Ketolong-darnitsa®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOLONG-DARNITSA® (KETOLONG-DARNITSA)

Composition:

active substance: ketorolac;

1 ml of solution contains ketorolac tromethamine 30 mg;

excipients: sodium chloride, disodium edetate, anhydrous sodium sulfite (E 221), benzyl alcohol, povidone, propylene glycol, tromethamine, water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical characteristics: clear slightly yellowish or greenish-yellow liquid.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Acetic acid derivatives and related substances. Ketorolac. ATC code M01A B15.

Pharmacological Properties

Pharmacodynamics

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID), a cyclooxygenase (COX) inhibitor, and a derivative of pyrrolizine carboxylic acid, which exerts a pronounced analgesic effect. Due to the characteristics of its dosage form, the duration of analgesic action lasts 10–12 hours. It is capable of suppressing or reducing mild to moderate pain.

Like other NSAIDs, it exerts antipyretic and anti-inflammatory effects. It can also inhibit platelet aggregation.

Pharmacokinetics

After intramuscular administration, the drug forms a depot at the injection site, from which ketorolac gradually enters the systemic circulation.

The time to reach maximum plasma concentration (Cmax = 3 mg/L), Tmax, is 40–50 minutes. Plasma protein binding exceeds 99%. Up to 10% of the administered dose is metabolized in the liver, and the remainder in the kidneys. The drug is primarily excreted via the urine (up to 90%), with 60% of the administered dose excreted unchanged. Up to 10% of the administered dose is excreted in feces. The elimination half-life (T1/2) is 4–6 hours in patients with impaired renal function; in elderly individuals, the elimination rate decreases and T1/2 increases. The drug crosses the placental barrier and is excreted into breast milk.

Clinical characteristics.

Indications.

Management of moderate to severe postoperative pain for a short duration.

Contraindications.

Hypersensitivity to ketorolac or to any other component of the medicinal product, as well as to other NSAIDs.

Active peptic ulcer, recent gastrointestinal bleeding or perforation, or history of peptic ulcer or gastrointestinal bleeding.

Presence or suspicion of gastrointestinal bleeding or intracranial hemorrhage. Conditions with high risk of bleeding or incomplete hemostasis, hemorrhagic diathesis.

Moderate or severe renal impairment (serum creatinine above 160 µmol/L).

Risk of renal failure due to reduced fluid volume.

Coagulation disorders.

Concomitant use of antiplatelet agents (acetylsalicylic acid), anticoagulants, including warfarin and low-dose heparin (2500–5000 IU every 12 hours).

Severe heart or liver failure.

Contraindicated in patients in whom other inhibitors of prostaglandin synthesis cause allergic reactions such as asthma, rhinitis, angioedema, or urticaria.

Bronchial asthma, bronchospasm, nasal polyps, angioedema in history.

The medicinal product is contraindicated during pregnancy, labor, or breastfeeding.

Children under 16 years of age.

Concomitant treatment with other NSAIDs, including selective COX inhibitors, acetylsalicylic acid, warfarin, pentoxifylline, probenecid, or lithium salts.

Hypersensitivity to acetylsalicylic acid or to other inhibitors of prostaglandin synthesis (in such patients, severe anaphylactic reactions are observed).

Do not use as an analgesic before or during surgery.

Epidural or intrathecal administration is contraindicated, as the medicinal product contains benzyl alcohol.

Interaction with other medicinal products and other types of interactions.

Ketorolac is highly bound to plasma proteins (approximately 99.2%), independent of concentration. Ketorolac tromethamine does not alter the pharmacokinetics of other drugs via induction or inhibition of enzymes.

Warfarin, digoxin, salicylates, and heparin. Ketorolac tromethamine significantly reduced the protein binding of warfarin in vitro and did not alter the protein binding of digox游戏副本

Special precautions for use.

It is recommended to use the drug under hospital conditions.

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

The combined use of intramuscular and oral ketorolac tromethamine in adult patients should not exceed 5 days.

