Ketorol Express, 10 mg 20 pcs.

NSAID, has a pronounced analgesic effect, has anti-inflammatory and moderate antipyretic effects. The mechanism of action is associated with non-selective inhibition of COX activity – COX-1 and COX-2, catalyzing formation of prostaglandins from arachidonic acid, which play an important role in the pathogenesis of inflammation, pain and fever.

Ketorolac is a racemic mixture of [-]S- and [+]R-enantiomers with analgesic effect caused by [-]S-form.

The drug does not affect opioid receptors, does not depress respiration, does not cause drug addiction, has no sedative and anxiolytic action.
After oral administration the onset of analgesic effect is noted after 1 hour, the maximum effect is achieved after 1-2 hours.

Pharmacokinetics

Absorption

After oral administration, ketorolac is well absorbed from the GI tract, Cmax in plasma (0.7-1.1 mcg/ml) is reached 40 min after an empty stomach dose of 10 mg. High-fat food decreases Cmax in blood and delays its achieving by 1 h. Bioavailability – 80-100%.

Distribution

Binding to plasma proteins is 99% , with hypoalbuminemia the amount of free substance in blood increases. Time to reach Css (0.39-0.79 mcg/ml), when administered orally 10 mg ketorolac 4 times/day (above subtherapeutic dose), is 24 hours. Vd – 0.15-0.33 l/kg.

Penetrates into breast milk: after maternal administration of 10 mg ketorolac Cmax in breast milk is reached after 2 hours and is 7.3 ng/ml after the first dose and 7.9 ng/ml after the second dose of the drug.

Metabolism

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

Excretion
Excreted by the kidneys (91%) and through the gut (6%).T1/2 in patients with normal renal function is 2.4-9 h after an oral dose of 10 mg.When taken orally at a dose of 10 mg, total clearance is 0.025 l/h/kg.

Pharmacokinetics in special clinical cases

In patients with renal insufficiency, the Vd of ketorolac may increase twice and the Vd of its R-enantiomer by 20%.T1/2 is increased in older patients and decreased in younger patients.
Liver function disorders have no effect on T1/2. In patients with impaired renal function, with plasma creatinine concentration of 19-50 mg/l (168-442 μmol/l), T1/2 is 10.3-10.8 h, with more severe renal failure – more than 13.6 h.

When administered orally at a dose of 10 mg, total clearance in patients with renal insufficiency (at plasma creatinine concentration of 19-50 mg/l) is 0.016 l/kg.

Not excreted by hemodialysis.

Indications

Pain syndrome of severe and moderate severity:

injuries;
toothache;
pain in the postoperative period;
oncological diseases;
myalgia;
arthralgia;
neuralgia;
radiculitis;
dislocations, sprains;
rheumatic diseases.

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

Pharmacological effect

NSAIDs have a pronounced analgesic effect, have anti-inflammatory and moderate antipyretic effects. The mechanism of action is associated with non-selective inhibition of the activity of COX – COX-1 and COX-2, which catalyzes the formation of prostaglandins from arachidonic acid, which play an important role in the pathogenesis of inflammation, pain and fever.

Ketorolac is a racemic mixture of [-]S- and [+]R-enantiomers, and the analgesic effect is due to the [-]S-form. In terms of the strength of the analgesic effect, ketorolac is comparable to morphine, significantly superior to other NSAIDs.

The drug does not affect opioid receptors, does not depress respiration, does not cause drug dependence, and does not have a sedative or anxiolytic effect.
After oral administration, the onset of analgesic action is noted after 1 hour, the maximum effect is achieved after 1-2 hours.

Pharmacokinetics

Suction

After oral administration, ketorolac is well absorbed from the gastrointestinal tract, Cmax in blood plasma (0.7-1.1 mcg/ml) is achieved 40 minutes after administration on an empty stomach at a dose of 10 mg. Food rich in fat reduces the Cmax of ketorolac in the blood and delays its achievement by 1 hour. Bioavailability is 80-100%.

Distribution

Plasma protein binding is 99%; with hypoalbuminemia, the amount of free substance in the blood increases. The time to reach Css (0.39-0.79 mcg/ml) when taking 10 mg ketorolac orally 4 times a day (a dose higher than subtherapeutic) is 24 hours. Vd – 0.15-0.33 l/kg.

Penetrates into breast milk: after the mother takes 10 mg of ketorolac, Cmax in breast milk is reached after 2 hours and is 7.3 ng/ml after the first dose and 7.9 ng/ml after the second dose of the drug.

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-hydroxyketorolac.

Removal
Excreted by the kidneys (91%) and through the intestines (6%). T1/2 in patients with normal renal function is 2.4-9 hours after oral administration of a dose of 10 mg. When taken orally at a dose of 10 mg, the total clearance is 0.025 l/h/kg.

Pharmacokinetics in special clinical situations

In patients with renal failure, the Vd of ketorolac may increase by 2 times, and the Vd of its R-enantiomer by 20%. T1/2 increases in elderly patients and decreases in young ones.
Liver dysfunction does not affect T1/2. In patients with impaired renal function, with a plasma creatinine concentration of 19-50 mg/l (168-442 µmol/l), T1/2 is 10.3-10.8 hours, with more severe renal failure – more than 13.6 hours.

