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

The mechanism of action is associated with a non-selective inhibition of the activity of the enzyme cyclooxygenases 1 and 2, mainly in peripheral tissues, resulting in inhibition of the biosynthesis of prostaglandins - 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. The drug does not affect opioid receptors, does not depress respiration, does not cause drug dependence, does not have sedative and anxiolytic effects.

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

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

Pharmacokinetics:

Absorption for intramuscular injection is complete and rapid. After intramuscular injection of 30 mg of the drug, the maximum concentration in the blood plasma (C_mOh) - 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; the maximum concentration after intravenous infusion is 15 mg - 1.96-2.98 μg / ml, 30 mg - 3.69-5.61 μg / ml. Time to reach equilibrium concentration (C_ss) with parenteral administration - 24 hours when administered 4 times a day (above the subtherapeutic dose) and is 15 mg to 0.65-1.13 μg / ml intramuscularly, 30 mg to 1.29 to 2.47 μg / ml , with intravenous infusion of 15 mg - 0.79-1.39 μg / ml, 30 mg - 1.68-2.76 μg / ml.

99.2% of the drug binds to blood plasma proteins and the amount of free substance in the blood increases with hypoalbuminemia.

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.

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, which is excreted 91% by the kidneys, 6% through the intestine.

The half-life (T1 / 2) in patients with normal renal function averaged 5.3 hours (3.5-9.2 hours after intramuscular injection of 30 mg and 4-7.9 hours after intravenous administration of 30 mg). Half-life is prolonged in elderly patients and is shortened in young patients. The function of the liver has no effect on the half-life. In patients with impaired renal function with a creatinine concentration in the blood plasma of 19-50 mg / l (168-442 μmol / L), the half-life is 10.3-10.8 hours, with more pronounced renal failure - more than 13.6 hours.

The total clearance is 30 mg to 0.023 l / kg / h (0.019 l / kg / h in elderly patients) with intramuscular injection, 30 mg to 0.03 l / kg / h intravenously; 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 during hemodialysis.

There is information about the effectiveness of the drug in migraine attacks.

Indications:

Pain syndrome of medium and strong intensity of various genesis (including pain in the postoperative period, with cancer). The drug 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 or any component of the drug; non-steroidal anti-inflammatory drugs, complete or incomplete combination of bronchial asthma, recurrent polyposis of the nasal mucosa and paranasal sinuses and intolerance to acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (including in the history), bronchospasm, angioedema;

- hypovolemia (regardless of the cause that caused it), dehydration;

- active gastrointestinal hemorrhage; exacerbation of inflammatory bowel diseases (ulcerative colitis, Crohn's disease), erosive and ulcerative lesions of the gastrointestinal tract in the acute stage, peptic ulcers;

- severe renal failure (creatinine clearance less than 30 ml / min) in patients not undergoing hemodialysis, progressive kidney disease, including confirmed hyperkalemia;

- severe hepatic impairment or active liver disease;

- severe uncontrolled heart failure; period after aortocoronary shunting;

- hemorrhagic stroke (confirmed or suspected); hemorrhagic diathesis; simultaneous administration with other non-steroidal anti-inflammatory drugs; high risk of developing or recurrence of bleeding (including after surgery), hemopoiesis disorder, hypocoagulation (including hemophilia);

- Pregnancy, childbirth and lactation;

- Children's age till 16 years.

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:

Bronchial asthma; cholecystitis, cholestasis, active hepatitis, a history of the gastrointestinal tract; infection Helicobacter pylori; chronic heart failure,cardiac ischemia; arterial hypertension; cerebrovascular diseases; diabetes; dyslipidemia / hyperlipidemia; renal failure (creatinine clearance 30-60 ml / min); sepsis; systemic lupus erythematosus; polyps of the nasal mucosa and nasopharynx; concomitant therapy with the following drugs: anticoagulants, oral glucocorticoids, antiaggregants, selective serotonin reuptake inhibitors; diseases of peripheral arteries; long-term use of non-steroidal anti-inflammatory drugs (NSAIDs); smoking; frequent use of alcohol; Thyroid gland diseases; tuberculosis; severe physical illness; Older age (over 65 years).

Pregnancy and lactation:

The use in pregnancy is contraindicated: adequate and strictly controlled studies in pregnant women are not conducted.

In childbirth and delivery, the use of the drug is contraindicated. inhibiting the synthesis of prostaglandins, it can adversely affect the blood circulation of the fetus and weaken the contractile activity of the uterus, which increases the risk of uterine bleeding.

At the time of treatment, breastfeeding should be discontinued, as the drug, by inhibiting the synthesis of prostaglandins, can cause adverse effects in newborns.

Dosing and Administration:

Intravenously, the drug should be administered at least 15 seconds (for dosage forms containing ethanol).

Intramuscularly injected slowly, deep into the muscle, in minimally effective doses, selected according to the intensity of pain and the patient's reaction. If necessary, it is also possible to additionally prescribe opioid analgesics in reduced doses.

Single doses for single intramuscular or intravenous administration:

- patients 16-64 years old with a body weight of more than 50 kg - 10-30 mg, depending on the severity of the pain syndrome;

- patients 16-64 years old with a body weight of less than 50 kg, patients older than 65 years or with impaired renal function - 10-15 mg.

