Instructions Ambit 10 mg tablets No. 10
Composition
active ingredient: ketorolac trometamol;
1 tablet contains ketorolac trometamol 10 mg;
excipients: microcrystalline cellulose; lactose monohydrate; magnesium stearate;
film coating: hypromellose, titanium dioxide (E 171), macrogol.
Dosage form
Film-coated tablets.
Main physicochemical properties: round tablets with a biconvex surface, coated with a white or almost white film coating.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs. ATC code M01A B15.
Pharmacological properties
Pharmacodynamics.
The analgesic ketorolac trometamol is a non-narcotic analgesic. It is a non-steroidal anti-inflammatory drug that exhibits strong analgesic, anti-inflammatory and weak antipyretic activity. Ketorolac trometamol inhibits prostaglandin synthesis and is considered a peripherally acting analgesic. It has no known effect on opiate receptors. No evidence of respiratory depression has been observed in controlled clinical trials following the use of ketorolac trometamol. Ketorolac trometamol does not cause mydriasis.
Pharmacokinetics.
Ketorolac trometamol is rapidly and completely absorbed after oral administration with a peak plasma concentration of 0.87 mg/kg 45 minutes after a single 10 mg dose. In healthy volunteers, the terminal plasma half-life averages 5.4 hours. In elderly subjects (mean age 72 years), it is 6.2 hours. More than 99% of ketorolac in plasma is protein bound. Ketorolac penetrates the brain tissue with great difficulty. A small amount of it can be detected in breast milk. In healthy humans, less than 50% of the administered dose is metabolized. The important metabolites are the glucuronide conjugate and 4-hydroxy-ketorolac, the metabolites of which are pharmacologically inactive. In humans, the pharmacokinetics of ketorolac are linear after single or multiple doses. Steady-state plasma levels are reached after 1 day when administered 4 times a day. No changes were observed with long-term dosing. In healthy volunteers, the terminal plasma half-life is 4–6 hours (mean 5.4 hours). The plasma half-life increases in patients with renal insufficiency and in the elderly. In the elderly (mean age 72 years), it is 6.2 hours. After a single intravenous dose, the volume of distribution is 0.25 l/kg, the half-life is 5 hours, and the clearance is 0.55 ml/min/kg. The main route of excretion of ketorolac and its metabolites (conjugates and p-hydroxymetabolites) is urine (90%), with the remainder excreted in the feces. Foods rich in fat and difficult to digest reduce the rate of absorption, but not the extent, while antacids do not affect the absorption of ketorolac.
Indication
Short-term treatment of moderate pain, including postoperative pain.
The maximum duration of treatment is 5 days.
Contraindication
Hypersensitivity to ketorolac or to other NSAIDs or to other components of the drug;
hypersensitivity reactions, such as bronchial asthma, rhinitis, angioedema or urticaria in history, caused by the use of acetylsalicylic acid or other NSAIDs (due to the possibility of severe anaphylactic reactions);
gastrointestinal bleeding or perforation, active or in history, associated with taking NSAIDs;
active recurrent peptic ulcer/gastrointestinal bleeding (two or more episodes) in the acute stage or in history;
do not use as an analgesic before and during surgery and after manipulations on coronary vessels due to inhibition of platelet aggregation, which may cause bleeding;
suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, including blood clotting disorders and a high risk of bleeding, as well as in the postoperative period, if there is a high risk of bleeding or incomplete hemostasis;
complete or partial nasal polyps syndrome, angioedema or bronchospasm;
concomitant treatment with other non-steroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, oxpentoxifylline, probenecid or lithium salts, anticoagulants, including low-dose heparin (2500–5000 units every 12 hours);
violation of hematopoiesis of unknown etiology;
severe heart failure;
history of bronchial asthma;
hepatic or moderate to severe renal failure (serum creatinine level more than 160 μmol/l);
risk of kidney failure due to fluid depletion;
hypovolemia, dehydration;
the drug is contraindicated during pregnancy, labor and delivery, and during breastfeeding;
Do not use in children and adolescents under 16 years of age.
Interaction with other medicinal products and other types of interactions
Ketorolac binds readily to plasma proteins (mean 99.2%), and the extent of binding is concentration dependent.
Ketorolac should not be used with other NSAIDs, including selective cyclooxygenase-2 inhibitors, including in patients receiving acetylsalicylic acid, due to the risk of severe adverse reactions.
Ketorolac inhibits platelet aggregation, reduces thromboxane concentration, and prolongs bleeding time. In contrast to the long-term effects of acetylsalicylic acid, platelet function is restored within 24–48 hours after discontinuation of ketorolac.