When taken orally at a dose of 10 mg, the total clearance in patients with renal failure (with plasma creatinine concentrations of 19-50 mg/l) is 0.016 l/h/kg.

Not excreted during hemodialysis.

Special instructions

The choice of dosage form of the drug depends on the severity of the pain syndrome and the patient’s condition.

The drug Ketorol® is available in the following dosage forms: gel for external use; film-coated tablets; tablets, dispersible in the oral cavity; solution for intravenous and intramuscular administration.

Before using the drug, it is necessary to find out whether there is a previous allergy to the drug or other NSAIDs. Due to the risk of allergic reactions, the first dose should be taken under close medical supervision.

Ketorolac inhibits platelet aggregation and increases blood clotting time. The effect on platelet aggregation ceases 24-48 hours after taking the drug.

Patients with bleeding disorders are prescribed the drug only with constant monitoring of the platelet count, which is especially important in the postoperative period when careful control of hemostasis is required. Hypovolemia increases the risk of developing nephrotoxic adverse reactions.

If necessary, can be used in combination with narcotic analgesics.

Do not use with paracetamol for more than 2 days. The risk of adverse reactions increases with lengthening the course of treatment and increasing the oral dose of ketorolac to more than 40 mg/day.

Concomitant use of ketorolac with probenecid, pentoxifylline, acetylsalicylic acid and other NSAIDs (including COX-2 inhibitors), lithium salts, anticoagulants (including warfarin and heparin) is contraindicated.

The use of ketorolac for prophylactic pain relief before and during major surgical interventions is contraindicated due to the high risk of bleeding.

Ketorolac is not recommended for use as a premedication or maintenance anesthesia. Cases of fluid retention, increased blood pressure and edema have been reported with the use of ketorolac.

Caution must be exercised when prescribing to patients with heart failure and arterial hypertension.

Concomitant use of ketorolac with other NSAIDs can lead to disorders such as decompensated heart failure and increased blood pressure. According to clinical studies, the use of certain NSAIDs in high doses may lead to an increased risk of arterial thrombotic complications (eg, myocardial infarction, stroke). Although such complications have not been reported with ketorolac, current data are insufficient to exclude the risk of such complications.

To reduce the risk of developing NSAID-induced gastropathy, the use of antacid drugs, misoprostol, as well as drugs that reduce gastric secretion (histamine H2 receptor blockers, proton pump inhibitors) is recommended.

To reduce the risk of adverse events, the minimum effective dose of ketorolac should be used for the shortest possible short course.

Impact on the ability to drive vehicles and machinery

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Active ingredient

Ketorolac

Composition

Each tablet, dispersible in the oral cavity, contains:

Active ingredient:

ketorolac tromethamine (ketorolac trometamol) 10,000 mg;

Excipients:

microcrystalline cellulose,

silicon dioxide,

butylhydroxyanisole,

mannitol,

crospovidone (type A),

sucralose,

mint flavor,

quinoline yellow dye (E104),

magnesium stearate.

Contraindications

Hypersensitivity (including to 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 a history);
erosive and ulcerative lesions of the gastrointestinal tract;
active gastrointestinal bleeding;
inflammatory bowel diseases (including ulcerative colitis, Crohn’s disease);
diseases of the bone marrow and blood (leukopenia, including history; thrombocytopenia; hypocoagulation, including hemophilia),
myelosuppression;
bleeding or a high risk of developing it;
severe renal failure (creatinine clearance less than 30 ml/min);
confirmed hyperkalemia;
severe liver failure or active liver disease;
condition after coronary artery bypass surgery;
preventive pain relief before and during major surgical interventions due to the high risk of bleeding;
active cerebrovascular diseases (including intracranial hemorrhage or suspicion of it);
pregnancy;
period of childbirth;
breastfeeding period;
children under 16 years of age (safety and effectiveness of use have not been established);
simultaneous use with probenecid;
simultaneous use with pentoxifylline;
simultaneous use of acetylsalicylic acid with other NSAIDs (including selective COX-2 inhibitors);
simultaneous use with lithium salts;
simultaneous use with anticoagulants (including warfarin and heparin).

With caution

Bronchial asthma; the presence of factors that increase gastrointestinal toxicity: alcoholism, smoking and cholecystitis; postoperative period; chronic heart failure; edema syndrome; arterial hypertension; moderate renal failure (creatinine clearance 30-60 ml/min); cholestasis; active hepatitis; sepsis; systemic lupus erythematosus; IHD; cerebrovascular diseases; dyslipidemia/hyperlipidemia; diabetes mellitus; peripheral arterial disease; history of ulcerative lesions of the gastrointestinal tract; presence of Helicobacter pylori infection; long-term use of NSAIDs; severe somatic diseases; thyroid diseases; tuberculosis; simultaneous use of oral corticosteroids (including prednisolone), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline); old age (over 65 years).