It should be noted that analgesia may occur only 30 minutes after intramuscular administration in some patients.

Ketorolac tromethamine has no sedative or anxiolytic properties.

Careful monitoring of diuresis and renal function is required in patients with cardiac, renal, or hepatic insufficiency, those receiving diuretics, or those with hypovolemia following surgery.

Gastrointestinal tract effects.

Ketorolac tromethamine may cause severe adverse reactions in the gastrointestinal tract at any stage of treatment, with or without preceding symptoms. Such adverse reactions may be fatal. The risk of clinically significant gastrointestinal bleeding is dose-dependent. However, adverse effects may occur even during short-term therapy. In addition to a history of peptic ulcer disease, predisposing factors include concomitant use of oral corticosteroids, anticoagulants, prolonged NSAID therapy, smoking, alcohol consumption, advanced age, and poor general health.

These patients should start treatment with the lowest available dose. The condition of such patients, as well as patients requiring concomitant use of low-dose acetylsalicylic acid or other drugs that may increase the risk of gastrointestinal bleeding, should be closely monitored, and combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered. If any unusual gastrointestinal symptoms occur, particularly bleeding or ulcers, especially in elderly patients, during ketorolac therapy, the drug should be discontinued.

Most spontaneous reports of gastrointestinal adverse events involved elderly or debilitated patients; therefore, special attention should be paid to such patients, and ketorolac should be discontinued if any suspicion arises. Alternative therapies not involving NSAIDs should be considered for patients at high risk.

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.

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

Effects on hemostasis.

Ketorolac inhibits platelet aggregation and prolongs bleeding time.

Single-dose administration of ketorolac tromethamine in patients receiving anticoagulant therapy may increase the risk of bleeding. Detailed studies on the concomitant use of ketorolac with prophylactic low-dose heparin (2500–5000 IU every 12 hours), warfarin, or dextrans have not been conducted; therefore, such regimens may also increase the risk of bleeding. Patients already receiving anticoagulants or requiring low-dose heparin should not use ketorolac tromethamine. Patients receiving other agents that adversely affect hemostasis should be closely monitored during ketorolac tromethamine administration. In controlled clinical trials, the incidence of clinically significant postoperative bleeding was less than 1%. In patients with normal bleeding function, bleeding time was prolonged but remained 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.

Postoperative wound bleeding has been reported in association with immediate perioperative use of ketorolac. Therefore, ketorolac should not be used in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis.

Ketorolac tromethamine should be used with caution in cases with significant hemostatic concerns, but not limited to cosmetic or routine surgeries, prostatectomy, or tonsillectomy.

Hematoma, epistaxis, and other signs of wound bleeding have been observed during ketorolac use. Physicians should be aware of the pharmacological similarity of ketorolac to other NSAIDs that inhibit COX and the risk of bleeding, especially in elderly patients.

Use in patients with renal impairment.

Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have nephrotoxic effects; therefore, it should be used with caution in patients with impaired renal function or a history of kidney disease. Usually, after discontinuation of NSAID therapy, kidney function returns to its previous state.

Patients at risk include those with blood loss, impaired renal function, hypovolemia, heart failure, hepatic impairment, those receiving diuretics, and elderly patients.

Ketorolac for injection should not be administered to patients with moderate or severe renal impairment (serum creatinine >160 µmol/L), as ketorolac and its metabolites are primarily excreted by the kidneys.

Patients with mild renal impairment should receive lower doses of ketorolac (not exceeding 60 mg/day intramuscularly). Renal function and serum urea/creatinine levels should be closely monitored in these patients. Patients should be well hydrated before initiating treatment. In patients undergoing hemodialysis, ketorolac clearance was reduced by approximately half compared to normal, and terminal half-life (T_1/2) was nearly tripled.

As with other drugs that inhibit prostaglandin synthesis, ketorolac may increase serum levels of urea, creatinine, and potassium, which may be observed even after a single dose.

Effects on the cardiovascular system and cerebral vessels.