Anticoagulants: Although studies have not shown a significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac and therapies that affect hemostasis, including therapeutic doses of anticoagulants (warfarin), prophylactic low-dose heparin (2500–5000 units 12 hourly), and dextrans, may increase the risk of bleeding. Concomitant use with anticoagulants (such as warfarin) is contraindicated.
Inhibition of renal clearance of lithium by some drugs that inhibit prostaglandin synthesis has resulted in increased plasma lithium concentrations. Cases of increased plasma lithium concentrations have been reported during ketorolac therapy.
Probenecid should not be administered concomitantly with ketorolac due to a decrease in the plasma clearance and volume of distribution of ketorolac, an increase in the plasma concentration of ketorolac, and an increase in its half-life.
Nonsteroidal anti-inflammatory drugs should not be used for 8–12 days after taking mifepristone, as NSAIDs may reduce the effect of mifepristone.
If ketorolac is administered concomitantly with oxpentifylline, an increased tendency to bleed is observed.
Drugs that should be prescribed with caution in combination with ketorolac.
As with all NSAIDs, caution should be exercised when corticosteroids are administered concomitantly due to the increased risk of gastrointestinal ulceration or bleeding. There is an increased risk of gastrointestinal bleeding when NSAIDs are administered in combination with antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs).
Caution is advised when methotrexate is co-administered, as some prostaglandin synthesis inhibitors have been reported to reduce the clearance of methotrexate and therefore possibly increase its toxicity.
In normal, normovolemic healthy subjects, ketorolac reduces the diuretic effect of furosemide by approximately 20%. Concomitant administration with diuretics may result in a weakening of the diuretic effect and an increased risk of NSAID nephrotoxicity.
Ketorolac is recommended to be administered with caution simultaneously with cyclosporine due to the increased risk of nephrotoxicity.
There is a risk of nephrotoxicity if NSAIDs are administered with tacrolimus.
The drug should be prescribed with special caution to patients with cardiac decompensation. NSAIDs can aggravate heart failure, reduce glomerular filtration rate and increase plasma levels of cardiac glycosides when administered simultaneously with cardiac glycosides.
Ketorolac and other NSAIDs may reduce the effect of antihypertensive agents. There is an increased risk of renal impairment (usually reversible) when ketorolac is used concomitantly with ACE inhibitors or ARBs, especially in patients with reduced blood volume or in the elderly. If such a combination is used in such patients, careful monitoring of renal function is necessary at the beginning of treatment and periodically during therapy.
Opioid analgesics (e.g. morphine, pethidine) can be used concomitantly, ketorolac does not affect the binding of opioid drugs and does not increase the respiratory depression or sedative effects caused by opioids. It has been demonstrated that in cases of postoperative pain, the simultaneous use of ketorolac with opioid analgesics reduced the need for the latter.
Oral administration of ketorolac tablets after a high-fat meal resulted in a decrease in peak plasma concentrations of ketorolac and an increase in time to peak concentration by approximately 1 hour. Antacids do not affect the extent of absorption.
Patients taking NSAIDs and quinolones are at increased risk of developing seizures.
Concomitant use of NSAIDs with zidovudine increases the risk of hematological toxicity. There is an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia treated concomitantly with zidovudine and ibuprofen.
The following drugs are unlikely to interact with ketorolac.
In animal and human studies, there was no evidence that ketorolac trometamol induces or inhibits hepatic enzymes that are capable of metabolizing it or other drugs. Therefore, ketorolac is not expected to alter the pharmacokinetics of other drugs by enzyme induction or inhibition.
Antiepileptic drugs.
Isolated cases of epileptic seizures have been reported during the concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).
Psychotropic drugs.
Hallucinations have been reported with the concomitant use of ketorolac and psychotropic drugs (fluoxetine, thiotexene, alprazolam).
Impact on laboratory test results.
Ketorolac inhibits platelet aggregation and may prolong bleeding time.
Application features
Epidemiological data suggest that ketorolac may be associated with a higher risk of gastrointestinal toxicity compared with other NSAIDs, especially when used off-label and/or for prolonged periods of time.
To reduce the risk of adverse effects, treatment with ketorolac should be for the shortest duration and at the lowest dose necessary to control pain. The maximum duration of treatment should not exceed 5 days.
Gastrointestinal bleeding, ulceration and perforation.
Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with NSAIDs at any time during treatment, with or without pre-existing symptoms or a history of serious gastrointestinal events. The risk of serious gastrointestinal bleeding is dose-dependent. The risk of gastrointestinal bleeding, ulceration or perforation increases with increasing dose of NSAIDs, including ketorolac, in patients with a history of ulcer, especially if complicated by bleeding or perforation, and in the elderly. The risk of a clinically significant bleeding episode is dose-dependent. In such patients, treatment should be started at the lowest available dose. This is particularly true in elderly and debilitated patients receiving a mean daily dose of ketorolac above 60 mg. The highest number of deaths from gastrointestinal adverse reactions associated with NSAIDs was observed in elderly or debilitated patients. Such patients should be advised to report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), especially in the initial stages of treatment. For such patients, as well as for patients who are concomitantly taking low doses of acetylsalicylic acid or other drugs that may increase the risk for the gastrointestinal tract, the possibility of combined treatment with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered. Ambit® should be used with caution in patients receiving concomitant medication that may increase the risk of ulceration or bleeding, such as oral corticosteroids, selective serotonin reuptake inhibitors (SSRIs) or antiplatelet agents such as acetylsalicylic acid. NSAIDs should be used with caution in patients with inflammatory bowel diseases (Crohn's disease, ulcerative colitis).
If gastrointestinal bleeding or ulceration occurs in patients receiving Ambit®, treatment should be discontinued.
NSAIDs, including ketorolac, may be associated with an increased risk of gastrointestinal anastomotic rupture. Close medical supervision and caution are recommended when ketorolac is used following gastrointestinal surgery.
Hematological effects.
Patients with bleeding disorders should not be prescribed Ambit®. Patients receiving anticoagulant therapy may be at increased risk of bleeding if ketorolac is used concomitantly (see “Interaction with other drugs and other types of interactions”). Patients receiving other drugs that may affect the rate of bleeding should be carefully monitored when prescribing ketorolac. In controlled clinical trials, the incidence of major postoperative bleeding was less than 1%. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding times, bleeding time was increased, but did not exceed the normal range of 2–11 minutes. In contrast to the prolonged effect of acetylsalicylic acid, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac. Ketorolac should not be prescribed to patients who have undergone surgery with a high risk of bleeding or incomplete bleeding. Caution should be exercised if mandatory control of bleeding is critical. Hypovolemia should be corrected before initiating ketorolac.
Dermatological effects.
There is an increased risk of such reactions at the beginning of treatment: the onset of these reactions occurs in most cases within the first month of treatment. Ambit® should be discontinued at the first signs of skin rash, mucosal lesions or any other signs of hypersensitivity (see "Adverse reactions").
Increasing the dose of ketorolac tablets above the daily dose of 40 mg does not increase its effectiveness, but increases the risk of adverse reactions.
Ketorolac is not addictive; no withdrawal syndrome has been reported when the drug is discontinued.
Systemic lupus erythematosus and mixed connective tissue diseases.
Patients with systemic lupus erythematosus and various mixed connective tissue diseases are at increased risk of developing aseptic meningitis.
Sodium retention, fluid retention, and edema.
Fluid retention, hypertension, and edema have been reported with ketorolac, so it should be administered with caution to patients with mild to moderate heart failure, hypertension, or similar conditions.
Cardiovascular and cerebrovascular effects.
Patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease should be monitored closely as the use of the drug may be associated with a slightly increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Clinical trials and epidemiological data suggest that the use of coxibs and some NSAIDs (mainly at high doses) may be associated with a slightly increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Although treatment with ketorolac has not been shown to increase the incidence of thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk for ketorolac trometamol.
Disorders of the cardiovascular system, kidneys and liver.
Caution should be exercised in patients with conditions that result in decreased blood volume and/or renal blood flow, where renal prostaglandins play a supporting role in maintaining renal perfusion. Renal function should be monitored in such patients. Volume depletion should be corrected and serum urea and creatinine and urine output should be closely monitored until the patient is normovolemic, as there is a risk of renal failure if these recommendations are not followed. In patients on dialysis, creatinine clearance was reduced by approximately half compared to normal and terminal half-life was increased by approximately threefold. Patients with impaired liver function due to cirrhosis did not have any clinically significant changes in ketorolac clearance or residual half-life. Borderline elevations in one or more liver function tests (ALT/AST) may occur. These abnormalities may be transient, may remain unchanged, or may progress with continued treatment. If clinical signs and symptoms suggestive of liver disease develop or if systemic manifestations occur, Ambit® should be discontinued.
Ketorolac should be administered with caution to patients with a history of cardiovascular disorders.
Effect on the kidneys.