Doses with multiple parenteral administration:

intramuscularly

- patients 16-64 years with a body weight of more than 50 kg are administered 10-30 mg per first injection, then 10-30 mg every 4-6 hours;

- with a body weight of less than 50 kg, patients older than 65 years or with impaired renal function - 10-15 mg every 4-6 hours.

intravenously

- patients 16-64 years old with a body weight of more than 50 kg are injected 10-30 mg, then 10-30 mg every 6 hours,with continuous infusion with an infusomator, the initial dose is 30 mg, and then the infusion rate is 5 mg / h;

- patients 16-64 years old with a body weight of less than 50 kg, patients older than 65 years or with impaired renal function injected 10-15 mg every 6 hours.

The maximum daily dose for patients 16-64 years with a body weight of more than 50 kg should not exceed 90 mg, and for patients 16-64 years with a body weight of less than 50 kg, over 65 years old or with impaired renal function - 60 mg, as with intramuscular , and the intravenous route of administration.

Continuous intravenous infusion should not last more than 24 hours.

For parenteral administration, the duration of treatment should not exceed 5 days.

When switching from parenteral administration of the drug to its intake, the total daily dose of both dosage forms on the day of transfer should not exceed 90 mg for patients aged 16-64 with a body weight of more than 50 kg and 60 mg for patients 16-64 years of age with a body weight less than 50 kg, over 65 years of age 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 - 1-10%, infrequently - 0.1-1%, rarely - 0.01% -0.1%, very rarely - less than 0.001%, including individual cases.

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 thick, "nausea, heartburn, etc.), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.

From the urinary system: rare - acute renal failure, back pain with or without hematuria and / or azotemia, hemolytic uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura) frequent urination, increase or decrease in urine volume, nephritis, edema of renal genesis.

From the sense organs: rarely - hearing loss, ringing in the ears, impaired vision (including blurred vision).

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

From the side of 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 - pulmonary edema, fainting.

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

From the side of the hemostasis system: rarely bleeding from a postoperative wound, epistaxis, rectal bleeding.

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

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

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

Other: often - swelling (face, legs, ankles, fingers, feet), weight gain, infrequent - excessive sweating, rarely - swelling of the tongue, fever.

Overdose:

Symptoms: abdominal pain, nausea, vomiting, the occurrence of peptic ulcers of the stomach or erosive gastritis, impaired renal function, metabolic acidosis.

Treatment: conducting symptomatic therapy (maintenance of vital functions in the body). It is not excreted sufficiently by dialysis.

Interaction:

The simultaneous use of ketorolac with acetylsalicylic acid or other non-steroidal anti-inflammatory drugs, calcium preparations, glucocorticoids, ethanol, corticotropin can lead to the formation of gastrointestinal ulcers and the development of gastrointestinal bleeding.

Co-administration with paracetamol increases nephrotoxicity, with methotrexate-hepato- and nephrotoxicity.

The joint administration of ketorolac and methotrexate is possible only with the use of low doses of the latter (it is necessary to monitor the concentration of methotrexate in the blood plasma).

Probenecid reduces plasma clearance and the volume of ketorolac distribution, increases its concentration in blood plasma and increases its half-life.

Against the background of the use of ketorolac, a decrease in the clearance of methotrexate and lithium is possible, and the toxicity of these substances is increased.

Simultaneous administration with indirect anticoagulants, heparin, thrombolytic agents, antiaggregants, cefoperazone, cefotetan and pentoxifylline increases the risk of bleeding.

Reduces the effect of antihypertensive and diuretic drugs (decreases the synthesis of prostaglandins in the kidneys).

When combined with opioid analgesics, the doses of the latter can be significantly reduced.

Antacids do not affect the full absorption of the drug.

The hypoglycemic effect of insulin and oral hypoglycemic drugs is increased (dose recalculation is necessary).

Co-administration with sodium valproate causes disruption of platelet aggregation.

Increases the concentration in the blood plasma of verapamil and nifedipine.

At appointment with other nefrotoksicnymi medical products (including with preparations of gold) the risk of development nefrotoksichnosti raises.

Drugs that block tubular secretion, reduce the clearance of ketorolac and increase its concentration in the blood plasma.

The solution for injections should not be mixed in the same syringe with morphine sulfate, promasin and hydroxyzine due to precipitation.

Pharmaceutically it is not compatible with a solution of tramadol, lithium preparations.

The solution for injection is compatible with physiological saline solution, 5% dextrose solution, Ringer's and Ringer's lactate solution, as well as with infusion solutions containing aminophylline, lidocaine hydrochloride, dopamine hydrochloride, human short-acting insulin and heparin sodium salt.

Special instructions:

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 5 days.

Patients with a violation of blood clotting drug is prescribed only with a constant control of the number of platelets,is especially important in the postoperative period and requires careful monitoring of hemostasis.

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

As a significant part of patients with the administration 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 response (driving vehicles, working with mechanisms, etc.).

Form release / dosage:

Solution for intravenous and intramuscular injection 30 mg / ml.

Packaging:

1 ml or 2 ml of ampoules from the light-protective glass.

5 ampoules of 1 ml or 2 ml each are placed in a contour mesh package made of a polyvinyl chloride film.

1, 2 contour squares are placed in a pack of cardboard.

10 ampoules of 1 ml or 2 ml are placed in a box of cardboard.

In each pack and box, put the instructions for use, a knife ampoule or scarifier. At packing of ampoules with a ring of a break, points and notches the knife ampullum or skarifikator do not put.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Freezing is not allowed.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002378

Date of registration:18.02.2014

The owner of the registration certificate:BIOSINTEZ, PAO BIOSINTEZ, PAO Russia

Manufacturer: & nbsp

BIOSINTEZ, PAO Russia

Representation: & nbspBIOSINTEZ JSC BIOSINTEZ JSC Russia

Information update date: & nbsp18.02.2014

Illustrated instructions

Instructions

Ketorolac (Ketorolac)