Ketorolac Tromethamine

Package leaflet (information for patients)

Tradename
Ketorolac Tromethamine

Dosage form
Solution for injection 30 mg / ml.

Description
Transparent liquid of light yellow color with a weak odor.

Structure
1 ml of solution contains:
Active ingredient: Ketorolac Tromethamine 30mg.
Auxiliary components: ethyl oleate.

Pharmacotherapeutic group
Non-steroidal anti-inflammatory drug.

Pharmacological properties
It has a pronounced analgesic effect, also has an anti-inflammatory and moderate antipyretic effect. The mechanism of action is associated with non-selective inhibition of the activity of cyclooxygenase (COX-1 and COX-2), which catalyzes the formation of prostaglandins from arachidonic acid, which play an important role in the pathogenesis of pain, inflammation and fever. In terms of the strength of the analgesic effect, it is comparable to that of morphine, significantly superior to other non-steroidal anti-inflammatory drugs.
After oral administration, the onset of the analgesic effect is noted after 1 hour, the maximum effect is achieved after 2-3 hours.
Pharmacokinetics
Oral absorption - fast, bioavailability - 80-100%; Cmax after oral administration of 10 mg is 0.82–1.46 μg / ml, TCm ax - 10–78 minutes.
Communication with plasma proteins - 99%.
The time to reach Css with parenteral and oral administration is 24 hours when administered 4 times a day (higher than subtherapeutic) and after oral administration of 10 mg is 0.39–0.79 μg / ml.
The volume of distribution is 0.15-0.33 l / kg. In patients with renal insufficiency, the volume of distribution of ketorolac can increase by 2 times, and the volume of distribution of its R - enantiomer - by 20%.
Penetrates into breast milk: when the mother takes 10 mg of ketorolac Cmax in milk, it is reached 2 hours after taking the first dose and is 7.3 ng / ml, 2 hours after the second dose of ketorolac (when using the drug 4 times a day) - 7, 9 ng / l. More than 50% of the administered dose is metabolized in the liver with the formation of pharmacologically inactive metabolites. The main metabolites are glucuronides, which are excreted by the kidneys, and p- hydroxyketorolac. It is excreted by 91 % by the kidneys, 6% through the intestines.
T1 / 2 in patients with normal renal function - an average of 5.3 hours (2.4-9 hours after oral administration of 10 mg). T1 / 2 increases in older patients and is shortened in younger patients. Liver function has no effect on T1 / 2. In patients with impaired renal function with a plasma creatinine concentration of 19-50 mg / L (168-442 μmol / L) T1 / 2 - 10.3-10.8 hours, with more severe renal failure - more than 13.6 hours.
The total clearance is when taken orally 10 mg - 0.025 l / h / kg; in patients with renal failure at a plasma creatinine concentration of 19–50 mg / l with oral administration of 10 mg - 0.016 l / h / kg.
Not excreted by hemodialysis.

Indications for use
B Olevia syndrome strong to moderate severity: trauma, dental pain, postoperative pain, cancer, myalgia, arthralgia, neuralgia, sciatica, sprains, strains, rheumatic diseases.
It is intended for symptomatic therapy, reducing pain and inflammation at the time of use, does not affect the progression of the disease.

Method of administration and dosage
When administered intramuscularly to adults under the age of 65 and children over 16 years of age, 10-60 mg is administered intramuscularly in the first administration, then 10-30 mg every 6 hours (usually 30 mg every 6 hours); elderly patients over 65 years of age or with impaired renal function - 10-15 mg every 4-6 hours.
When administered intravenously, adults under the age of 65 and children over 16 years of age are injected in a stream at a dose of 10-30 mg, then 10-30 mg every 6 hours. With continuous infusion using an infusion pump, the initial dose is 30 mg, then the infusion rate is 5 mg / h.
When administered intravenously to elderly patients over 65 years of age or with impaired renal function, a jet is injected at a dose of 10-15 mg every 6 hours.
The maximum daily dose for intramuscular and intravenous administration for adults under the age of 65 and children over 16 years of age is 90 mg; for elderly patients over 65 years of age or with impaired renal function - 60 mg.
Continuous IV infusion should not last more than 24 hours.
With parenteral administration, the duration of the course of treatment should not exceed 5 days.
When switching from parenteral administration of the drug to oral administration, the total daily dose of the drug in both dosage forms on the day of transfer should not exceed: 90 mg for adults under the age of 65 and children over 16 years old and 60 mg for elderly patients over 65 years old or with impaired renal function. In this case, the dose of the drug in tablets on the day of transition should not exceed 30 mg.