Side Effects

Determination of the frequency of side effects: often (1-10%), uncommon (0.1-1%), rare (0.01-0.1%), very rare (<0.01%) and frequency unknown, including isolated reports.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; infrequently – stomatitis, flatulence, constipation, vomiting, feeling of fullness of the stomach; 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, melena, vomiting 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, oliguria, polyuria, interstitial nephritis, edema of renal origin; frequency unknown – urinary retention.From the senses: rarely – hearing loss, ringing in the ears, visual impairment (including blurred visual perception); frequency unknown – taste disturbance.From the respiratory system: rarely – bronchospasm or dyspnea, rhinitis, 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, stiffness of the neck and/or back muscles), hyperactivity (mood changes, anxiety), hallucinations, depression, psychosis.From the cardiovascular system: infrequently – increased blood pressure; rarely – pulmonary edema, fainting.From the hematopoietic organs: rarely – anemia, eosinophilia, leukopenia.From the hemostasis system: rarely – bleeding from a postoperative wound, nosebleeds, rectal bleeding.From the skin: infrequently – skin rash (including maculopapular rash), purpura; rarely – exfoliative dermatitis (fever with or without chills, redness, thickening or peeling of the skin, swelling and/or tenderness of the tonsils), urticaria, Stevens-Johnson syndrome, Lyell’s syndrome.Allergic reactions: rarely – anaphylaxis or anaphylactoid reactions (change in facial skin color, skin rash, urticaria, itching, tachypnea or dyspnea, swelling of the eyelids, swelling of the tongue, periorbital edema, shortness of breath, difficulty breathing, heaviness in the chest, wheezing).Other: often – swelling (face, legs, ankles, fingers, feet, weight gain); uncommon – increased sweating; rarely – fever; frequency unknown – hyperkalemia, hyponatremia.

Interaction

The simultaneous use of ketorolac with acetylsalicylic acid or other NSAIDs, calcium preparations, glucocorticosteroids, ethanol, corticotropin can lead to a significant increase in the risk of adverse reactions, including the formation of gastrointestinal ulcers and the development of gastrointestinal bleeding.

When ketorolac is used simultaneously with other NSAIDs (including COX-2 inhibitors), fluid retention, cardiac decompensation, and increased blood pressure may occur.

Concomitant use of ketorolac with indirect anticoagulants, thrombolytics, antiplatelet agents, cefoperazone, cefotetan and pentoxifylline increases the risk of bleeding.

Probenecid reduces the plasma clearance and volume of distribution of ketorolac, increases its concentration in the blood plasma and increases its T1/2. The combined use of ketorolac with valproate causes a violation of platelet aggregation. When using ketorolac with other nephrotoxic drugs (including gold preparations), the risk of developing nephrotoxicity increases.

Combined use with paracetamol increases the nephrotoxicity of ketorolac. Drugs that block tubular secretion reduce the clearance of ketorolac and increase its concentration in the blood plasma.

The combined use of ketorolac with methotrexate increases the hepato- and nephrotoxicity of methotrexate. The combined use of ketorolac and methotrexate is possible only when using low doses of the latter. The clearance of methotrexate may decrease (it is necessary to control the concentration of methotrexate in the blood plasma). With the use of ketorolac, the clearance of lithium may decrease, its concentration in the blood plasma may increase, and the toxic effect of lithium may increase.

Concomitant use with lithium salts is contraindicated.

Ketorolac reduces the effect of antihypertensive and diuretic drugs (the synthesis of prostaglandins in the kidneys is reduced).

Ketorolac enhances the effect of narcotic analgesics. When combined with opioid analgesics, the doses of the latter can be significantly reduced.

Ketorolac enhances the hypoglycemic effect of insulin and oral hypoglycemic drugs, and therefore it is necessary to recalculate the dose of these drugs.

Ketorolac increases the plasma concentrations of verapamil and nifedipine.

Concomitant use of NSAIDs and mifepristone may reduce the effectiveness of mifepristone. NSAIDs are not recommended for use within 8-12 days after using mifepristone. The simultaneous use of NSAIDs and cyclosporine increases the risk of nephrotoxicity. The simultaneous use of NSAIDs and quinolone antibiotics increases the risk of seizures. Concomitant use of NSAIDs and tacrolimus increases the risk of nephrotoxicity. Concomitant use of NSAIDs and zidovudine increases the risk of hematological toxicity.

When used simultaneously with digoxin, ketorolac does not interfere with the binding of digoxin to plasma proteins. Therapeutic concentrations of digoxin do not affect the binding of ketorolac to plasma proteins. Antacids do not affect the absorption of ketorolac. Myelotoxic drugs increase the manifestations of hematotoxicity of ketorolac.

Overdose

Symptoms: abdominal pain, nausea, vomiting, erosive and ulcerative lesions of the gastrointestinal tract, impaired renal function, metabolic acidosis.

Treatment: gastric lavage, administration of adsorbents (activated carbon) and symptomatic therapy (maintaining vital body functions). Hemodialysis is ineffective.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C.

Shelf life

2 years.

Manufacturer

Dr. Reddy’s Laboratories Ltd, India