Ketorolac - instructions for use, dose, side effects, contraindications

Excipients: propylene glycol 200.0 mg, disodium edetate dihydrate (Trilon B) 1 mg, ethanol 95%, based on anhydrous substance 100.0 mg, sodium chloride 4.35 mg, 1 M sodium hydroxide solution to pH 6, 9 to 7.9, water for injection to 1 ml.

Description:Transparent solution from colorless to light yellow color.

Pharmacotherapeutic group:Non-steroidal anti-inflammatory drug (NSAID)

ATX: & nbsp

M.01.A.B.15 Ketorolac

Pharmacodynamics:

Ketorolac has a pronounced analgesic effect, it also has an anti-inflammatory and moderate antipyretic effect.

The mechanism of action is associated with a non-selective inhibition of the activity of the enzyme cyclooxygenase 1 and 2, mainly in peripheral tissues, resulting in the inhibition of biosynthesis of prostaglandin modulators of pain sensitivity, thermoregulation and inflammation. Ketorolac is a racemic mixture [-]S and [+]R enantiomers, while the analgesic effect is due to [-]S form.

By the strength of the analgesic effect comparable to morphine, it is much superior to other non-steroidal anti-inflammatory drugs.

The drug does not affect opioid receptors, does not depress respiration, does not cause drug dependence, does not have sedative and anxiolytic effects.

After intramuscular injection, the beginning of analgesic effect is observed after 0.5 h, the maximum effect is achieved in 1-2 hours.

Pharmacokinetics:

Suction. Bioavailability - 80-100%, absorption at intramuscular injection - complete and fast. After intramuscular injection, 30 mg the maximum concentration in the blood plasma (C_mOh) is 1.74-3.1 μg / ml, 60 mg - 3.23-5.77 μg / ml, the time to reach the maximum concentration, respectively - 15-73 min and 30-60 min; FROM_mOh after intravenous infusion 15 mg - 1.96-2.98 mcg / ml, 30 mg - 3.69-5.61 mcg / ml. Time to reach equilibrium concentrations (C_ss) with parenteral administration - 24 hours when administered 4 times a day (above the sub-therapeutic) and is 15 mg-0.65-1.13 μg / ml for intramuscular injection, 30 mg-1.29-2.47 μg / ml.

Distribution. 99% of the drug binds to blood plasma proteins and the hypoalbuminemia increases the amount of free substance in the blood.

The volume of distribution is 0.15-0.33 l / kg. In patients with renal insufficiency, the volume of distribution of the drug can be increased 2-fold, and the volume of its distribution R-enantiomer by 20%.

Poorly passes through the blood-brain barrier, penetrates the placenta (10%). In small quantities found in breast milk.

Metabolism. 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-hydroxycetorolac.

Excretion. Listed on 91% kidneys (40% in the form of metabolites), 6% - through the intestines.

The half-life (T_1/2) in patients with normal renal function averages 5.3 hours (3.5-9.2 hours after intramuscular injection of 30 mg, 4-7.9 hours after intravenous administration of 30 mg). T_1/2lengthens in elderly patients and is shortened in young patients. The function of the liver does not affect T_1/2. In patients with impaired renal function with a creatinine concentration in the blood plasma of 19-50 mg / l (168-442 μmol / l) T_1/2is 10.3-10.8 hours, with more pronounced renal failure - more than 13.6 hours.

The total clearance is at intramuscular injection of 30 mg - 0.023 l / kg / h (0.019 l / kg / h in elderly patients); in patients with renal insufficiency with a creatinine concentration in the blood plasma of 19-50 mg / l with intramuscular injection of 30 mg-0.015 l / kg / h.

It is not excreted by hemodialysis.

Indications:

Pain syndrome of strong and moderate severity: trauma, toothache, pain in the postoperative period, oncological diseases, myalgia, arthralgia, neuralgia, sciatica, dislocations, sprains, rheumatic diseases.

It is intended for symptomatic therapy, reducing pain and inflammation at the time of use, the progression of the disease is not affected.

