Ketofreel (Tablets, Solution) Instructions for Use

ATC Code

M01AB15 (Ketorolac)

Active Substance

Ketorolac (Rec.INN registered by WHO)

Clinical-Pharmacological Group

NSAIDs with pronounced analgesic action

Pharmacotherapeutic Group

NSAID

Pharmacological Action

NSAID, has a pronounced analgesic effect, also has anti-inflammatory and moderate antipyretic effects.

The mechanism of action is associated with non-selective inhibition of the activity of COX-1 and COX-2 enzymes, mainly in peripheral tissues, resulting in inhibition of the biosynthesis of prostaglandins – modulators of pain sensitivity, inflammation and thermoregulation. Ketorolac is a racemic mixture of R(+) and S(-)-enantiomers, with the analgesic effect due to the S(-)-enantiomer.

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

In terms of the strength of the analgesic effect, it is comparable to morphine and significantly exceeds other NSAIDs.

After intramuscular administration, the onset of analgesic action is noted after 0.5 hours, the maximum effect is achieved after 1-2 hours.

Pharmacokinetics

With intramuscular administration, absorption is complete and rapid. After intramuscular administration of the drug at a dose of 30 mg, C_max in blood plasma is 1.74-3.1 µg/ml, at a dose of 60 mg – 3.23-5.77 µg/ml. T_max is 15-73 min and 30-60 min, respectively.

After intravenous infusion of the drug at a dose of 15 mg, C_max is 1.96-2.98 µg/ml, at a dose of 30 mg – 3.69-5.61 µg/ml.

Binding to plasma proteins is 99%. In hypoalbuminemia, the amount of free substance in the blood increases.

V_d is 0.15-0.33 l/kg.

C_ss with parenteral administration is achieved after 24 hours when used 4 times/day (above subtherapeutic) and with intramuscular administration at a dose of 15 mg is 0.65-1.13 µg/ml, with intramuscular administration at a dose of 30 mg – 1.29-2.47 µg/ml; with intravenous infusion at a dose of 15 mg – 0.79-1.39 µg/ml, with intravenous infusion at a dose of 30 mg – 1.68-2.76 µg/ml.

It poorly passes through the blood-brain barrier, penetrates the placental barrier (10%).

With parenteral administration, it is excreted in breast milk in small amounts.

More than 50% of the administered dose is metabolized in the liver to form pharmacologically inactive metabolites. The main metabolites are glucuronides and p-hydroxyketorolac.

Excreted in urine – 91% (40% as metabolites), in feces – 6%. It is not excreted by hemodialysis.

After intramuscular administration of 30 mg, T_1/2 is 3.5-9.2 hours, after intravenous administration of 30 mg, T_1/2 is 4-7.9 hours.

Total clearance with intramuscular administration of 30 mg is 0.023 l/kg/h, with intravenous infusion of 30 mg – 0.03 l/kg/h.

In patients with renal failure, the V_d of ketorolac may double, and the V_d of its R-enantiomer may increase by 20%. With a plasma creatinine concentration of 19-50 mg/l with intramuscular administration of 30 mg of the drug, the total clearance is 0.015 l/kg/h.

In patients with impaired renal function with a plasma creatinine concentration of 19-50 mg/l (168-442 µmol/l), T_1/2 is 10.3-10.8 hours, with more severe renal failure – more than 13.6 hours.

Liver function does not affect T_1/2.

In elderly patients, the total clearance with intramuscular administration at a dose of 30 mg is 0.019 l/kg/h. T_1/2 is prolonged in elderly patients and shortened in young patients.

Indications

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

Intended for symptomatic therapy, reducing pain and inflammation at the time of use, does not affect the progression of the disease.

ICD codes

Dosage Regimen

Solution

It is set individually, depending on the patient’s age and the severity of the pain syndrome. With intramuscular or intravenous administration, a single dose can vary from 10 mg to 60 mg.

The maximum daily dose for intramuscular and intravenous administration for adults under 65 years of age 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 intravenous 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 to oral administration, the total daily dose of ketorolac in both dosage forms on the day of transition should not exceed: 90 mg for adults under 65 years of age and children over 16 years of age and 60 mg – for elderly patients (over 65 years of age) or with impaired renal function. In this case, the dose of ketorolac for oral administration on the day of transition should not exceed 30 mg.

Tablets

It is set individually, depending on the severity of the pain syndrome. Ketorolac should be taken orally once or repeatedly. A single dose is 10 mg, with repeated administration it is recommended to take 10 mg up to 4 times/day, depending on the severity of the pain. The maximum daily dose should not exceed 40 mg. When taken orally, the duration of the course should not exceed 5 days.

When switching from parenteral administration to oral administration, the total daily dose of ketorolac in both dosage forms on the day of transition should not exceed: 90 mg for adults under 65 years of age and children over 16 years of age and 60 mg – for elderly patients over 65 years of age or with impaired renal function. In this case, the dose of ketorolac for oral administration on the day of transition should not exceed 30 mg.

Adverse Reactions

From 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, feeling of stomach fullness; rarely – decreased appetite, nausea, erosive and ulcerative lesions of the gastrointestinal tract (including with perforation and/or bleeding – abdominal pain, spasm or burning in the epigastric region, melena, vomiting blood or like “coffee grounds”, nausea, heartburn), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.

From the urinary system: rarely – acute renal failure, lower back pain, hematuria, azotemia, hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), frequent urination, increase or decrease in urine volume, nephritis, edema of renal origin.

From the nervous system: often – headache, dizziness, drowsiness; rarely – aseptic meningitis (including fever, severe headache, convulsions, rigidity of the neck and/or back muscles), hyperactivity (including mood changes, anxiety), hallucinations, depression, psychosis.

