Ketorolak

General characteristics. Structure:

Active ingredient: 3 mg of a ketorolak in 1 ml of solution.

The drug rendering analgeziruyushchy, antiinflammatory, febrifugal and antiagregantny action.

Pharmacological properties:

Pharmacodynamics. Inhibits activity of cyclooxygenase (TsOG-1 and TsOG-2) and synthesis of PG oppresses. Has the expressed analgeziruyushchy activity associated with a S-form. The maximum analgeziruyushchy effect develops during 2–3 h. Inhibits aggregation of thrombocytes, the effect is reversible. Unlike anti-aggregation effect of acetylsalicylic acid (remains during thrombocyte life time), influence of a ketorolak of a trometamin on aggregation of thrombocytes stops in 24–48 h Ketorolak трометамин does not possess sedative or anxiolytic action.

Pharmacokinetics. Comparison of pharmacokinetics of a ketorolak of a trometamin later in/in, in oil and oral administration showed that bioavailability at adults makes 100% regardless of a way of introduction. After introduction in oil it is quickly and completely absorbed. Cmax  is reached in 50 min. after a single injection of 30 mg in oil and makes 2,2–3,0 mkg/ml. At in/in infusion of 10 mg the largest content in plasma (2,4 mkg/ml) is defined in 5,4 min. Time of achievement of equilibrium concentration at parenteral and peroral administration — 24 h at use each 6 h. At intake it is quickly and completely absorbed. Cmax  is reached, on average, in 40 min. and makes 0,7–1,1 mkg/ml after a dose of 10 mg. Food rich with fats reduces C
max also detains it achievement na1 h. Antacids do not influence absorption size. Linkng with proteins of a blood plasma — 99,2%. Extent of binding does not depend on concentration in a vascular bed. It is metabolized in a liver with formation of the conjugated and hydroxylated forms. The main metabolite — гидроксикеторолак — pharmacological is inactive. It Eliminirutsya preferential by kidneys. At patients with a renal failure excretion is slowed down. Its speed decreases in proportion to degree of a renal failure, except for patients with a heavy renal failure (the plasma clearance is slightly higher than the damage of kidneys expected for this degree). In urine 92% of the entered dose, in excrements — 6% are found. At repeated introduction the clearance of a ketorolak does not change.

There are messages on efficiency of a ketorolak of a trometamin at migraine attacks. Shows antiinflammatory properties when using in ophthalmology in the form of eye drops.

Carcinogenicity, mutagenicity, influence on fertility. In a 18-month research at mice at use inside in doses to 2 mg/kg/days (0,9 AUC persons) and in a 24-month research at rats at doses to 5 mg/kg/days (0,5 AUC persons) of cancerogenic effect it is not revealed.

The mutagenicity of a ketorolak of a trometamin in a number of bacterial in vitro tests in concentration of 1590 mkg/ml and is not revealed above, a ketorolaka трометамин caused increase in frequency of aberation chromosomes on cells of ovaries of the Chinese hamster.

In reproduction researches in two generation at the level of doses to 0,5 mg/kg/days did not exert impact on fertility at mice and at rats.

Indications to use:

Pain syndrome of moderate and strong expressiveness, including in the postoperative period (after band, gynecologic, orthopedic, urological and other operations), a pain syndrome at injuries (dislocation, a fracture, gaps and sprains), a pain syndrome at an osteoarthrosis, osteochondrosis, neuralgia, pain at oncological diseases, a dentagra, pain after dental interventions, at a pericoronitis, a pulpitis, a dorsodynia and muscles.

Route of administration and doses:

Inside, in oil, in / century. At children only in the form of injections. The dose is selected individually, taking into account expressiveness of a pain syndrome. The single dose makes 10–30 mg, frequency rate of introduction — to 4 times a day (each 6–8 h). The maximum daily dose for elderly patients — 60 mg. Solution appoint in oil or in/in for treatment of acute and severe pains within no more than 5 days, at children — 2 days.

Tablets apply no more than 5-7 days.

Features of use:

Use at pregnancy and feeding by a breast. Teratogenic effects. In the researches of a reproduction executed in the period of an organogenesis with use of daily peroral doses of a ketorolak of a trometamin of 3,6 mg/kg (0,37 MRDCh) at rabbits and 10 mg/kg (1,0 MRDCh) at rats teratogenic action on a fruit was not revealed. However reproductive researches at animals not always predict effects at the person.

Adequate and strictly controlled researches at pregnant women are not conducted. Use at pregnancy is possible if the expected effect of therapy exceeds potential risk for a fruit.

