Anaphylactic (anaphylactoid) reactions

Anaphylactic (anaphylactoid) reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) may occur in patients with or without known hypersensitivity to acetylsalicylic acid, other NSAIDs, or intravenous ketorolac tromethamine. These reactions may also occur in individuals with a history of angioedema, bronchospastic reactions (e.g., asthma), or nasal polyps. Such anaphylactoid reactions, including anaphylaxis, may be fatal. Therefore, ketorolac tromethamine should not be used in patients with asthma or those with a history of complete or partial nasal polyposis, angioedema, or bronchospasm.

Safety measures related to fertility

As with other inhibitors of cyclooxygenase/prostaglandin synthesis, use of ketorolac tromethamine may adversely affect female fertility and is not recommended for women attempting to conceive. For women experiencing fertility problems or undergoing infertility evaluation, use of BLOCKANE should be discontinued.

Fluid retention and edema

Fluid retention, arterial hypertension, and edema have been reported with the use of ketorolac tromethamine; therefore, the drug should be used cautiously in patients with cardiac decompensation, hypertension, or similar conditions.

Caution is recommended when using methotrexate concomitantly with drugs that inhibit prostaglandin synthesis, as some such drugs reduce renal clearance of methotrexate, thereby increasing its toxicity.

Abuse and dependence

Ketorolac tromethamine does not cause dependence. Withdrawal symptoms have not been observed after abrupt discontinuation of intravenous ketorolac tromethamine.

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

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

Use during pregnancy or breastfeeding.

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

The safety of BLOCKANE use during human pregnancy has not been established. In studies in rats and rabbits, ketorolac did not show teratogenic effects at maternally toxic doses. In rats, prolonged gestation and/or delayed delivery were observed. Congenital anomalies have been reported in humans after NSAID use, although their frequency is low and no clear trend has been observed.

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

From the 20th week of pregnancy, use of BLOCKANE may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible upon discontinuation. Additionally, there are reports of ductus arteriosus constriction after second-trimester treatment, which in most cases resolves after stopping therapy.

Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable after exposure to BLOCKANE for several days starting from the 20th gestational week. Use of BLOCKANE should be discontinued if oligohydramnios or ductus arteriosus constriction is detected.

Throughout pregnancy, all prostaglandin synthesis inhibitors may cause the following fetal disorders:

• cardiopulmonary toxicity (with premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction with possible progression to renal failure with oligohydramnios (see above).

Towards the end of pregnancy, in the mother and newborn, the following may occur:

• prolonged bleeding time, anti-aggregatory effect, which may occur even at low doses;
• inhibition of uterine contractions, potentially leading to delayed or prolonged labor.

Approximately 10% of the administered dose of ketorolac tromethamine crosses the placenta.

Labor and delivery

BLOCKANE is contraindicated during labor and delivery because its inhibitory effect on prostaglandin synthesis may adversely affect fetal circulation and suppress uterine contractions, increasing the risk of uterine bleeding.

There is an increased risk of bleeding in both mother and child.

Lactation period

It has been confirmed that ketorolac and its metabolites pass into the fetus and animal milk. Ketorolac tromethamine is present in human milk in low concentrations; therefore, BLOCKANE is contraindicated in women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

In some patients, use of BLOCKANE may cause dizziness, somnolence, visual disturbances, headache, vertigo, insomnia, or depression. If these or similar adverse reactions occur, patients should not drive or operate machinery.

Method of Administration and Dosage

BLOKPEYN is intended for intramuscular or bolus intravenous injection. Bolus intravenous doses should be administered over at least 15 seconds. BLOKPEYN must not be used for epidural or spinal administration.

Analgesic effect occurs similarly after intravenous and intramuscular administration, typically within approximately 30 minutes, with maximum analgesic effect achieved within 1–2 hours. The average duration of analgesia usually lasts 4–6 hours.

The dose should be selected and adjusted according to the severity of pain and the patient's response.

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

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

Adults

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

In patients with body weight < 50 kg, the dose should be reduced.

Concomitant use of opioid analgesics (e.g., morphine, pethidine) may be considered to achieve optimal analgesia in the early postoperative period when pain is most intense. Ketorolac tromethamine does not interfere with binding to opioid receptors and does not potentiate respiratory depression or sedative effects of opioid drugs. When opioid analgesics are used concomitantly with intramuscular or intravenous BLOKPEYN, their daily dose is typically lower than usual. However, adverse effects of opioid analgesics should be taken into account, especially in outpatient surgery settings.

Elderly Patients

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

Patients with Renal Impairment

The drug is contraindicated in moderate to severe renal impairment. In mild renal impairment, the dose should be reduced (not exceeding 60 mg per day administered intravenously or intramuscularly).

Children

The safety and efficacy of the drug in children have not been established. Therefore, BLOKPEYN cannot be recommended for use in children under 16 years of age.

Overdose

Symptoms

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

Gastrointestinal bleeding may occur. After oral NSAID overdose, arterial hypertension, acute renal failure, respiratory depression, and coma may be observed, although such symptoms are rare.