Side effects
Often -> 3%; IU her often - 1-3%; rarely - <1%.
On the part of the digestive system: often (especially in elderly patients over 65 years of age with a history of erosive and ulcerative lesions of the gastrointestinal tract) - gastralgia, diarrhea; less often - stomatitis, flatulence, constipation, vomiting, a feeling of fullness in the stomach; rarely - decreased appetite, nausea, erosive and ulcerative lesions of the gastrointestinal tract (including with perforation and / or bleeding - abdominal pain, spasm or burning sensation in the epigastric region, melena, vomiting with blood or "coffee grounds", nausea, heartburn), cholestatic jaundice, hepatitis, n patomegaliya, acute pancreatitis.
From the urinary system: rarely - acute renal failure, back pain, hematuria, azotemia, hemolytic- uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), increased urination, increased or decreased urine volume, nephritis, renal edema.
From the side of the central nervous system and peripheral nervous system: often - headache, dizziness, drowsiness; rarely - aseptic meningitis (including fever, severe headache, cramps, stiff neck and / or back muscles), hyperactivity (including mood changes, anxiety), d allucination, depression, psychosis.
From the side of the cardiovascular system: less often - increased blood pressure; rarely - fainting.
From the respiratory system: rarely - bronchospasm, dyspnea, rhinitis, pulmonary edema, laryngeal edema (including shortness of breath, difficulty breathing).
From the sensory organs: rarely - hearing loss, ringing in the ears, impaired vision (incl neche. Tkost visual perception).
From the hematopoietic system: rarely - and nemia, eosinophilia, leukopenia.
From the side of the blood coagulation system: rarely - bleeding from a postoperative wound, nasal bleeding, rectal bleeding.
For the skin: less often - skin rash (incl. Maculopapular), purpura; rarely - exfoliative dermatitis (in incl. fever with / without fever, redness, induration or skin peeling, swelling and / or tenderness of the tonsils), urticaria syndrome Steve Jens -Dzhonsona, syndrome, Lyell.
Allergic reactions: rarely - anaphylaxis or anaphylactoid reactions (including discoloration of the face, skin rash, urticaria, itching of the skin, tachypnea or dyspnoea, swelling of the eyelids, periorbital edema, shortness of breath, shortness of breath, heaviness in the chest, wheezing breath).
Local reactions: less often - burning or pain at the injection site.
Others: often - edema (including of the face, legs, ankles, fingers, feet), increased body weight; less often - increased sweating; rarely - tongue edema, fever.

Contraindication
complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including a history);
urticaria, rhinitis caused by taking NSAIDs (in history);
intolerance to drugs of the pyrazolone series;
dehydration, hypovolemia (regardless of the cause that caused it);
bleeding or a high risk of developing them;
condition after coronary artery bypass grafting;
confirmed hyperkalemia ;
inflammatory bowel disease;
erosive and ulcerative lesions of the gastrointestinal tract in the acute stage, peptic ulcers;
hypocoagulation (including hemophilia);
severe renal failure (CC less than 30 ml / min);
severe liver failure or active liver disease;
hemorrhagic stroke (confirmed or suspected);
hemorrhagic diathesis;
violation of hematopoiesis;
pregnancy;
childbirth;
lactation period (breastfeeding);
children under 16 years of age (efficacy and safety have not been established);
hypersensitivity to ketorolac and other NSAIDs.
The drug is not used as a means for premedication, maintenance anesthesia, pain relief before and during surgery (including in obstetric practice) because of the high risk of bleeding.
The drug is not indicated for the treatment of chronic pain.
With care: bronchial asthma; cholecystitis; chronic heart failure; arterial hypertension; impaired renal function (plasma creatinine below 50 mg / l); cholestasis ; active hepatitis; sepsis; systemic lupus erythematosus; advanced age (over 65); polyps of the mucous membrane of the nose and nasopharynx, concomitant use with other NSAIDs; the presence of factors that increase the toxicity of the gastrointestinal tract: alcoholism, tobacco smoking ; postoperative period, edematous syndrome, ischemic heart disease, cerebrovascular diseases, dyslipidemia / hyperlipidemia, diabetes mellitus, peripheral arterial disease, creatinine clearance less than 60 ml / min, gastrointestinal ulcerative lesions in history, presence of Helicobacter pylori infection, long-term use of NSAIDs, severe somatic diseases, receiving oral corticosteroids (in incl. prednisone), anticoagulants (in incl. warfarin), antiplatelet agents (in incl. clopidogrel), selective serotonin reuptake inhibitors (in incl. citalopram, fluoxetine, paroxetine, sertraline).

Overdose
Symptoms: abdominal pain, nausea, vomiting, erosive and ulcerative lesions of the gastrointestinal tract, impaired renal function, metabolic acidosis.
Treatment: in case of taking the drug inside - gastric lavage, administration of adsorbents (activated carbon); when taken orally and parenterally - symptomatic therapy (maintenance of vital body functions). Not excreted sufficiently by dialysis.