Not teratogenic effects. As adverse influence of NPVS on cardiovascular system of a fruit (premature closing of an arterial channel) is known, it is necessary to avoid use at pregnancy (especially on late terms). The peroral doses of a ketorolak of a trometamin of 1,5 mg/kg (0,14 MRDCh) at rats applied after 17 in the afternoon pregnancies caused the complicated childbirth and the increased mortality of cubs.

Childbirth and delivery. Use of a ketorolak of a trometamin is contraindicated since, inhibiting synthesis of prostaglandins, it can negatively influence blood circulation of a fruit and weaken sokratitelny activity of a uterus that increases risk of uterine bleedings.

Category of action on a fruit on FDA — Page. After single oral administration of 10 mg of a ketorolak of a trometamin the maximum concentration defined in breast milk at the person makes 7,3 ng/ml, the maximum ratio milk/plasma — 0,037; after one day of reception (4 times a day) similar indicators make 7,9 ng/ml, after 0,025. As the HP inhibiting synthesis of PG can cause adverse effects in newborns, for the period of treatment it is necessary to stop breastfeeding.

At the patients receiving NPVS, including a ketorolak трометамин such heavy complications of treatment as a GIT ulceration, bleeding and perforation, postoperative bleeding, an acute renal failure, anaphylactic and anaphylactoid reactions, a liver failure are possible.

The risk of development of complications of medicinal therapy increases during the lengthening of treatment and increase in a peroral dose of drug more than 40 mg/days. The patient with disturbance of a blood coagulation appoint only at constant control of number of thrombocytes, especially it is important for the postoperative patients demanding a careful hemostasis. The hypovolemia increases risk of development of side reactions from kidneys. Not to apply more than 5 days along with paracetamol. It is not recommended to use drug for a labor pain relief (due to the lack of adequate researches and possible influence of NPVS on sokratitelny ability of a uterus).

Possible emergence during treatment of drowsiness, dizziness, sleeplessness or a depression causes need of respect for care during the occupations potentially dangerous types of activity requiring special attention and speed of psychomotor reactions (driving of vehicles).

Side effects:

Frequency of side effects increases with increase in a dose. When carrying out clinical tests the following side effects, perhaps connected using a ketorolak of a trometamin were noted:

From bodies of a GIT: gastralgia (13%), nausea (12%), dyspepsia (12%), diarrhea (7%);> 1% — a lock, a meteorism, feeling of overflow of a stomach, vomiting, stomatitis; ≤1% — gastritis, an eructation, anorexia, increase in appetite, dryness in a mouth.

From a nervous system and sense bodys: headache (17%), dizziness (7%), drowsiness (6%); ≤1% — an adynamy, a tremor, unusual dreams, an insomniya, hallucinations, euphoria, extrapyramidal symptoms, вертиго, paresthesia, a depression, nervousness, disturbances of thinking, inability to concentration of attention, hyperkinesias, a stupor, excessive thirst, taste disturbances, a vision disorder (including an illegibility of visual perception), decrease in hearing, a ring in ears.

From cardiovascular system and blood (a hemopoiesis, a hemostasis):> 1% — increase in the ABP; ≤1% — heartbeat, pallor, a faint, anemia, an eosinophilia.

From respiratory system: ≤1% — диспноэ, rhinitis, a fluid lungs, cough.

From urinogenital system: ≤1% — a hamaturia, a proteinuria, an oliguria, an ischuria, a frequent urination.

From integuments:> 1% — an itch, rash.

Allergic reactions:

Others: hypostases (4%),> 1% — a purpura, the increased perspiration; ≤1% — nasal bleeding, rectal bleeding, increase in body weight, fever, an infection.

Local reactions: pain in an injection site (2% — at repeated introduction).

In post-market researches the following side effects were noted:

From bodies of a GIT: GIT erosive cankers (including with perforation and/or bleeding — abdominal pain, a spasm or burning in epigastric area, a melena, vomiting as "a coffee thick", nausea, heartburn, etc.), cholestatic jaundice, an abnormal liver function, hepatitis, a hepatomegalia, acute pancreatitis.

From a nervous system and sense bodys: spasms, psychosis, aseptic meningitis (fever, severe headache, spasms, muscle tension of a neck and/or back).

From cardiovascular system and blood (a hemopoiesis, a hemostasis): hypotension, rushes of blood to the person, thrombocytopenia, a leukopenia.

From respiratory system: ≤1% — asthma, a bronchospasm.