Prostaglandin biosynthesis inhibitors (including NSAIDs) have been reported to be nephrotoxic. Caution should be exercised in patients with impaired renal, cardiac, or hepatic function, and in patients with pre-existing renal disease, as NSAIDs may worsen renal function due to inhibition of prostaglandin synthesis (see above). Since ketorolac trometamol and its metabolites are primarily excreted by the kidneys, patients with moderate to severe renal impairment (serum creatinine > 160 μmol/l) should not take Ambit. Patients with mild renal impairment should be given lower doses of ketorolac (not exceeding 60 mg/day intramuscularly) and their renal function should be closely monitored. As with other drugs that inhibit prostaglandin synthesis, increases in serum urea, creatinine, and potassium have been reported with ketorolac trometamol, which may occur after a single dose. Discontinuation of the drug usually results in recovery of renal function.
Respiratory dysfunction.
Caution is required when using the drug in patients with bronchial asthma (or with a history of asthma), since NSAIDs have been reported to precipitate bronchospasm in such patients.
Anaphylactic/anaphylactoid reactions (including but not limited to anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) have occurred in patients with a history of hypersensitivity to acetylsalicylic acid or any other NSAID or to intravenous ketorolac trometamol. They may also occur in people with angioedema, bronchospasm (e.g., asthma), and adenoids. Anaphylactoid reactions, such as anaphylaxis, may develop slowly. Therefore, ketorolac trometamol is contraindicated in patients with a history of asthma and in patients with complete or partial nasal polyposis syndrome, angioedema, and bronchospasm.
Impact on fertility.
The use of ketorolac, as with any drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. For women who are unable to conceive or are undergoing investigation of fertility, discontinuation of ketorolac should be considered.
Lactose
This medicine contains lactose.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
Use during pregnancy or breastfeeding
The safety of ketorolac during human pregnancy has not been established. Approximately 10% of ketorolac crosses the placenta.
Given the known effects of NSAIDs on the cardiovascular system of the fetus (risk of premature narrowing/closure of the ductus arteriosus and pulmonary hypertension), ketorolac is contraindicated during pregnancy, labor and delivery. The safety of ketorolac during pregnancy has not been established. There was no evidence of teratogenicity in rats or rabbits studied at maternally toxic doses of ketorolac. In rats, prolongation of gestation and/or delayed parturition have been observed. Congenital abnormalities have been reported in association with NSAIDs in humans, but their incidence is very low and no causal relationship can be established. The onset of labor may be delayed and the duration prolonged due to suppression of uterine contractility. The risk of bleeding in both mother and child is increased.
Starting from the 20th week of pregnancy, the use of ketorolac may cause oligohydramnios due to fetal renal dysfunction.
Inhibition of prostaglandin synthesis by NSAIDs in early pregnancy may lead to embryo/fetal malformations; heart defects and gastroschisis, urinary tract abnormalities with oligohydramnios following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiovascular malformation increases from less than 1% to approximately 1.5%. The risk is thought to increase with dose and duration of therapy.
Epidemiological studies indicate an increased risk of spontaneous abortion (miscarriage).
Ketorolac passes into breast milk in small amounts, so Ambit® is contraindicated during breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
Some patients may experience drowsiness, dizziness, vertigo, insomnia, fatigue, visual disturbances, headache, or depression when taking ketorolac. If patients experience these or similar effects, they should not drive or operate machinery.
Method of administration and doses
It is advisable to take the tablets during or after meals.
Adverse reactions can be minimized by using the lowest effective dose for the shortest period necessary to control symptoms.
The total duration of treatment (parenteral administration followed by oral administration) should not exceed 5 days.
Adults.
The usual recommended dose is 10 mg every 4 or 6 hours. It is not recommended to administer more than 40 mg per day.
If the treatment is a continuation of injection treatment:
patients aged 16 to 64 years, with a body weight of at least 50 kg and with normal kidney function - initially administer 20 mg, then administer 10 mg each time a maximum of 4 times a day with an interval of 4 to 6 hours;
patients with a body weight of less than 50 kg, elderly patients or patients with impaired renal function - 10 mg a maximum of 4 times a day with an interval of 4 to 6 hours.
For patients who have received parenteral ketorolac and then used oral administration, the combined dose of ketorolac should not exceed 90 mg in adults and 60 mg in elderly patients with impaired renal function and patients weighing less than 50 kg.
Patients should be switched to oral administration as early as possible.
Elderly patients.