Contraindications:

Hypersensitivity to ketorolac, as well as to other non-steroidal anti-inflammatory drugs, complete or incomplete combination of bronchial asthma, recurrent nasal polyposis and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including in anamnesis); erosive and ulcerative lesions of the gastrointestinal tract and duodenum, active gastrointestinal bleeding; cerebrovascular or other bleeding, intracranial hemorrhage or suspicion of it; inflammatory bowel disease (ulcerative colitis, Crohn's disease) in the stage of exacerbation; hemophilia and other disorders of blood clotting; decompensated heart failure,period after aortocoronary shunting; severe hepatic impairment or active liver disease; severe renal failure (creatinine clearance less than 30 ml / min), progressive kidney disease, confirmed hyperkalemia; concurrent use with probenecid. pentoxifylline, acetylsalicylic acid and other NSAIDs (including cyclooxygenase-2 inhibitors), lithium salts, anticoagulants, including warfarin and heparin, children's age (up to 16 years); pregnancy, the period of breastfeeding.

The drug is not used for anesthesia before and during surgery due to high risk of bleeding, as well as for the treatment of chronic pain.

Carefully:

Stomach and duodenal ulcer, inflammatory bowel disease (ulcerative colitis, Crohn's disease) without exacerbation, liver disease in history, hepatic porphyria, chronic renal failure (creatinine clearance 30-60 ml / min), chronic heart failure, arterial hypertension, significant decrease in the volume of circulating blood (including after surgery), elderly patients (incl.receiving diuretics, debilitated patients with low body weight), bronchial asthma, simultaneous glucocorticosteroids (including prednisone), anticoagulants (including warfarin), antiplatelet agents (including acetylsalicylic acid, clopidogrel), selective serotonin reuptake inhibitors ( including citalopram, fluoxetine, paroxetine, sertraline), ischemic heart disease, cerebrovascular disease, systemic connective tissue diseases, dyslipidemia / hyperlipidemia, diabetes mellitus, Zabolev Ia peripheral arterial disease, smoking, presence of infection Helicobacter pylori, Long-term use of NSAIDs, tuberculosis, marked osteoporosis, alcoholism, severe somatic diseases.

Pregnancy and lactation:

The drug is contraindicated in pregnancy.

If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped.

Dosing and Administration:

Enter deep into the muscle, slowly for at least 15 seconds in minimally effective doses by a minimally short course. If necessary, it is also possible to additionally prescribe opioid analgesics in reduced doses.

Single doses for single intramuscular injection:

- for adults up to 65 years - 10-30 mg (0.3-1 ml), depending on the severity of the pain syndrome,

- adults over 65 years of age or with impaired renal function - for 10-15 mg (0.3-0.5 ml) every 4-6 hours.

- children over 16 years - 10-30 mg (0.3-1 ml), depending on the severity of the pain syndrome,

Doses with multiple intramuscular injection:

- for adults up to 65 years 10-60 mg (0.3-2 ml) are injected into the first administration, then 10-30 mg (0.3-1 ml) every 6 hours (usually 30 mg every 6 hours),

- adults over 65 years of age or with impaired renal function - 10-15 mg (0.3-0.5 ml) every 4-6 hours;

- children over 16 years 10-60 mg (0.3-2 ml) are injected into the first administration, then 10-30 mg (0.3-1 ml) every 6 hours (usually 30 mg every 6 hours),

The maximum daily dose for patients under 65 years of age should not exceed 90 mg, and for patients older than 65 years or with impaired renal function - 60 mg with an intramuscular route of administration.

The maximum duration of treatment should not exceed 2 days.

Side effects:

According to the World Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (1/10), often (from 1/100 to ≤1 / 10), infrequently (from 1/1000 to ≤1 / 100), rarely (from 1/10000 to ≤1 / 1000), very rarely (≤1 / 10000),the frequency is unknown (the frequency of occurrence of phenomena can not be determined on the basis of available data).

In connection with the use of ketorolac, the following side effects were noted:

From the digestive system: often (especially in elderly patients, over 65 years of age, having a history of erosive and ulcerative lesions of the gastrointestinal tract) - gastralgia, diarrhea; infrequently - stomatitis, flatulence, constipation, vomiting, sensation of stomach overflow; rarely - nausea, erosive and ulcerative lesions of the gastrointestinal tract (including with perforation and / or bleeding - abdominal pain, spasm or burning in the epigastric region, blood in the feces or melena, vomiting with blood or the type of "coffee grounds ", nausea, heartburn, etc.), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.