From urinogenital system: an acute renal failure, a back pain with or without hamaturia and/or azotemias, a hemolitic uraemic syndrome (hemolitic anemia, a renal failure, thrombocytopenia), a hyponatremia, a hyperpotassemia, nephrite, hypostases of renal genesis.

From integuments: Lyell's disease, Stephens-Johnson's syndrome, exfoliative dermatitis, makulopapullezny rash, small tortoiseshell.

Allergic reactions: anaphylaxis or anaphylactoid reactions, throat hypostasis, paraglossa, angioedem.

Others: bleeding from a postoperative wound, a mialgiya.

Interaction with other medicines:

Simultaneous use with acetylsalicylic acid or other NPVS, glucocorticoids, ethanol, corticotropin can lead to formation of ulcers of a GIT and development of gastrointestinal bleedings. Joint appointment with paracetamol increases nephrotoxicity, with a methotrexate — gepato-and nephrotoxicity. Co-administration of a ketorolak of a trometamin and methotrexate is possible only when using low doses of the last (it is necessary to control concentration of a methotrexate in a blood plasma).

Against the background of use of a ketorolak of a trometamin reduction of clearance of a methotrexate and lithium and strengthening of toxicity of these substances is possible. Probenetsid reduces plasma clearance and volume of distribution of a ketorolak of a trometamin, increases its concentration in a blood plasma and increases T1/2. Reduces diuretic effect of furosemide at people with a normovolemia. Co-administration with indirect anticoagulants, heparin, trombolitika, antiagregant, tsefoperazony, tsefotetany and pentoksifilliny increases risk of bleeding. Reduces effect of hypotensive and diuretic drugs (synthesis of PG in kidneys goes down). At simultaneous use with APF inhibitors the probability of a renal failure increases. At a combination with opioid analgetics of a dose of the last can be significantly reduced.

Antiacid means do not influence completeness of absorption of a ketorolak of a trometamin. Increases hypoglycemic effect of insulin and peroral hypoglycemic drugs (recalculation of a dose is necessary). Joint appointment with Valproatum of sodium causes disturbance of aggregation of thrombocytes. Increases concentration in a blood plasma of verapamil and nifedipine. At appointment with other nefrotoksichny HP (including with gold drugs) the risk of development of nephrotoxicity increases. The HP blocking canalicular secretion reduce clearance of a ketorolak and increase its concentration in a blood plasma.

Solution for injections should not be mixed in one syringe from morphine sulfate, promethazine and Hydroxyzinum because of loss of a deposit. Pharmaceutical it is incompatible with solution of a tramadol, lithium drugs. Solution for injections is compatible to a number of solutions, including to normal saline solution, 5% dextrose solution, Ringer's solution, and also to the infusion solutions containing Aminophyllinum, lidocaine a hydrochloride, a dopamine a hydrochloride, insulin of the person of short action and heparin sodium salt.

In post-market researches it was reported about the possible interaction of a ketorolak of a trometamin (in/in, in oil) with not depolarizing muscular relaxants leading to an apnoea (special researches of this interaction were not conducted).

Contraindications:

Hypersensitivity (including to other NPVS), "aspirinovy" asthma (a combination of bronchial asthma, the nose recuring a polypose and okolonosovy bosoms, and also intolerance of acetylsalicylic acid and HP of a pyrazolon row), a bronchospasm, a Quincke's disease, GIT erosive cankers in aggravation stages, round ulcers, a hypovolemia, dehydration, hypocoagulation (including hemophilia), high risk of development of bleeding or its recurrence (including after operations), the hemopoiesis disturbance, the hemorrhagic stroke (confirmed or suspected), hemorrhagic diathesis, a renal and/or liver failure (creatinine of plasma is higher than 50 mg/l), a concomitant use with other NPVS, childbirth and delivery, age up to 16 years. Do not apply to anesthesia before and during surgeries because of high risk of bleeding, and also to treatment of chronic pains.

Restrictions to use. Bronchial asthma, cholecystitis, a cholestasia, active hepatitis, chronic heart failure, arterial hypertension, a renal failure (creatinine of plasma is lower than 50 mg/l), sepsis, a system lupus erythematosus, polyps of a mucous membrane of a nose and nasopharynx, advanced age (65 years are more senior).

Overdose:

Symptoms: slackness, drowsiness, nausea, vomiting, abdominal pain, emergence of round ulcers of a stomach and/or erosive gastritis, renal failure, metabolic acidosis.

Treatment: symptomatic therapy, maintenance of the vital functions of an organism. The specific antidote is not found. It is not removed sufficiently by means of dialysis.

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 3%, on 3 ml in each ampoule. On 5 or on 10 ampoules in cardboard packaging.