Precautions
The maximum duration of treatment should not exceed 5 days.
Impact on fertility
The use of ketorolac, like any drug that inhibits cyclooxygenase / prostaglandin synthesis, may impair fertility and is not recommended for women planning to become pregnant. For women who cannot get pregnant or are undergoing fertility tests, consider discontinuing ketorolac.
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 precursor symptoms or in a history of severe digestive tract disorders. The risk of developing severe gastrointestinal bleeding depends on the dosage of the drug. This is particularly true of patients pozhilo- of age who used ketorolac mean daily dose higher than 60 mg. For these patients, as well as for patients who are simultaneously using low doses of acetylsalicylic acid or other drugs that may increase the risk to the digestive tract, the possibility of combination treatment with protective agents (for example, misoprostol or proton pump inhibitors) should be considered. Ketorolac is used with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid. In case of gastrointestinal bleeding or ulceration in patients who obtain -yut Ketorolac, treatment should be discontinued.
Respiratory dysfunction
Caution is required when using the drug in patients with bronchial asthma (or with a history of asthma), since it was reported that NSAIDs in such patients accelerate the onset of bronchospasm.
Effects on the kidneys
It has been reported that inhibitors of prostaglandin biosynthesis (including NSAIDs) have nephrotoxic effects. The drug is prescribed with caution to patients with impaired renal, heart, and liver function, since the use of NSAIDs can lead to a deterioration in renal function. Patients with minor impairment of renal function are prescribed smaller doses of ketorolac (those that do not exceed 60 mg per day intramuscularly or intravenously), and the condition of the kidneys in such patients should also be carefully monitored. As with other drugs that inhibit prostaglandin synthesis, there have been reports of increases in serum urea, creatinine and potassium while taking ketorolac tromethamine, which may occur after taking a single dose.
Violation of the cardiovascular system, kidneys and liver
The drug is used with caution in patients with conditions that lead to a decrease in blood volume and / or renal blood flow, when renal prostaglandins play a supporting role in providing renal perfusion. In these patients, it is necessary to monitor renal function. Volume reduction should be corrected and the serum urea and creatinine levels should be carefully monitored, as well as the volume of urine that is excreted until the patient develops normo-volemia. In patients on renal dialysis, the clearance of ketorolac was approximately halved compared to the normal rate, and the terminal half-life was increased approximately threefold. Patients with impaired liver function as a result of cirrhosis did not have any clinically significant changes in ketorolac clearance or terminal half-life. There may be marginal increases in values from one or more liver function tests. These abnormalities may be temporary, may remain unchanged, or may progress with continued treatment. If clinical signs and symptoms indicate the development of liver disease or if systemic manifestations are observed, Ketorolac should be canceled.
Fluid retention and edema
It has been reported about fluid retention and edema during the use of ketorolac, so it should be used with caution in patients with cardiac decompensation, hypertension or similar conditions.
Cardiovascular and cerebrovascular effects
There is currently insufficient information to assess this risk for ketorolac tromethamine. Patients with uncontrolled arterial hypertension, congestive heart failure diagnosed with coronary artery disease, peripheral arterial disease and / or cerebrovascular disease should be under medical supervision.
Systemic lupus erythematosus and mixed connective tissue diseases
Patients with systemic lupus erythematosus and various mixed connective tissue diseases increase the risk of developing aseptic meningitis.
Dermatological
Ketorolac should be discontinued at the first signs of a skin rash, mucosal lesions, or any other sign of hypersensitivity.
Anaphylactic (anaphylactoid) reactions
As with the use of other NSAIDs, anaphylactic (anaphylactoid) reactions (including anaphylaxis, bronchospasm, hyperemia, rash, arterial hypotension, laryngeal edema, Quincke's edema) may occur in patients who have had no or had a history of hypersensitivity to aspirin, other NSAIDs, or ketorolac. This complex of symptoms can also be observed in individuals who have a history of bronchospastic reactivity (eg, asthma) and nasal polyps. Anaphylactoid reactions such as anaphylaxis can be fatal. Therefore, ketorolac should not be taken in patients with a history of asthma, and in patients with complete or partial nasal polyp syndrome, Quincke's edema and bronchospasm. If anaphylactoid reactions occur, you should seek emergency medical attention.
Hematological effects
Patients with blood clotting disorders should not be prescribed Ketorolac. Patients receiving anticoagulant therapy may have an increased risk of bleeding if ketorolac is used concomitantly. The condition of patients who receive other drugs that may affect the rate of stopping bleeding should be carefully monitored when prescribing ketorolac. In controlled clinical trials, the incidence of significant postoperative bleeding was less than 1%. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding time duration of bleeding increased, but did not exceed the normalized mal range 2-11 minutes values. In contrast to the long-term effect resulting from the use of acetylsalicylic acid, platelet function returns to normal within 24–48 hours after ketorolac is discontinued. Ketorolac should not be prescribed to patients who have undergone surgery with a high risk of bleeding or incomplete stopping. Care should be taken if mandatory stopping of bleeding is critical. Ketorolac is not an anesthetic and does not have sedative or anxiolytic properties; therefore, it is not recommended as a preoperative premedication to maintain anesthesia.