From the urinary system: rarely acute renal failure, back pain with or without hematuria and / or azotemia, haemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), frequent urination, oliguria, polyuria, interstitial nephritis, edema of renal genesis, delay urination, hyperkalemia, hyponatremia, an increase in the concentration of urea and creatinine in the blood plasma.

From the sense organs: rarely - hearing loss, ringing in the ears, visual impairment (including blurred vision), a taste disorder.

From the respiratory system: rarely - bronchospasm or dyspnoea, rhinitis, pulmonary edema, laryngeal edema (shortness of breath, difficulty breathing).

From the central nervous system: often - headache, dizziness, drowsiness; rarely - aseptic meningitis (fever, severe headache, convulsions, neck and / or neck stiffness), hyperactivity (mood changes, anxiety), hallucinations, depression, psychosis.

From the side of the cardiovascular system: infrequently - increased blood pressure; rarely - faint; decrease in blood pressure, palpitations, heart failure, myocardial infarction, stroke.

On the part of the organs of hematopoiesis: rarely - anemia, eosinophilia, leukopenia thrombocytopenia.

From the side of the hemostasis system: rarely bleeding from a postoperative wound, epistaxis, rectal bleeding, exacerbation of ulcerative colitis or Crohn's disease.

From the skin: infrequently - skin rash (including maculopapular rash),purpura; rarely - exfoliative dermatitis (fever with chills or without, redness, densification or flaking of the skin, swelling and / or tenderness of the tonsils), hives, Stevens-Johnson syndrome, Lyell's syndrome.

Local Reactions: infrequent - burning or pain at the injection site.

Allergic reactions: rarely anaphylaxis or anaphylactoid reactions (discoloration of the face, itching of the skin, tachypnea or dyspnea, edema of the eyelids, periorbital edema, shortness of breath, shortness of breath, heaviness in the chest, wheezing).

Other: often - swelling (face, shins, ankles, fingers, feet, weight gain); infrequently - increased sweating; rarely swelling of the tongue, fever.

Overdose:

Symptoms (with a single injection): abdominal pain, nausea, vomiting, erosive ulcerative lesions of the gastrointestinal tract, impaired renal function, metabolic acidosis.

Treatment: symptomatic (maintenance of vital body functions). Hemodialysis is ineffective.

Interaction:

When combined with opioid analgesics the doses of the latter can be significantly reduced, since their action is enhanced.

The drug solution should not be mixed in a single syringe with morphine sulfate, promethazine and hydroxysine because of precipitation.

Pharmaceutically incompatible with a solution of tramadol, lithium preparations.

The drug solution is compatible with 0,9% solution of sodium chloride, 5% solution of dextrose, Ringer's solution.

Glucocorticosteroids: increased risk of ulceration and gastrointestinal bleeding.

Anticoagulants: NSAIDs can enhance the effects of anticoagulants, such as warfarin.

Antiaggregants and selective serotonin reuptake inhibitors: increased risk of bleeding.

Interactions related to all NSAIDs:

Combinations that must be avoided

- Other NSAIDs, including high doses of salicylates (> 3 g / day): concomitant administration of several NSAIDs may increase the risk of ulceration and gastrointestinal bleeding, which is due to a synergistic effect.

- Oral anticoagulants, parenteral heparin and ticlopidine: increased risk of bleeding caused by inhibition of platelet function and damage to the stomach and intestinal mucosa.

- Lithium: NSAIDs increase the level of lithium in the plasma (decreases the excretion of lithium in the kidneys), which can reach a toxic level.This parameter should be monitored at the beginning of treatment, with dose adjustment and after cessation of treatment with ketoprofen.

- Methotrexate in high doses (more than 15 mg per week): the hematotoxicity of methotrexate is increased, as its excretion in the urine, which occurs when taking anti-inflammatory drugs, is reduced.

- Hydantoin and sulfonamides: the toxic effects of these substances can increase.