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

To minimize the potential risk of cardiovascular complications in patients using NSAIDs, the lowest effective dose should be used for the shortest possible duration. Ketorolac tromethamine should be prescribed to patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful assessment of benefits and risks. Similarly, the appropriateness of prescribing ketorolac should be considered before initiating long-term treatment in patients at risk for cardiovascular disease (e.g., those with arterial hypertension, hyperlipidemia, diabetes mellitus, or smokers).

Clinical trials and epidemiological data suggest that the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction or stroke. Such a risk cannot be excluded for ketorolac.

Use in patients with hepatic impairment.

Ketorolac tromethamine should be prescribed with caution in patients with hepatic impairment or a history of liver disease. Significant increases (more than three times the upper normal limit) in serum ALT and AST were observed in less than 1% of patients in controlled clinical trials.

Additionally, isolated cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of which were fatal, have been reported. Ketorolac should be discontinued if clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.

Patients with hepatic impairment due to cirrhosis show no clinically significant differences in ketorolac clearance or half-life.

Marginal elevations in one or more liver function tests may occur. These abnormalities may be transient, remain unchanged, or progress with continued therapy.

Respiratory system.

The patient's condition should be monitored due to the high likelihood of bronchospasm development.

Connective tissue diseases.

The use of the drug in patients with systemic lupus erythematosus or other connective tissue diseases may be associated with an increased risk of aseptic meningitis.

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 hypersensitivity to acetylsalicylic acid, other NSAIDs, or ketorolac. These reactions may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g., asthma), or nasal polyps. Anaphylactoid reactions, such as anaphylaxis, may be fatal. Therefore, ketorolac should not be used in such patients.

Skin reactions.

Serious skin reactions have been reported with NSAID use, some of which were fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk of these reactions occurs early in treatment, with most cases appearing within the first month of therapy. Patients should discontinue the drug at the first sign of rash, mucosal lesions, or other signs of hypersensitivity.

Abuse or dependence.

Ketorolac has no potential for addiction. No withdrawal symptoms have been observed after abrupt discontinuation of ketorolac.

Important information about excipients.

This medicinal product contains anhydrous sodium sulfite (E 221), which may rarely cause hypersensitivity reactions and bronchospasm.

This medicinal product contains benzyl alcohol, which may cause toxic and allergic reactions in infants and children under 3 years of age. The use of this medicinal product is contraindicated in children under 16 years of age.

This medicinal product contains propylene glycol, which may cause symptoms similar to those associated with alcohol consumption.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of ketorolac tromethamine is contraindicated during pregnancy, labor, and delivery due to known effects of NSAIDs on the fetal cardiovascular system (risk of failure to close the arterial duct).

The safety of ketorolac use during pregnancy has not been established. Teratogenicity was not confirmed in studies with toxic doses of ketorolac in rats and rabbits. In rats, prolonged gestation and/or delayed delivery were observed.

Low rates of congenital anomalies have been reported with NSAID use in men, without any consistent pattern.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of miscarriage and various fetal malformations (cardiovascular system and gastroschisis) after use of prostaglandin synthesis inhibitors in early pregnancy. Starting from the 20th week of pregnancy, the use of the drug Ketolong-Darnitsya® may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible after discontinuation of therapy. Additionally, there are reports of arterial duct constriction after second-trimester treatment, which resolved in most cases after discontinuation of therapy. Prenatal monitoring for oligohydramnios and arterial duct constriction may be advisable after exposure to ketorolac for several days, starting from the 20th gestational week.

The absolute risk of cardiovascular malformations with NSAID use increases from less than 1% to approximately 1.5%. The risk is considered to increase with dose and duration of therapy.

In the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• cardiopulmonary toxicity (premature constriction/closure of the arterial duct and pulmonary hypertension);
• impaired renal function with possible subsequent development of renal failure with oligohydramnios (see above).