Elderly patients are at greater risk of developing serious complications, particularly from the gastrointestinal tract. During treatment with NSAIDs, the patient's condition should be regularly monitored, and a longer interval between doses, such as 6-8 hours, is usually recommended.
Children.
Do not use in children under 16 years of age.
Overdose
Symptoms: headache, nausea, vomiting, epigastric pain, peptic ulcers, erosive gastritis, gastrointestinal bleeding; hyperventilation, hypertension, rarely - diarrhea, disorientation, agitation, coma, drowsiness, dizziness, tinnitus, loss of consciousness, convulsions. In cases of severe poisoning, acute renal failure and liver damage are possible.
Treatment: gastric lavage, administration of activated charcoal. Adequate diuresis should be ensured. Renal and hepatic function should be closely monitored. Patients should be observed for at least 4 hours after ingestion of a potentially toxic amount. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be prescribed depending on the clinical condition of the patient. Treatment is symptomatic. There is no specific antidote. Dialysis does not remove ketorolac from the circulation.
Side effects
On the part of the digestive tract: peptic ulcer, perforation or gastrointestinal bleeding, sometimes fatal (especially in the elderly), nausea, dry mouth, dyspepsia, gastrointestinal pain, abdominal discomfort, spasm or burning in the epigastric region, vomiting with blood, gastritis, esophagitis, diarrhea, belching, constipation, flatulence, feeling of fullness of the stomach, melena, rectal bleeding, stomatitis, ulcerative stomatitis, vomiting, hemorrhages, perforation, pancreatitis, exacerbation of colitis and Crohn's disease.
From the blood and lymphatic system: purpura, thrombocytopenia, neutropenia, agranulocytosis, aplastic and hemolytic anemia, eosinophilia.
Immune system (hypersensitivity): Hypersensitivity reactions, including non-specific allergic reactions and anaphylactoid reactions such as anaphylaxis, respiratory tract reactivity including asthma, worsening of asthma, bronchospasm, laryngeal edema or dyspnea, and various skin disorders including rashes of various types, pruritus, urticaria, flushing, purpura, angioedema, hypotension and, in rare cases, exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme), have been reported.
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, bronchospastic reactivity (e.g. asthma and nasal polyps). Anaphylactic reactions may be fatal.
Metabolic and nutritional disorders: hyponatremia, hyperkalemia, anorexia.
Central nervous system and psychiatric disorders: dizziness, headache, hyperkinesia, nervousness, paresthesia, functional disorders, depression, euphoria, convulsions, inability to concentrate, insomnia, malaise, anxiety, drowsiness, increased fatigue, agitation, unusual dreams, confusion, hallucinations, dysgeusia, aseptic meningitis with corresponding symptoms (neck stiffness, headache, nausea, vomiting, fever or disorientation), psychotic reactions, thinking disorders.
On the part of the organs of vision: visual impairment, blurred vision, optic neuritis.
On the part of the auditory organs: hearing loss, tinnitus, vertigo.
Cardiovascular system: hot flashes, bradycardia, pallor, hypertension, hypotension, palpitations, chest pain, edema, heart failure. Clinical and epidemiological data suggest that the use of some NSAIDs, especially in high doses and for a long time, may be associated with an increased risk of arterial thromboembolic complications (myocardial infarction or stroke). Although such reactions have not been observed with ketorolac, the risk of their occurrence cannot be excluded.
Respiratory system: shortness of breath, asthma, pulmonary edema.
From the hepatobiliary system: liver dysfunction, hepatitis, jaundice and liver failure, hepatomegaly, impaired functional laboratory parameters.
Skin: itching, urticaria, sweating, skin photosensitivity, Lyell's syndrome, bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), exfoliative dermatitis, maculopapular rashes.
Musculoskeletal and connective tissue disorders: myalgia, functional disorders.
From the urinary system: increased urinary frequency, oliguria, acute renal failure, hemolytic uremic syndrome, flank pain (with/without hematuria), increased serum urea and creatinine, interstitial nephritis, urinary retention, nephrotic syndrome, renal failure.
From the reproductive system: female infertility.
Others: postoperative bleeding from the wound, hematoma, nosebleed, prolonged bleeding, asthenia, malaise, anorexia, weight gain, edema, fever, increased, intensified thirst.
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua.
Expiration date
2 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Does not require any special storage conditions. Keep out of the reach of children.
Packaging
10 tablets in a blister. 1 or 10 blisters in a pack.
Vacation category
According to the recipe.
Producer
JSC "Farmak".
Location of the manufacturer and its business address.
Ukraine, 04080, Kyiv, Kyrylivska St., 74.