Combinations that require precautions

- Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the effectiveness of diuretics and other antihypertensive drugs. In patients with impaired renal function (eg, patients with dehydration or elderly patients with impaired renal function) concomitant use of ACE inhibitors or angiotensin II antagonists with preparations inhibiting the cyclooxygenase system can cause additional renal dysfunction, including acute kidney failure, usually reversible. The combination of the drug with ACE inhibitors and angiotensin II antagonists should be used with caution, especially in elderly patients.

Patients should be sufficiently hydrated, and after the initiation of concomitant therapy, renal function monitoring should be performed.

- Methotrexate in low doses (less than 15 mg per week): the hematotoxicity of methotrexate is increased, as its excretion in the urine, which occurs when taking anti-inflammatory drugs, is reduced. It is necessary to conduct a general blood test once a week during the first few weeks of joint application. The frequency of monitoring should be increased in the presence of even a slight deterioration in the function of the kidneys, as well as in elderly patients.

- Pentoxifylline: increased risk of bleeding. Increased clinical monitoring and control of clotting time.

- Zidovudine: increased risk of toxicity in relation to red blood cells by affecting reticulocytes with severe anemia a week after initiation of NSAID treatment. It is necessary to carry out a general blood test and monitor the amount of reticulocytes once or twice a week after the initiation of NSAID treatment.

- Increased hypoglycemic effect insulin and oral hypoglycemic drugs (dose recalculation is necessary).

Combinations that need to be taken into account:

- Beta-blockers: treatment of NSAIDs may reduce their hypotensive effect due to inhibition of prostaglandin synthesis.

- Mifepristone. After using mifepristone for 8-12 consecutive days, NSAIDs should not be used because they can weaken the effects of mifepristone.

- Cyclosporine and tacrolimus: NSAIDs may increase nephrotoxicity due to effects associated with kidney prostaglandins. When combined, it is necessary to monitor kidney function.

- Thrombolytics: increased risk of bleeding.

- Probenecid: the concentration of ketoprofen in the plasma may increase; this increase may be due to an inhibitory mechanism in the site of renal tubular secretion and glucuronoconjugation and requires a dose adjustment of ketoprofen.

- Selective serotonin reuptake inhibitors when used with ketorolac increases the risk of bleeding due to inhibition of platelet function. In the case of simultaneous use, careful monitoring of the blood coagulation system is necessary.

- Antacids affect the completeness of absorption of the drug

Special instructions:

When combined with other non-steroidal anti-inflammatory drugs, fluid retention, cardiac decompensation, and hypertension can occur.

The effect on platelet aggregation stops after 24-48 hours.

Hypovolemia increases the risk of adverse reactions from the kidneys.

If necessary, you can prescribe in combination with narcotic analgesics.

Ketorolac is not recommended for use as a means for premedication, supporting anesthesia and anesthesia in obstetric practice.

Do not use simultaneously with paracetamol for more than 2 days.

Patients with blood clotting disorder are prescribed a drug only with a constant control of the number of platelets, especially in the post-operation period, which require close monitoring of the hemostasis.

Patients with an increased risk of developing gastrointestinal complications are advised to take ketorolac preparations together and gastroprotectors together.

Effect on the ability to drive transp. cf. and fur:

The drug has a limited and moderate effect on the ability to drive vehicles or mechanisms due to the possible occurrence of dizziness and drowsiness.If after the application of ketorolac the patient is drowsy, dizzy or convulsed, the management of vehicles and mechanisms should be avoided, and other activities requiring concentration of attention should be avoided.

Form release / dosage:

Solution for intramuscular injection, 30 mg / ml.

Packaging:

By 1 ml in polymeric ampoules from low-density polyethylene of high pressure, manufactured using the "blow-fill-seal"" blow-fill-seal ".

For 5 or 10 ampoules, together with instructions for medical use, in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003693

Date of registration:21.06.2016

Expiration Date:21.06.2021

The owner of the registration certificate:TRIVIUM-XXI, LLC TRIVIUM-XXI, LLC Russia

Manufacturer: & nbsp

SLAVYANSKAYA APTEKA, LLC Russia

Information update date: & nbsp07.01.2018

Illustrated instructions

Instructions

Ketorolac (Ketorolac)