On the mother and fetus near the end of pregnancy, prostaglandin synthesis inhibitors may have the following effects:

• prolonged bleeding time, anti-aggregatory effect, which may occur even after very low doses, may result in increased bleeding in both mother and child;
• inhibition of uterine contractions, which may lead to delayed or prolonged labor.

Approximately 10% of ketorolac crosses the placenta.

Breastfeeding period.

Ketorolac and its metabolites pass into breast milk in low concentrations.

Due to the potential negative effects of prostaglandin synthesis inhibitors on infants, ketorolac is contraindicated during breastfeeding.

Fertility.

The use of ketorolac, like any drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair female fertility and is not recommended for women attempting to conceive.

Women who have difficulty conceiving or are undergoing infertility evaluation.

Ability to influence reaction rate when driving or operating machinery.

In some patients, the use of ketorolac tromethamine may cause dizziness, somnolence, visual disturbances, headache, vertigo, insomnia, or depression. If these or similar adverse effects occur, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

It is recommended to use the drug under hospital conditions. After intramuscular administration, analgesic effect occurs approximately after 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 depending on the severity of pain and the patient's response to treatment.

Continuous intramuscular administration of multiple daily doses of ketorolac should not last longer than 2 days, as prolonged use increases the risk of adverse reactions. Experience with long-term use is limited, since most patients were switched to oral medication or no longer required analgesic therapy after the intramuscular administration period.

The likelihood of adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. The drug must not be administered epidurally or intraspinally.

Adults.

The recommended initial dose of ketorolac tromethamine, solution for intramuscular injection, is 0, mg, followed by doses of 10–30 mg every 4–6 hours as needed. In the initial postoperative period, ketorolac tromethamine may be administered every 2 hours if necessary. The minimum effective dose should be prescribed. The total daily dose must not exceed 90 mg for younger patients, and 60 mg for elderly patients, patients with renal impairment, and patients with body weight less than 50 kg. The maximum duration of treatment must not exceed 2 days. In patients with body weight less than 50 kg, the dose should be reduced. Concomitant use of opioid analgesics (morphine, pethidine) is possible. Ketorolac has no negative effect on opioid receptor binding and does not enhance respiratory depression or sedative effects of opioid drugs. For patients receiving parenteral Ketolong-Darnitsya® solution who are being switched to oral Ketolong-Darnitsya® tablets, the total combined daily dose must not exceed 90 mg (60 mg for elderly patients, patients with impaired renal function, and patients with body weight less than 50 kg), and on the day of switching formulations, the dose of the oral component must not exceed 40 mg. Patients should be switched to oral formulation as soon as possible.

Elderly Patients.

For patients aged 65 years and older, it is recommended to prescribe the lowest dose within the dosing range. The total daily dose must not exceed 60 mg.

Patients with Renal Impairment.

Ketorolac is contraindicated in moderate to severe renal impairment. In mild to moderate impairment, dosage reduction is required (not exceeding 60 mg per day intramuscularly).

Children.

The drug is contraindicated in children under 16 years of age, as safety and efficacy in children have not been established.

Overdose.

Symptoms. Acute overdose of ketorolac has at various times led to abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal function disturbances, which resolved after discontinuation of the drug.

Possible symptoms include disorientation, agitation, dizziness, hearing disturbances, loss of consciousness, lethargy, drowsiness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, arterial hypertension, acute renal failure, respiratory depression, and coma. Anaphylactoid reactions have been reported, which may also occur in cases of overdose.

Rare cases of diarrhea and accidental seizures have been recorded.

Treatment. Therapy is symptomatic and supportive. There is no specific antidote. Within 1 hour and no later than 4 hours after drug intake with symptoms of overdose or after a large overdose (oral dose 5–10 times higher than usual), induction of vomiting is recommended, along with activated charcoal (60–100 g for adults) and/or administration of an osmotic laxative.

Forced diuresis, urine alkalinization, hemodialysis, or blood transfusion are ineffective due to the high degree of plasma protein binding of the drug.

Frequent or prolonged convulsions should be treated with intravenous diazepam. Close monitoring of kidney and liver function is required.