From 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, visual impairment (including blurred vision).

From the hematopoietic system: rarely – anemia, eosinophilia, leukopenia.

From the blood coagulation system rarely – bleeding from the postoperative wound, nosebleed, rectal bleeding.

From the skin and subcutaneous tissues less often – skin rash (including maculopapular), purpura; rarely – exfoliative dermatitis (including fever with/without chills, redness, induration or peeling of the skin, swelling and/or soreness of the tonsils), urticaria, Stevens-Johnson syndrome, Lyell’s syndrome.

Allergic reactions rarely – anaphylaxis or anaphylactoid reactions (including facial skin discoloration, skin rash, urticaria, skin itching, tachypnea or dyspnea, eyelid swelling, periorbital edema, shortness of breath, difficulty breathing, chest tightness, wheezing).

Local reactions less often – burning or pain at the injection site.

Other: often – edema (including face, legs, ankles, fingers, feet), weight gain; less often – increased sweating; rarely – tongue swelling, fever.

Contraindications

Hypersensitivity to ketorolac and other NSAIDs; complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose and paranasal sinuses and intolerance to acetylsalicylic acid or other NSAIDs (including in history); urticaria, rhinitis caused by taking NSAIDs (in history); intolerance to drugs of the pyrazolone series; dehydration, hypovolemia (regardless of the cause); bleeding or high risk of their development; condition after coronary artery bypass surgery; confirmed hyperkalemia; inflammatory bowel diseases; erosive and ulcerative lesions of the gastrointestinal tract in the acute stage, peptic ulcers; hypocoagulation (including hemophilia); severe renal failure (creatinine clearance less than 30 ml/min); severe hepatic failure or active liver disease; hemorrhagic stroke (confirmed or suspected); hemorrhagic diathesis; hematopoiesis disorder; pregnancy; childbirth; lactation period (breastfeeding); children under 16 years of age (efficacy and safety not established).

Not used as a means for premedication, maintenance anesthesia, pain relief before and during surgical operations (including in obstetric practice) due to the high risk of bleeding.

Not indicated for the treatment of chronic pain.

With caution

Bronchial asthma; cholecystitis; chronic heart failure; arterial hypertension; impaired renal function (plasma creatinine below 50 mg/l); cholestasis; active hepatitis; sepsis; systemic lupus erythematosus; elderly age (over 65 years); polyps of the nasal mucosa and nasopharynx, simultaneous use with other NSAIDs; presence of factors that increase gastrointestinal toxicity: alcoholism, tobacco smoking; postoperative period, edematous syndrome, coronary artery disease, cerebrovascular diseases, dyslipidemia/hyperlipidemia, diabetes mellitus, peripheral artery diseases, creatinine clearance less than 60 ml/min, history of ulcerative lesions of the gastrointestinal tract, presence of Helicobacter pylori infection, long-term use of NSAIDs, severe somatic diseases, simultaneous use of oral corticosteroids (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline).

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and during childbirth, during breastfeeding.

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency.

Should be used with caution in cholecystitis, cholestasis, active hepatitis.

Use in Renal Impairment

Contraindicated in renal failure (plasma creatinine >50 mg/l).

Should be used with caution in impaired renal function (plasma creatinine < 50 mg/l).

Pediatric Use

Contraindicated in children and adolescents under 16 years of age (efficacy and safety not established).

Geriatric Use

Should be used with caution in elderly patients (over 65 years of age).

Special Precautions

When used concomitantly with other NSAIDs, fluid retention, decompensation of cardiac activity, and arterial hypertension may be observed.

To reduce the risk of developing NSAID gastropathies, antacids, misoprostol, omeprazole are prescribed.

The effect on platelet aggregation persists for 24-48 hours.

Hypovolemia increases the risk of adverse reactions 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.

In patients with bleeding disorders, use only with constant monitoring of platelet count, especially in the postoperative period, requiring careful monitoring of hemostasis.

Effect on the ability to drive vehicles and mechanisms

Since a significant proportion of patients develop side effects from the central nervous system (drowsiness, dizziness, headache) when using ketorolac, it is recommended to avoid work that requires increased attention and quick reaction (driving vehicles, working with mechanisms).

Drug Interactions

Simultaneous use of ketorolac with acetylsalicylic acid or other NSAIDs, calcium preparations, corticosteroids, ethanol, corticotropin can lead to the formation of gastrointestinal ulcers and the development of gastrointestinal bleeding.

Concomitant use with paracetamol increases nephrotoxicity, with methotrexate – hepato- and nephrotoxicity.

Concomitant use of ketorolac and methotrexate is possible only when using low doses of the latter (monitor the concentration of methotrexate in blood plasma).

Against the background of ketorolac use, a decrease in the clearance of methotrexate and lithium and an increase in the toxicity of these substances are possible.

Simultaneous administration with indirect anticoagulants, heparin, thrombolytics, antiplatelet agents, 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 used simultaneously with opioid analgesics, the doses of the latter can be significantly reduced, as their effect is enhanced.

When used simultaneously, it enhances the hypoglycemic effect of insulin and oral hypoglycemic drugs (dose recalculation is necessary).

Concomitant use with valproic acid causes impaired platelet aggregation.

Increases the concentration in blood plasma of verapamil and nifedipine.

When prescribed with other nephrotoxic drugs (including gold preparations), the risk of nephrotoxicity increases.

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

Myelotoxic drugs enhance the manifestations of hematotoxicity of ketorolac.

Pharmaceutically incompatible with tramadol solution, lithium preparations.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.