Interaction with other medicinal products
The simultaneous use of ketorolac with acetylsalicylic acid or other NSAIDs, calcium preparations, GCS, ethanol, corticotropin can lead to the formation of gastrointestinal ulcers and the development of gastrointestinal bleeding.
Joint administration with paracetamol increases nephrotoxicity, with methotrexato m - hepato- and nephrotoxicity.
Co-administration of ketorolac and methotrexate only possible by using low doses of the latter (control concentration w methotrexate in blood plasma).
Against the background of the use of ketorolac, a decrease in the clearance of methotrexate and lithium and an increase in the toxicity of these substances is possible.
Simultaneous with the appointment indirect anticoagulants, heparin, thrombolytics, antiplatelet, cefoperazone, tsefotetanom and pentoksifilli nom increases the risk of bleeding.
Reduces the effect of antihypertensive and diuretic drugs (decreases the synthesis of prostaglandins in the kidneys).
With simultaneous use with opioid analgesics, the doses of the latter can be significantly reduced, because their effect is enhanced.
With simultaneous use, it enhances the hypoglycemic effect of insulin and oral hypoglycemic drugs (dose recalculation is required).
Co-administration with valproic acid causes disruption of platelet aggregation.
Increases plasma concentration of verapamil and nifedipine.
When administered with other nephrotoxic drugs (including with gold preparations), the risk of developing nephrotoxicity increases.
Probenecid and drugs that block tubular secretion reduce the clearance of ketorolac and increase its plasma concentration.
Myelotoxicity medicines contribute expressed Ia gematotoksichnosti drug.
A solution for injection should not be mixed in the same syringe with morphine sulfate, promethazine and hydroxyechinenone sizinom due to precipitation.
Pharmaceutically compatible with plaster m tramadol, lithium preparations.
Solution for injection is compatible with 0.9% sodium chloride solution, 5% dextrose (glucose) solution, Ringer's and Ringer's lactate solution, Plasmalit solution, as well as infusion solutions containing aminophylline, lidocaine hydrochloride, dopamine hydrochloride, short-acting human insulin and heparin sodium salt.

Special instructions
When used together with other NSAIDs, fluid retention, cardiac decompensation, arterial hypertension can be observed.
To reduce the risk of developing NSAID gastropathy, antacids, misoprostol, omeprazole are prescribed.
The effect on platelet aggregation persists for 24-48 hours.
Hypovolemia increases the risk of developing side effects from the kidneys.
If necessary, it can be prescribed in combination with opioid analgesics.
Do not use simultaneously with paracetamol for more than 5 days.
Patients with blood clotting disorders are prescribed the drug only with constant monitoring of the number of platelets, especially in the postoperative period, requiring careful control of hemostasis.
Influence on the ability to drive vehicles and mechanisms
Since a significant part of patients with the appointment of Ketorolac develop side effects from the central nervous system (drowsiness, dizziness, headache), it is recommended to avoid performing work that requires increased attention and quick reactions (driving vehicles, working with mechanisms).

Pregnancy and elbowing
It is not recommended to take the drug during pregnancy (adverse effect on the fetal cardiovascular system - premature closure of the ductus arteriosus), during childbirth, in the early postpartum period (by inhibiting the synthesis of prostaglandins, it can adversely affect the fetal blood circulation and weaken the contractile activity of the uterus, which increases the risk of uterine bleeding) and during lactation.
Penetrates into breast milk: after the mother takes 10 mg of ketorolac Cmax in milk is reached 2 hours after taking the first dose and is 7.3 ng / ml, 2 hours after the second dose of ketorolac (when using the drug 4 times a day) is 7.9 ng / l.
Oral doses of ketorolac tromethamine 1.5 mg / kg (0.14 MRDC) in rats, administered after 17 days of gestation, caused obstructed labor and increased mortality in pups.
Category action tions on the fetus by FDA - C.

Influence on the ability to drive vehicles and work with mechanisms
Does not affect.

Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ° C, out of the reach of children.

Shelf life
3 years. Do not use after the expiration date printed on the package.

Vacation conditions
On prescription.

Packaging
The solution is in 2 ml glass ampoules. Each ampoule is fixed in a plastic clip for 5 ampoules. 5 ampoules are packed in a cardboard box in a fixer together with an enclosed leaflet.