Other symptoms reported include headache, epigastric pain, confusion, agitation, drowsiness, dizziness, tinnitus, and loss of consciousness.

Rare cases of diarrhea and isolated cases of seizures have also been reported.

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

Treatment

Patients should receive symptomatic and supportive treatment to maintain vital functions following NSAID overdose. There is no specific antidote. Dialysis does not lead to significant removal of ketorolac from the blood.

Activated charcoal should be administered within one hour after ingestion of a potentially toxic dose. In adults, gastric lavage may be considered within one hour after ingestion of a potentially life-threatening dose.

Adequate diuresis should be maintained. Renal and hepatic functions must be closely monitored. The patient should be observed for at least four hours after ingestion of a potentially toxic dose. Frequent or prolonged seizures should be treated with intravenous diazepam. Additional measures may be implemented depending on the patient’s clinical condition.

Adverse reactions.

Post-marketing period

The following adverse reactions may occur in patients receiving intravenous ketorolac tromethamine. The frequency of reported reactions is unknown, as they were reported voluntarily from an unknown number of patients.

Gastrointestinal disorders: Adverse gastrointestinal reactions are the most commonly observed. Peptic ulcer disease, ulcers, perforation, and gastrointestinal bleeding—sometimes leading to fatal outcomes—may occur, particularly in elderly patients. Nausea, vomiting, diarrhea, constipation, dyspepsia, abdominal pain/discomfort, melena, hematemesis, stomatitis, ulcerative stomatitis, eructation, bloating, esophagitis, gastrointestinal ulcers, rectal bleeding, pancreatitis, dry mouth, sensation of stomach fullness, and exacerbations of colitis and Crohn’s disease have been reported following drug administration. Gastritis has been observed less frequently.

Infections: Aseptic meningitis (particularly in patients with autoimmune diseases such as SLE or mixed connective tissue disorders), with symptoms including nuchal rigidity, headache, nausea, vomiting, fever, or disorientation.

Blood and lymphatic system disorders: Thrombocytopenia. Purpura, neutropenia, agranulocytosis, aplastic anemia, and hemolytic anemia have also been observed.

Immune system disorders: Anaphylaxis, anaphylactoid reactions resembling anaphylaxis; potentially life-threatening anaphylactoid reactions; hypersensitivity reactions such as bronchospasm, flushing, rash, hypotension, and laryngeal edema.

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

Metabolism and nutrition disorders: Anorexia, hyperkalemia, hyponatremia.

Psychiatric disorders: Thought disorders, depression, insomnia, anxiety, nervousness, psychotic reactions, unusual dreams, hallucinations, euphoria, difficulty concentrating, somnolence.

Confusion and agitation have also been observed.

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

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

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

Renal and urinary disorders: Acute renal failure, frequent urination, interstitial nephritis, nephrotic syndrome, urinary retention, oliguria, hemolytic uremic syndrome, flank pain (with or without hematuria and azotemia). As with other prostaglandin synthesis inhibitors, symptoms of impaired renal function—including, but not limited to, increased serum creatinine and potassium levels—may occur after administration of a single intravenous dose of ketorolac tromethamine.

Cardiac disorders: Palpitations, bradycardia, heart failure.

Vascular disorders: Arterial hypertension, hematomas, flushing, pallor, bleeding from postoperative wounds.

Clinical and epidemiological data suggest that the use of coxibs and certain NSAIDs (particularly at high doses) may be associated with a small increased risk of arterial thrombotic events (e.g., myocardial infarction and stroke). Although ketorolac has not demonstrated an increased risk of thrombotic complications such as myocardial infarction, there are insufficient data to exclude such a risk with the use of ketorolac tromethamine.

Reproductive system disorders: Infertility in women.

Respiratory, thoracic and mediastinal disorders: Asthma, dyspnea, pulmonary edema. Epistaxis has also been observed.

Hepatobiliary disorders: Hepatitis, cholestatic jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: Exfoliative dermatitis, maculopapular rash, pruritus, urticaria, angioneurotic edema, increased sweating, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).

Multiform erythema and photosensitivity have also been observed.

Musculoskeletal and connective tissue disorders: Myalgia, functional impairment.

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

Malaise, general weakness, and weight gain have also been reported.

Laboratory investigations: Prolonged bleeding time, increased serum urea nitrogen, elevated creatinine levels, abnormal liver function tests.

Laboratory test abnormalities: Prolonged bleeding time, increased serum urea nitrogen, elevated creatinine levels, abnormal liver function tests.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility

BLOCKANE cannot be mixed in small volumes (e.g., in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride, or hydroxyzine hydrochloride, as ketorolac will precipitate.

The drug is compatible with normal saline, 5% dextrose solution, Ringer’s solution, Ringer’s lactate solution, and Plasmalyte solution. Compatibility of BLOCKANE with other medicinal products is unknown.

Packaging. 1 ml in an ampoule; 5 ampoules in a blister, 1 or 2 blisters per carton, or 100 ampoules per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer’s address and location of business activity.

36 Severin Pototskoho Street, Kharkiv, Kharkiv region, 61115, Ukraine.