Other measures may be indicated depending on the patient's clinical condition.

Adverse Reactions

Eye disorders: blurred vision, optic neuritis, retrobulbar neuritis, visual disturbances.

Ear and labyrinth disorders: tinnitus, hearing loss, deafness.

Respiratory, thoracic and mediastinal disorders: dyspnea, tachypnea or dyspnea, chest tightness or chest pain, wheezing, asthma, worsening of asthma, pulmonary edema.

Gastrointestinal disorders: anorexia, abdominal discomfort, bloating, nausea, dyspepsia, gastrointestinal pain, epigastric pain, diarrhea; less frequently – flatulence, belching, vomiting, constipation, erosive-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 disorders: very rarely – liver function abnormalities, hepatic failure, jaundice, hepatitis, hepatomegaly, increased hepatic transaminase activity.

Renal and urinary disorders: severe pain in the renal area, dysuria, frequent urination, oliguria, hyponatremia, hyperkalemia, hematuria, proteinuria, increased blood urea and creatinine levels, azotemia, urinary retention, acute renal failure, renal failure, interstitial nephritis, papillary necrosis, nephrotic syndrome, hemolytic uremic syndrome, flank pain (with or without hematuria).

Nervous system disorders: headache, dizziness, altered consciousness, increased fatigue, weakness, irritability, dry mouth, increased thirst, nervousness, confusion, paresthesia, functional disturbances, somnolence, sleep disturbances, insomnia, difficulty concentrating, euphoria, excitement, hyperkinesia, convulsions, aseptic meningitis (with corresponding symptoms), nuchal rigidity, anxiety, vertigo, disorientation.

Psychiatric disorders: hyperactivity (mood changes, restlessness), hallucinations, unusual dreams, depression, psychotic reactions, pathological thoughts, thinking disorders.

Cardiovascular disorders: pallor, flushing, chest pain, palpitations, bradycardia, heart failure, arterial hypertension or hypotension, palpitation, edema. Clinical and epidemiological data indicate 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).

Blood and lymphatic system disorders: purpura, leukopenia, eosinophilia, thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia, which may lead to subcutaneous hemorrhages, hematoma, epistaxis, reduced blood clotting speed, prolonged bleeding time, and increased postoperative wound bleeding.

Immune system disorders: hypersensitivity reactions, including anaphylactic and anaphylactoid reactions, urticaria, airway reactivity, asthma, worsening of asthma, bronchospasm, laryngeal edema, angioedema, eyelid edema, periorbital edema, facial edema, leg edema, finger edema, foot edema, tongue edema, dyspnea, arterial hypotension, flushing, exfoliative dermatitis, bullous dermatosis. 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 angioedema or bronchospastic reactivity (e.g., asthma and nasal polyps). Anaphylactoid reactions such as anaphylaxis may be fatal.

Skin and subcutaneous tissue disorders: erythema, pruritus, urticaria, photosensitivity reactions, Lyell’s syndrome (toxic epidermal necrolysis), bullous reactions, exfoliative dermatitis, Stevens-Johnson syndrome, skin rashes including maculopapular and exudative rashes, facial skin discoloration.

Musculoskeletal and connective tissue disorders: myalgia, functional disorders.

Reproductive system and breast disorders: infertility (in women).

General disorders and administration site conditions: general weakness, thirst, asthenic syndrome, malaise, edema, fever with or without chills, increased sweating, weight gain; rash, pruritus, pain, swelling, and erythema at the injection site.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze.

Keep out of reach and sight of children.

Incompatibilities.

Ketorolac injection solution should not be mixed in small volumes (e.g., in the same syringe) with morphine sulfate, meperidine hydrochloride, promethazine, or hydroxyzine, as ketorolac may precipitate.

Packaging.

1 ml in an ampoule; 5 ampoules in a blister pack, 2 blisters per carton; or 10 ampoules in a blister pack, 1 blister per carton.

Prescription category. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer’s address.

13, Borispilska Street, Kyiv, 02093, Ukraine.